Ligands for extrahepatic delivery of siRNA

Abstract

This invention provides an oligonucleotide comprising one or more compounds of formula (I), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, wherein LG is a ligand, and L1, L2, L3, and L4 are each independently absent, chemically bonded, or linker. This invention also relates to double-stranded RNA comprising compounds of formula (I), cells, pharmaceutical compositions, and kits. (I)

Description

[0001] This invention claims priority to Chinese invention patent applications CN202311396697.4 (filed October 25, 2023), CN202410412449.2 (filed April 7, 2024), and CN202411321783.3 (filed September 20, 2024), all of which are incorporated herein by reference in their entirety as a part of this disclosure. Invention Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to SORT1 ligands that enhance the extrahepatic delivery of double-stranded RNA, and compounds of formula (I) that link the SORT1 ligand to nucleotides, or pharmaceutically acceptable salts, tautomers or stereoisomers thereof. Background Technology

[0003] RNA interference is a phenomenon in which target mRNA is efficiently and specifically degraded by double-stranded RNA (dsRNA, also known as siRNA).

[0004] However, the presence of the blood-brain barrier makes it difficult to deliver siRNA to extrahepatic tissues such as the central nervous system to exert its effects, which limits the application of siRNA. Several attempts have been made in this field to deliver siRNA to the central nervous system. For example, WO2004094595A2 discloses the delivery of siRNA using a single lipid ligand (e.g., cholesterol or long-chain alkanes) at the chain end, WO2019217459A1 discloses the delivery of siRNA using a single lipid ligand inside the chain, and WO2021092371A2 discloses a series of novel lipid ligand structures.

[0005] There is still a need in this field to develop more delivery ligands to more effectively deliver siRNA to the central nervous system and other extrahepatic tissues. Summary of the Invention

[0006] This invention provides a new class of oligonucleotides that can efficiently deliver siRNA containing SORT1 ligands to extrahepatic tissues.

[0007] In one aspect, the present invention provides an oligonucleotide comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0008] (I)

[0009] in,

[0010] LG is a SORT1 ligand. A monovalent group formed by connecting L1 to any position of the SORT1 ligand;

[0011] L1, L2, L3, and L4 are each independently nonexistent, chemical bonds, or linkers.

[0012] In another aspect, the present invention provides a double-stranded RNA having a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the antisense strand contains a sequence sufficiently complementary to the sense strand and the target mRNA, wherein the sense strand and / or antisense strand comprises one or more compounds of formula (I), (II), (IIIa), (IIIb) or (IIIc), or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, wherein the compounds of formula (I), (II), (IIIa), (IIIb) or (IIIc) are as defined herein.

[0013] In another aspect, the present invention provides compounds of formula (V), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0014] (V)

[0015] Wherein LG, L1 and L2 are as defined herein, and PG is a protection base.

[0016] In another aspect, the present invention provides a cell comprising the double-stranded RNA described herein.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising the double-stranded RNA or cells described herein, and optionally a pharmaceutically acceptable carrier or excipient.

[0018] In another aspect, the present invention provides a kit comprising the double-stranded RNA described herein or the cells described herein.

[0019] In another aspect, the present invention provides a method for administering oligonucleotides to a subject via extrahepatic delivery, the oligonucleotides being as defined herein, the extrahepatic delivery comprising delivery to one or more tissues from the group consisting of: the eye, central nervous system, lung, muscle, kidney, fat, spleen, and tumor, the muscle preferably being the quadriceps femoris or heart, and the fat preferably being subcutaneous fat or gonadal fat.

[0020] In another aspect, the present invention provides a method for delivering SORT1 ligands to the brain of a subject, wherein the method comprises administering to the subject the oligonucleotides, double-stranded RNA, pharmaceutical compositions, or kits described herein;

[0021] Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to a subject via intrathecal administration;

[0022] Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to the subject in a therapeutically effective amount;

[0023] Preferably, the method includes delivering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to one or more brain regions selected from the striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord.

[0024] In another aspect, the present invention provides a method for preventing or treating a disease, comprising administering to a subject the oligonucleotide, double-stranded RNA, pharmaceutical composition or kit described herein;

[0025] Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to a subject via intrathecal administration;

[0026] Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to the subject in a therapeutically effective amount.

[0027] In another aspect, the present invention provides the use of the oligonucleotides, double-stranded RNAs, pharmaceutical compositions, or kits described herein in the preparation of medicaments for the prevention or treatment of diseases.

[0028] In another respect, the oligonucleotides, double-stranded RNAs, pharmaceutical compositions, or kits described herein are used for the prevention or treatment of diseases.

[0029] In one specific aspect, the disease is selected from diseases, conditions, or symptoms associated with SORT1. Preferably, the diseases, conditions, or symptoms associated with SORT1 refer to those that can be prevented, treated, alleviated, or relieved by regulating SORT1, including but not limited to neurodegenerative disorders, mental disorders, inflammatory disorders, cancer, pain, diabetes, diabetic retinopathy, glaucoma, uveitis, cardiovascular diseases, kidney diseases, psoriasis, hereditary eye diseases, hearing loss, or diseases characterized by misfolded tau protein.

[0030] In one specific aspect, the disease is selected from central nervous system (CNS) diseases, conditions, or symptoms thereof. Preferably, the CNS diseases, conditions, or symptoms thereof include, but are not limited to, those selected from: neurodegenerative disorders, including motor neuron disease, frontotemporal degeneration (FTLD), frontotemporal dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases such as Kreutzfeldt-Jacob disease (CJD), acute brain injury, spinal cord injury, and stroke; mental disorders, including bipolar disorder, major depressive disorder, post-traumatic stress disorder, and anxiety disorders; hearing loss, selected from noise-induced hearing loss, ototoxic hearing loss, age-related hearing loss, idiopathic hearing loss, tinnitus, and sudden hearing loss; brain tumors (e.g., glioblastoma), retinal diseases, glaucoma, neuroinflammation, chronic pain, and diseases characterized by misfolded tau protein.

[0031] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims. Detailed Implementation

[0032] The above-described features and advantages of the present invention, as well as their additional features and advantages, will become more clearly understood below in conjunction with the detailed description of the following embodiments.

[0033] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0034] definition

[0035] Chemical definition

[0036] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0037] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, this is preferred. 1-4 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), and isobutyl (C4). The term "C"... 1-4 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0038] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and so on. The term "C2-4 alkenyl" also includes heteroalkenyl groups, where one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] “C 2-6 "Alkyne" refers to a straight-chain or branched 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, and C 2-4 The alkynyl group is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0040] “C 1-6 Alkylene, C 2-6 "Ideinyl" and "C" 2-6 "Iso-ynyl group" refers to the group with C removed. 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is a divalent group formed by the other hydrogen atom of the alkynyl group, and can be substituted or unsubstituted. In some embodiments, the unsubstituted alkylene group includes, but is not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0041] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0042] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C is preferred. 1-4 Halogenated alkyl and C 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group. "C" 3-10"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. 3-6 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. 5-6 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 5 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having a cyclic carbon atom and zero heteroatoms. "C" 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

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

[0046] "Heterocyclic group" refers to a group having a non-aromatic ring system with a cyclic carbon atom and a cyclic heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 4-10 membered heterocyclic groups are preferred, which are 4-10 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, 3-8 membered heterocyclic groups are preferred, which are 3-8 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 4 cyclic heteroatoms; 3-6 membered heterocyclic groups are preferred, which are 3-6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; 4-7 membered heterocyclic groups are preferred, which are 4-7 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and more preferably, 5-6 membered heterocyclic groups are 5-6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc.Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring to 6,6-bicyclic heterocyclic groups herein) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] 5-10 membered heterocyclic groups also include spiroheterocyclic groups, which are groups in which two rings (e.g., heterocycles and carboalkyl groups) share a carbon atom, wherein at least one ring is a heterocyclic group as defined above. More specifically, the spiroheterocyclic group is a spirocycle formed by two 4-membered rings, two 5-membered rings, one 4-membered ring and one 5-membered ring, or one 4-membered ring and one 6-membered ring.

[0048] 5-10 membered heterocyclic groups also include cases where the carbon atom or heteroatom on the heterocycle is oxidized or sulfided, and cases where it is oxidized by one or more oxygen atoms, for example... , wait.

[0049] The various groups defined in this article (such as alkyl, alkenyl, and ynyl groups) are optional substituted groups.

[0050] In this article, "optional substitution" or "optionally substituted with..." is intended to cover both cases where the group is not substituted and cases where it is substituted.

[0051] The terms “substituted” or “substituted” are intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents of organic compounds include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents. Permissible substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the heteroatom valence. It should be understood that “substituted” or “substituted” includes implicit limitations: these substitutions are based on the permissible valence of the substituted atom and the substituent, and this substitution produces a stable compound, for example, which does not undergo spontaneous transformations such as rearrangement, cyclization, or elimination. Examples of possible substituents include (but are not limited to): halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphonate, phosphonite, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, acyl, aldehyde, ester, heteroalkyl, aromatic or heteroaromatic moiety, -CN. Exemplary substituents on carbon atoms and nitrogen atoms are detailed below.

[0052] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R)bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa-C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or =NOR cc replace;

[0054] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aaGroups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0056] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0057] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff)2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2Ree、-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 ee2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0058] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0059] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0060] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(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 groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -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 group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C10 aryl, C3-C7 heterocyclic, C5-C10 heteroaryl; or two geminal R groups. gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0061] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0062] Other definitions

[0063] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the terms and laboratory procedures related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology used herein are all widely used terms and routine procedures in their respective fields. To better understand this invention, definitions and explanations of relevant terms are provided below.

[0064] As used herein, the singular forms “a,” “an,” and “the” include plural objects unless the context clearly indicates otherwise. Unless otherwise stated or defined, the term “comprising” and its variations such as “including” and “containing” should be understood to mean including the stated element or step or group of elements or steps, but not excluding any other element or step or group of elements or steps.

[0065] SORT1, also known as sorting protein or sortilin, is a membrane-bound glycoprotein encoded by the SORT1 gene, such as the amino acid sequence shown in NCBI accession number NP_002950.3, or its naturally occurring fragments, homologs, or variants. In this article, SORT1 may also include secreted or soluble SORT1 (sSORT1), which lacks a transmembrane domain and a long cytoplasmic tail.

[0066] "SORT1 ligand" refers to a substance that can bind to SORT1. In this article, "SORT1 ligand" includes, but is not limited to, small molecule compounds or peptides, with small molecule compounds being preferred.

[0067] "Extrahepatic delivery" refers to the delivery of oligonucleotides or double-stranded RNA molecules to tissues outside the liver, including but not limited to the eye, central nervous system, lung, muscle, kidney, subcutaneous fat, gonadal fat, quadriceps femoris muscle, heart, spleen, and tumors. Those skilled in the art will understand that different administration methods are required to improve delivery efficiency depending on the target tissue. For example, delivery to the central nervous system may be via intrathecal injection, delivery to the eye may be via intraocular injection, delivery to muscle may be via intramuscular injection, delivery to the lung may be via aerosol formulation, and delivery to tumors may be via intratumoral injection or direct systemic administration.

[0068] "Extrahepatic expression" refers to genes that are specifically or non-specifically expressed in extrahepatic tissues, including but not limited to the eyes, central nervous system, lungs, muscles, kidneys, subcutaneous fat, gonadal fat, quadriceps femoris muscle, heart, spleen, tumors, etc.

[0069] "Amino acid group" includes both natural and non-natural amino acids, as well as α-amino acids and β-amino acids, which are linked to groups on both sides by their amino and carboxyl groups, and are also called "amino acid residues". Depending on the different groups on both sides of the amino acid, the amino acid group of the present invention can be linked in different directions, as is known to those skilled in the art. Furthermore, after linkage, the amino acid group forms -NH- and -C(O)- groups at both ends, respectively. Structures with omitted -NH- and / or -C(O)- groups are also included in the scope of "amino acid group". α-amino acids include monocarboxyl monoamino acids, dicarboxyl monoamino acids, polyamino acids, and heterocyclic amino acids. Examples of monocarboxylic acid monoamino acids include glycine, α-phenylglycine, α-alanine, serine, valine, normal valine, β-penicillamine, threonine, cysteine, leucine, isoleucine, hexane, N-methylleucine, β-hydroxyleucine, methionine, phenylalanine, N-methyl-phenylalanine, piperacillic acid, sarcosine, selenocysteine, tyrosine, 3,5-diiodotyrosine, triiodothyronine, and thyroxine.

[0070] "Linker" refers to a divalent or multivalent structure used to connect two or more groups or portions, including but not limited to optionally substituted alkyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, oxygen (-O-), optionally substituted nitrogen (e.g., -NR-), amide (e.g., -C(O)NR-), phosphodiester bonds, or thiophosphate bonds. In some embodiments, the "linker" herein may connect three or more groups or portions, for example, connecting an oligonucleotide (or siRNA) to two or more SORT1 ligands.

[0071] The term "polyethylene glycol (PEG) linker" refers to a linker that contains polyethylene glycol (PEG) units.

[0072] The terms "polyethylene glycol," "polyoxyethylene," or "PEG" refer to straight-chain, branched, or star-shaped configurations that include a (OCH2CH2) group. In some embodiments, the polyethylene or PEG group is -(OCH2CH2). t -、-(CH2CH2O) t -、-(CH2CH2O) t -CH2CH2- or -CH2CH2(OCH2CH2) t - where t is 1-40 or 4-40. For example, the term "PEG12" as used herein means that the total number of CH2CH2O and CH2CH2 fragments is 12.

[0073] The term "heteroalkyl linker" refers to a linker containing a heteroalkyl group, which forms a divalent group, i.e., a heteroalkylene group, after being linked as a linking group.

[0074] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently substituted by the same or different heteroatom groups. The term "heteroalkyl" includes straight-chain or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently substituted by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be optionally substituted. Examples of heteroalkyl groups include -CH2OCH3, -CH2SCH3, -CH2S(O)CH3, and CH2S(O)2CH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0075] The term "siRNA" refers to a class of double-stranded RNA molecules that can mediate the silencing of a target RNA (e.g., mRNA, such as the transcript of a gene encoding a protein) that is complementary to it. siRNA is typically double-stranded, consisting of an antisense strand complementary to the target RNA and a sense strand complementary to that antisense strand. For convenience, such mRNA is also referred to herein as the mRNA to be silenced. Such genes are also called target genes. Typically, the RNA to be silenced is an endogenous gene or a pathogen gene. Additionally, RNA other than mRNA (e.g., tRNA) and viral RNA can also be targeted.

[0076] The term "antisense strand" refers to a strand of siRNA that contains regions that are completely, sufficiently, or substantially complementary to the target sequence. The term "sense strand" refers to a strand of siRNA that includes regions that are completely, sufficiently, or substantially complementary to the regions defined herein as antisense strands.

[0077] The term "complementary region" refers to a region on the antisense strand that is completely, fully, or substantially complementary to the target mRNA sequence. In cases where the complementary region is not perfectly complementary to the target sequence, mismatches can occur within the molecule or at the ends. Typically, the most tolerant mismatches are located in the end regions, for example, within 5, 4, 3, 2, or 1 nucleotides at the 5' and / or 3' ends. The portion of the antisense strand most sensitive to mismatches is called the "seed region." For example, in a siRNA containing a 19-nt strand, the 19th position (from 5' to 3') can tolerate some mismatches.

[0078] The term "complementary" refers to the ability of a first polynucleotide to hybridize with a second polynucleotide under certain conditions, such as stringent conditions. For example, stringent conditions may include 400 mM NaCl, 40 mM PIPES at pH 6.4, and 1 mM EDTA at 50 or 70°C for 12–16 hours. In terms of meeting the above requirements regarding their hybridization ability, a "complementary" sequence may also include base pairs formed entirely from non-Watson-Crick base pairs and / or from non-natural and modified nucleotides. Such non-Watson-Crick base pairs include, but are not limited to, G:U swing base pairings or Hoogstein base pairs.

[0079] A polynucleotide that is “at least partially complementary,” “fully complementary,” or “substantially complementary” to messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a continuous portion of the mRNA of interest. For example, a polynucleotide is at least partially complementary to PCSK9 mRNA if its sequence is substantially complementary to an uninterrupted portion of the mRNA encoding PCSK9. The terms “complementary,” “fully complementary,” “fully complementary,” and “substantially complementary” can be used relative to base pairing between the sense and antisense strands of the siRNA, or between the antisense strand of the siRNA reagent and the target sequence.

[0080] "Perfect complementarity" means that in order to maintain the overall double-stranded character of the molecule, the sense strand only needs to be complementary to the antisense strand to a certain extent. In other words, although perfect complementarity is usually required, in some cases, especially in the antisense strand, there may be one or more mismatches (relative to the target mRNA), such as 6, 5, 4, 3, 2 or 1, but the sense and antisense strands can still maintain the overall double-stranded character of the molecule.

[0081] "shRNA" refers to short hairpin RNA. shRNA consists of two short inverted repeat sequences. The shRNA cloned into the shRNA expression vector comprises two short inverted repeat sequences separated by a stem-loop sequence, forming a hairpin structure controlled by the polIII promoter. Subsequently, 5-6 T molecules are added as a transcription terminator for RNA polymerase III.

[0082] "Nucleoside" is a compound composed of two substances: a purine or pyrimidine base and ribose or deoxyribose. "Nucleotide" is a compound composed of three substances: a purine or pyrimidine base, ribose or deoxyribose, and phosphate. "Oligonucleotide" refers to nucleic acid molecules (RNA or DNA) with a length of less than 100, 200, 300, or 400 nucleotides.

[0083] A "base" is the basic building block for the synthesis of nucleosides, nucleotides, and nucleic acids. Its constituent elements include nitrogen, hence it is also called a "nitrogenous base." In this article, unless otherwise specified, the capital letters A, U, T, G, and C represent the base composition of nucleotides, namely adenine, uracil, thymine, guanine, and cytosine, respectively.

[0084] The term "modification" of nucleotides as used herein includes, but is not limited to, methoxy modification, fluorination modification, thiophosphate linkage, or conventional protecting group protection. For example, a fluorinated nucleotide refers to a nucleotide in which the hydroxyl group at the 2' position of the ribosome is replaced by fluorine, and a methoxy modified nucleotide refers to a nucleotide in which the 2'-hydroxyl group of the ribosome is replaced by a methoxy group.

[0085] In this document, "modified nucleotides" include, but are not limited to, nucleotides modified with 2'-O-methyl, nucleotides modified with 2'-fluorine, nucleotides modified with 2'-deoxy-, inosine ribonucleotides, debased nucleotides, reverse abased deoxyribonucleotides, nucleotides containing a thiophosphate group, nucleotides modified with vinyl phosphate, locked nucleotides, nucleotides modified with 2'-amino, nucleotides modified with 2'-alkyl, morpholinonucleotides, aminophosphates, non-natural bases containing nucleotides, and terminal nucleotides linked to cholesterol derivatives or dodecanoic acid diecamide groups, deoxyribonucleotides, or those protected by conventional protecting groups. For example, a nucleotide modified with 2'-fluorine refers to a nucleotide in which the hydroxyl group at the 2' position of the ribosyl group is replaced by fluorine. A nucleotide modified with 2'-deoxy- refers to a nucleotide in which the 2'-hydroxyl group of the ribosyl group is replaced by a methoxy group.

[0086] "Ligand moiety" refers to the chemical part conjugated to siRNA that can alter the distribution, targeting, or lifespan of the siRNA. In a preferred embodiment, such a ligand provides enhanced affinity for selected targets (e.g., molecules, cells or cell types, compartments (e.g., cell or organ compartments, tissues, organs, or regions of the body) compared to siRNAs, for example, those without such a ligand.

[0087] "Reactive phosphorus group" refers to a phosphorus-containing group contained in a nucleotide unit or nucleotide analog unit that can react with a hydroxyl or amino group contained in another molecule, particularly in another nucleotide unit or another nucleotide analog, via a nucleophilic attack reaction. Typically, such a reaction produces an ester-type nucleoside bond linking the first nucleotide unit or the first nucleotide analog unit to the second nucleotide unit or the second nucleotide analog unit. The reactive phosphorus group can be selected from phosphorous amides, H-phosphonates, alkyl-phosphonates, phosphate esters, or phosphate ester analogs, including but not limited to: native phosphate esters, thiophosphate esters, dithiophosphate esters, boron phosphate esters, boron thiophosphate esters, phosphonates, halogen-substituted phosphonates and phosphate esters, aminophosphate esters, phosphate diesters, phosphate triesters, thiophosphate diesters, thiophosphate triesters, diphosphate esters, and triphosphate esters, preferably -P(OCH2CH2CN)(N(iPr)2).

[0088] A "protecting group" is any atom or group of atoms added to a molecule to prevent existing groups in the molecule from undergoing undesirable chemical reactions. A "protecting group" can be an unstable chemical motif known in the art, used to protect reactive groups, such as hydroxyl, amino, and thiol groups, to prevent unwanted or untimely reactions during chemical synthesis. Protecting groups are typically used selectively and / or orthogonally to protect sites during reactions at other reactive sites and can then be removed to leave unprotected groups intact or usable for further reactions. In one embodiment, the protecting group may be -N3.

[0089] A non-limiting list of protecting groups includes benzyl; substituted benzyl; alkyl carbonyl and alkoxy carbonyl (e.g., tert-butoxy carbonyl (BOC), acetyl, or isobutyryl); arylalkyl carbonyl and arylalkoxy carbonyl (e.g., benzyloxy carbonyl); substituted methyl ether (e.g., methoxymethyl ether); substituted diethyl ether; substituted benzyl ether; tetrahydropyranyl ether; silyl (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tri-isopropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl, or tert-butyldiphenylsilyl); esters (e.g., benzoates); carbonates (e.g., methoxymethyl carbonate). Esters); sulfonates (e.g., toluenesulfonates or methanesulfonates); noncyclic ketals (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolane, and those described herein); noncyclic acetals; cycloacetals (e.g., those described herein); noncyclic hemiacetals; cyclohemiacetals; cyclodithioketals (e.g., 1,3-dithiane or 1,3-dithiopentane); orthoesters (e.g., those described herein); and triarylmethyl groups (e.g., triphenylmethyl; monomethoxytriphenylmethyl (MMTr); 4,4'-dimethoxytriphenylmethyl (DMTr); 4,4',4''-trimethoxytriphenylmethyl (TMTr); and those described herein). Preferred protecting groups are selected from acetyl (Ac), benzoyl (Bzl), benzyl (Bn), isobutyryl (iBu), phenylacetyl, benzyloxymethyl acetal (BOM), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methyl thiomethyl ether, neopentanoyl (Piv), tetrahydropyranyl (THP), triphenylmethyl (Trt), methoxytriphenylmethyl [(4-methoxyphenyl)diphenylmethyl] (MMT), dimethoxytriphenylmethyl, [bis-(4-methoxyphenyl)phenylmethyl (DMT), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBDMS), tri-isopropylsilyloxymethyl ether (TOM), tri-isopropylsilyl ether (TIPS), methyl ether, ethoxyethyl ether (EE), N,N-dimethylformamidinium, and 2-cyanoethyl (CE).

[0090] A "hydroxyl protecting group" is a group that can prevent the hydroxyl group from undergoing chemical reactions and can be removed under specific conditions to restore the hydroxyl group. It mainly includes silane-type protecting groups, acyl-type protecting groups, or ether-type protecting groups, preferably the following: trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-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), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), bis-p-methoxytriphenylmethyl (DMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzylmethyl (PMBM), -C(O)CH2CH2C(O)OH or 4,4'-dimethoxytriphenylmethyl, preferably -C(O)CH2CH2C(O)OH or 4,4'-dimethoxytriphenylmethyl, more preferably -C(O)CH2CH2C(O)OH.

[0091] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0092] This invention includes tautomers, which are functional group isomers resulting from the rapid movement of an atom in a molecule to two positions. A compound exists in different tautomer forms, and a compound is not limited to any particular tautomer, but is intended to encompass all tautomer forms.

[0093] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0094] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when performing the processes disclosed in the following procedures and / or examples and preparation examples.

[0095] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0096] The terms “administration” or “dosage” refer to the route by which a compound is introduced into a subject to perform its intended function. Examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), local, oral, inhalation, rectal, and transdermal.

[0097] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0098] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0099] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target 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 target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0100] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0101] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0102] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

[0103] Oligonucleotides, double-stranded RNA, and cells containing compound (I)

[0104] In this document, compounds are generally described using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0105] In this article, “compound of formula (I)” refers to the following compounds of formula (I) and their sub-formulas, such as compounds of formula (II), formula (IIIa), formula (IIIb), formula (IIIc), etc., and their pharmaceutically acceptable salts, tautomers or stereoisomers.

[0106] In one embodiment, the present invention relates to an oligonucleotide comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0107] (I)

[0108] in,

[0109] LG is a SORT1 ligand. A monovalent group formed by connecting L1 to any position of the SORT1 ligand;

[0110] L1, L2, L3, and L4 are each independently nonexistent, chemical bonds, or linkers.

[0111] In another embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from compounds of formula (II), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0112] (II)

[0113] Among them, G1, S1, S2, G2, and R1 are as defined in this paper.

[0114] In another embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from compounds of formula (IIIa), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0115] (IIIa)

[0116] S1, A, Y, B, R1, and R5 are as defined in this paper.

[0117] In another embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from compounds of formula (IIIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0118] (IIIb)

[0119] S1, S2, B, R1, R2, R3, R4, and R5 are as defined in this paper.

[0120] In another embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from compounds of formula (IIIc), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0121] (IIIc)

[0122] S1, Aa, R1, and R5 are as defined in this paper.

[0123] In another embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein... Selected from compounds of formula (IIIa-1), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0124] (IIIa-1)

[0125] Wherein, Y' is a trivalent group formed by the connection of LG with L1 through Y, and S1, A, Y, B, R1 and R5 are as defined in this paper.

[0126] In another embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein... Selected from compounds of formula (IIIa-2), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0127] (IIIa-2)

[0128] Wherein, B' is a trivalent group formed by the connection of LG with L1 via B, and S1, A, Y, B, R1 and R5 are as defined in this paper.

[0129] In another embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein... Selected from compounds of formula (IIIb-1), or their pharmaceutically acceptable salts, tautomers, or stereoisomers:

[0130] (IIIb-1)

[0131] Wherein, B' is a trivalent group formed by the connection of LG with L1 via B. S1, S2, R1, R2, R3, R4 and B are as defined in this document.

[0132] LG and

[0133] In one specific implementation, the LG is selected from... , , , , or .

[0134] In one specific implementation scheme, the Selected from , , , , or .

[0135] G1

[0136] In one implementation, G1 does not exist; in another implementation, G1 is... In another implementation, G1 is In another implementation, G1 is .

[0137] G2

[0138] In one implementation, G2 does not exist; in another implementation, G2 is C. 1-4Alkyl group; in another embodiment, G2 is an amino acid group; in another embodiment, G2 is -AYB.

[0139] S1

[0140] In one embodiment, S1 is a chemical bond; in another embodiment, S1 is -O-; in another embodiment, S1 is -NH-; in another embodiment, S1 is -C(O)-; in another embodiment, S1 is -NHC(O)-; in another embodiment, S1 is -C(O)NH-; in another embodiment, S1 is -OC(O)-; in another embodiment, S1 is -C(O)O-; in another embodiment, S1 is -SS-; in another embodiment, S1 is -NHC(O)O-; in another embodiment, S1 is -NHC(O)NH-; in another embodiment, S1 is -OC(O)O-; in another embodiment, S1 is -OC(O)NH-; in another embodiment, S1 is -C(O)NHO-; in another embodiment, S1 is -C(O)NHS-; in another embodiment, S1 is -NHCH(CZ3)-; in another embodiment, S1 is -NHCOC(R )2CH2-; In another embodiment, S1 is C 1-6 Alkylene; in another embodiment, S1 is C 1-4 Alkylene, such as -CH2- or -CH2CH2-; in another embodiment, S1 is C 2-6 Alkenyl group.

[0141] In one embodiment, S1 is selected from chemical bonds, -NH-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 Alkenyl group.

[0142] In one embodiment, S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 Alkenyl group.

[0143] In one implementation, S1 is selected from C 1-4 Alkylene or C 2-4 alkenyl groups, preferably C 1-4 Alkylene, such as -CH2- or -CH2CH2-.

[0144] In one implementation, S1 is selected from C 1-4 Alkylene, such as -CH2- or -CH2CH2-.

[0145] In one implementation, S1 is selected from -CH=CH-, -CH2CH2-, or -CH2-.

[0146] S2

[0147] In one embodiment, S1 is a chemical bond; in another embodiment, S2 is -O-; in another embodiment, S2 is -NH-; in another embodiment, S2 is -C(O)-; in another embodiment, S2 is -NHC(O)-; in another embodiment, S2 is -C(O)NH-; in another embodiment, S2 is -OC(O)-; in another embodiment, S2 is -C(O)O-; in another embodiment, S2 is -SS-; in another embodiment, S2 is -NHC(O)O-; in another embodiment, S2 is -NHC(O)NH-; in another embodiment, S2 is -OC(O)O-; in another embodiment, S2 is -OC(O)NH-; in another embodiment, S2 is -C(O)NHO-; in another embodiment, S2 is -C(O)NHS-; in another embodiment, S2 is -NHCH(CZ3)-; in another embodiment, S2 is -NHCOC(R )2CH2-; In another embodiment, S2 is C 1-6 Alkylene; in another embodiment, S1 is C 1-4 Alkylene, such as -CH2- or -CH2CH2-; in another embodiment, S2 is C 2-6 imide groups, such as C 2-4 Alkenyl group.

[0148] In one embodiment, S2 is selected from -NH-, -C(O)-, -OC(O)-, -C(O)O-, -NHC(O)-, -C(O)NH-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, C 1-6 Alkylene or C 2-6 Alkenyl group.

[0149] In one embodiment, S2 is selected from -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 Alkenyl group.

[0150] In one implementation, S2 is selected from -NHC(O)-, -C(O)NH-, C 1-4 Alkylene or C 2-4 The alkenyl group is preferably -C(O)NH- or -CH2-.

[0151] Z

[0152] In one embodiment, Z is H; in another embodiment, Z is a halogen; in yet another embodiment, Z is C. 1-6 Alkyl; in another embodiment, Z is C 1-6 Halogenated alkyl groups.

[0153] Aa

[0154] In one embodiment, Aa is an amino acid group; in another embodiment, Aa is an amino acid residue; in yet another embodiment, Aa is... .

[0155]

[0156] In one implementation scheme For CR5; in another implementation, C 3-10 Cycloalkylene; in another embodiment, It is a 5-10 member subheterocyclic group; in another embodiment, C 6-10 arylene, such as phenylene; in another embodiment, It is a 5-10 member heteroaryl, for example, a 5-6 member heteroaryl.

[0157] In one implementation scheme Selected from C 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 Aromatic or 5-10 heteroaryl compounds.

[0158] In one implementation scheme Selected from C 5-6 Cycloalkylene, phenylene, 5-6 membered heteroalkylene or 5-6 membered heterocyclic group.

[0159] In one implementation scheme Not replaced; in another implementation, By 1 R Replace; in another implementation, By 2 R Replace; in another implementation, 3 Rs Replace; in another implementation, by 4 R Replace; in another implementation, By 5 or more R replace.

[0160] A

[0161] In one implementation, A does not exist; in another implementation, A is C. 3-10 Cycloalkylene; in another embodiment, A is a 5-10 membered heterocyclic alkylene group; in another embodiment, A is a C 6-10 A is an arylene, such as a phenylene; in another embodiment, A is a 5-10-membered heteroarylene, such as a 5-6-membered heteroarylene.

[0162] In one implementation, A does not exist, or is selected from C. 6-10 Aromatic or 5-10 heteroaryl compounds.

[0163] In one implementation, A is absent, or is selected from 5-6 member heteroaryl groups (e.g., ...). ).

[0164] In one implementation, A is not replaced; in another implementation, A is replaced by 1 R. Replace; in another implementation, A is replaced by 2 R Replace; in another implementation, A is replaced by 3 R Replace; in another implementation, A is replaced by 4 R Replace; in another implementation, A is replaced by 5 R Replace; in another implementation, A is replaced by more R replace.

[0165] Y

[0166] In one implementation, Y does not exist; in another implementation, Y is -O-; in yet another implementation, Y is -NR. a -; In another implementation, Y is -C 0-6 Alkylene-OC 0-6 alkylene-, for example -C 0-4 Alkylene-OC 0-4 Alkylene, such as -OCH2- or -CH2O-; in another embodiment, Y is C 1-6 Alkylene, such as C 1-4 Alkylene; in another embodiment, Y is C 1-6 Alkyl halides, such as C 1-4 Alkyl halides.

[0167] In one implementation, Y is selected from -O- and -C. 0-4 Alkylene-OC 0-4 Alkylene-, C 1-6 Alkylene or C 1-6 Alkyl halides.

[0168] In one implementation, Y is selected from -O-, -OCH2-, -CH2O-, or C. 1-4 Alkylene.

[0169] In one implementation, Y is C 1-4 Alkylene, optionally substituted with H, halogen, NH2, OH or CN, for example -CH(NH2)-CH2-.

[0170] In one specific implementation, Y is selected from -O- or -CH(NH2)-CH2.

[0171] In one embodiment, Y is not replaced; in another embodiment, Y is replaced by 1 R#; in another embodiment, Y is replaced by 2 R#; in another embodiment, Y is replaced by 3 R#; in another embodiment, Y is replaced by 4 R#; in another embodiment, Y is replaced by 5 R#.

[0172] B

[0173] In one implementation, B does not exist; in another implementation, B is C. 3-10 Cycloalkyl; in another embodiment, B is a 5-10 membered heterocyclic group; in another embodiment, B is a C 6-10 Aryl, such as phenyl; in another embodiment, B is a 5-10 heteroaryl, such as a 5-6 heteroaryl.

[0174] In one implementation, B is selected from C. 6-10 Aryl or 5-10 heteroaryl groups;

[0175] In one embodiment, B is selected from 5-6-membered heteroaryl or phenyl.

[0176] In one implementation, B is not replaced; in another implementation, B is replaced by 1 R. Replace; in another embodiment, the B is replaced by 2 R Replace; in another embodiment, the B is replaced by 3 R Replace; in another embodiment, the B is replaced by 4 R Replace; in another embodiment, the B is replaced by 5 R Replace; in another embodiment, the B is replaced by more R replace.

[0177] R1

[0178] In one embodiment, R1 is H; in another embodiment, R1 is OH; in yet another embodiment, R1 is C. 1-6 Alkyl, such as C1-4 Alkyl; in another embodiment, R1 is C 1-6 Alkoxy groups, such as C 1-4 alkoxy group; in another embodiment, R1 is C 1-6 Halogenated alkyl groups.

[0179] R2, R3, R4

[0180] In one embodiment, R2 is hydrogen; in another embodiment, R2 is a halogen; in yet another embodiment, R2 is C. 1-6 Alkyl; in another embodiment, R2 is C 1-6 Halogenated alkyl; in another embodiment, R2 is C 2-6 Alkenyl; in another embodiment, R2 is C 2-6 Haloalkenyl groups.

[0181] In one embodiment, R3 is hydrogen; in another embodiment, R3 is a halogen; in yet another embodiment, R3 is C. 1-6 Alkyl; in another embodiment, R3 is C 1-6 Halogenated alkyl; in another embodiment, R3 is C 2-6 Alkenyl; in another embodiment, R3 is C 2-6 Haloalkenyl groups.

[0182] In one embodiment, R4 is hydrogen; in another embodiment, R4 is a halogen; in yet another embodiment, R4 is C. 1-6 Alkyl; in another embodiment, R4 is C 1-6 Halogenated alkyl; in another embodiment, R4 is C 2-6 Alkenyl; in another embodiment, R4 is C 2-6 Haloalkenyl groups.

[0183] In one implementation, R2 and R3 can form C with the carbon atoms they are attached to. 3-6 Cycloalkyl.

[0184] R5

[0185] In one embodiment, R5 is hydrogen; in another embodiment, R5 is a halogen; in yet another embodiment, R5 is C. 1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R5 is C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl; in another embodiment, R5 is C 2-6 Alkenyl; in another embodiment, R5 is C 2-6 Haloalkenyl groups.

[0186] In one implementation, R5 is selected from H and C. 1-6 Alkyl or C 1-6 Haloalkyl, such as C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0187] R#

[0188] In one embodiment, R# is H; in another embodiment, R# is a halogen; in another embodiment, R# is NH2; in another embodiment, R# is OH; in another embodiment, R# is CN; in another embodiment, R# is C 1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R# is C 1-6 Alkoxy groups, such as C 1-4 Alkyl group; in another embodiment, R# is C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups.

[0189] R

[0190] In one implementation, R For H; in another implementation, R C 1-6 Alkyl; in another embodiment, R C 1-6 Halogenated alkyl; in another embodiment, R For nitro; in another embodiment, R For -NR b R c In another implementation, R For -C(O)CZ3; in another embodiment, R For -OR d In another implementation, R For CN; in another implementation, R For halogen; in another embodiment, R =O.

[0191] R a R b R c and R d

[0192] In one implementation, R a For H; in another implementation, R a For halogen; in another embodiment, R a C1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R a C 1-6 Alkoxy groups, such as C 1-4 Alkyl group; in another embodiment, R a C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups.

[0193] In one implementation, R b For H; in another implementation, R b For halogen; in another embodiment, R b C 1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R b C 1-6 Alkoxy groups, such as C 1-4 Alkyl group; in another embodiment, R b C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups.

[0194] In one implementation, R c For H; in another implementation, R c For halogen; in another embodiment, R c C 1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R c C 1-6 Alkoxy groups, such as C 1-4 Alkyl group; in another embodiment, R c C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups.

[0195] In one implementation, R d For H; in another implementation, R d For halogen; in another embodiment, R d C 1-6 Alkyl, such as C 1-4 Alkyl; in another embodiment, R d C 1-6 Alkoxy groups, such as C 1-4 Alkyl group; in another embodiment, R d C 1-6 Haloalkyl, such as C 1-4 Halogenated alkyl groups.

[0196] L1

[0197] In one implementation, L1 is absent, or includes chemical bonds, -OC 0-6 Alkylene-, -SC 0-6 Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links.

[0198] In one embodiment, L1 is absent; in another embodiment, L1 is a chemical bond; in yet another embodiment, L1 is -C. 0-6 Alkylene-OC 0-6 Alkylene; in another embodiment, L1 is -C 0-6 Alkylene-SC 0-6 Alkylene; in another embodiment, L1 is -C 0-6 Alkylene-C(O)-C 0-6 Alkylene; in another embodiment, L1 is -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene; in another embodiment, L1 is -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene; in another embodiment, L1 is an optionally substituted alkyl linker; in another embodiment, L1 is an optionally substituted alkenyl linker; in another embodiment, L1 is an optionally substituted polyethylene glycol (PEG) linker; in another embodiment, L1 is an optionally substituted heteroalkyl linker; in another embodiment, L1 is an optionally substituted heteroaryl linker; in another embodiment, L1 is an optionally substituted nitrogen; in another embodiment, L1 is an amide; in another embodiment, L1 is a phosphate diester bond; in another embodiment, L1 is a thiophosphate bond.

[0199] In one implementation, L1 is selected from chemical bonds, -C 0-10 Alkylene-OC 0-10 alkylene-, -C 0-10 Alkylene-SC 0-10 alkylene-, -C 0-10 Alkylene-C(O)-C 0-10 alkylene-, -C 0-10 Alkylene-C(O)NH-C 0-10alkylene-, -C 0-10 Alkylene-NHC(O)-C 0-10 alkylene-, -C 1-6 alkylene- or -C 2-6 Alkenyl-.

[0200] In one implementation, L1 is selected from chemical bonds, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 alkylene-, -C 1-6 alkylene- or -C 2-6 Alkenyl-.

[0201] In one embodiment, L1 is selected from chemical bonds, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -C 1-6 alkylene- or -C 2-6 Alkenyl-.

[0202] In one embodiment, L1 is selected from chemical bonds, -O-, -C(O)-, or -C 1-6 Alkylene-.

[0203] In one implementation, L1 is -O- or -C(O)-C. 0-4 Alkylene, such as -O-, -C(O)- or -C(O)CH2-.

[0204] In one embodiment, the substituent of L1 is selected from hydrogen, -OH, -NH2, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

[0205] L2

[0206] In one implementation, L2 is absent, or includes chemical bonds, -OC 0-6 Alkylene-, -SC 0-6Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links.

[0207] In one embodiment, L2 is absent; in another embodiment, L2 is a chemical bond; in yet another embodiment, L2 is -OC. 0-6 Alkylene; in another embodiment, L2 is -SC 0-6 Alkylene; in another embodiment, L2 is -C(O)-C 0-6 Alkylene; in another embodiment, L2 is -C(O)NH-C 0-6 Alkylene; in another embodiment, L2 is -NHC(O)-C 0-6 Alkylene; in another embodiment, L2 is an optionally substituted alkyl linker; in another embodiment, L2 is an optionally substituted alkenyl linker; in another embodiment, L2 is an optionally substituted polyethylene glycol (PEG) linker; in another embodiment, L2 is an optionally substituted heteroalkyl linker; in another embodiment, L2 is an optionally substituted heteroaryl linker; in another embodiment, L2 is an optionally substituted nitrogen; in another embodiment, L2 is an amide; in another embodiment, L2 is a phosphate diester bond; in another embodiment, L2 is a thiophosphate bond.

[0208] In one embodiment, L2 is an optionally substituted PEG linker, preferably a PEG linker with a length of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units, such as PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, or PEG10, wherein L2 is optionally replaced by one, two, or three elements selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups.

[0209] In one implementation, L2 is -C 0-4 Alkylene-(O-CH2CH2) n -C 0-4 Alkylene or -C 0-4 Alkylene-(CH2CH2-O) n -C 0-4Alkylene, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein L2 is optionally surrounded by one, two or three atoms selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups.

[0210] In one implementation, L2 is , or Where n2 and n5 are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 5 or 6.

[0211] In one embodiment, the substituent of L1 is selected from hydrogen, -OH, -NH2, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

[0212] L3

[0213] In one implementation, L3 is absent, or includes chemical bonds, -OC 0-6 Alkylene-, -SC 0-6 Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links.

[0214] In one embodiment, L3 is absent; in another embodiment, L3 is a chemical bond; in yet another embodiment, L3 is -OC. 0-6 Alkylene; in another embodiment, L3 is -SC 0-6 Alkylene; in another embodiment, L3 is -C(O)-C 0-6 Alkylene; in another embodiment, L3 is -C(O)NH-C 0-6 Alkylene; in another embodiment, L3 is -NHC(O)-C 0-6Alkylene; in another embodiment, L3 is an optionally substituted alkyl linker; in another embodiment, L3 is an optionally substituted alkenyl linker; in another embodiment, L3 is an optionally substituted polyethylene glycol (PEG) linker; in another embodiment, L3 is an optionally substituted heteroalkyl linker; in another embodiment, L3 is an optionally substituted heteroaryl linker; in another embodiment, L3 is an optionally substituted nitrogen; in another embodiment, L3 is an amide; in another embodiment, L3 is a phosphate diester bond; in another embodiment, L3 is a thiophosphate ester bond.

[0215] In one embodiment, the substituent of L3 is selected from hydrogen, -OH, -NH2, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

[0216] In one specific implementation, L3 is an optionally substituted 5-26 member heteroaryl linker.

[0217] In one specific implementation, L3 includes The L3 is optionally selected by one, two, or three elements chosen from H, halogens, OH, and C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups.

[0218] In a specific implementation, L3 is... .

[0219] L4

[0220] In one implementation, L4 is absent, or includes chemical bonds, -OC 0-6 Alkylene-, -SC 0-6 Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links.

[0221] In one embodiment, L4 is absent; in another embodiment, L4 is a chemical bond; in yet another embodiment, L4 is -OC. 0-6 Alkylene; in another embodiment, L4 is -SC 0-6 Alkylene; in another embodiment, L4 is -C(O)-C 0-6 Alkylene; in another embodiment, L4 is -C(O)NH-C 0-6 Alkylene; in another embodiment, L4 is -NHC(O)-C 0-6 Alkylene; in another embodiment, L4 is an optionally substituted alkyl linker; in another embodiment, L4 is an optionally substituted alkenyl linker; in another embodiment, L4 is an optionally substituted polyethylene glycol (PEG) linker; in another embodiment, L4 is an optionally substituted heteroalkyl linker; in another embodiment, L4 is an optionally substituted heteroaryl linker; in another embodiment, L4 is an optionally substituted nitrogen; in another embodiment, L4 is an amide; in another embodiment, L4 is a phosphate diester bond; in another embodiment, L4 is a thiophosphate bond.

[0222] In one embodiment, the substituent of L4 is selected from hydrogen, -OH, -NH2, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

[0223] In one specific implementation, L4 is a chemical bond or optionally substituted heteroalkyl linker.

[0224] In one specific implementation, L4 is selected from a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0225] (IV)

[0226] in,

[0227] The L4 is through L 4a Connected to L3;

[0228] X, L 4a L 4b L 4c and L 4d As defined in this article.

[0229] In one specific implementation, L4 is selected from the following structures or pharmaceutically acceptable salts thereof: or , where X is selected from O or S, and n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0230] X

[0231] In one implementation, X is O; in another implementation, X is S.

[0232] L 4a

[0233] In one implementation, L 4a For chemical bonds; in another embodiment, L 4a For -O-; in another implementation, L 4a It is -C(O)-.

[0234] L 4b

[0235] In one implementation, L 4b -C 1-6 alkylene-; in another embodiment, L 4b -C 1-6 Halogenated alkylene-; in another embodiment, L 4b -C 1-4 Alkylene, for example -CH2CH2-.

[0236] In one implementation, the L 4b Optionally selected by one, two, or three elements: halogen, OH, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups.

[0237] L 4c

[0238] In one implementation, L 4c For -O-; in another implementation, L 4c For -S-; in another implementation, L 4c For -C(O)-; in another embodiment, L 4c For -C(O)NH-; in another embodiment, L 4c It is -NHC(O)-.

[0239] L 4d

[0240] In one implementation, L 4d -C 1-22 Alkylene, preferably -C1-18 Alkylene-, more preferably -C 1-10 Alkylene-.

[0241] In one implementation, the -C 1-22 alkylene-, -C 1-18 alkylene- or -C 1-10 In the alkylene group, any one, two, or three carbon atoms are independently substituted by a 3-7 membered heterocyclic group selected from O, S, N, substituted or unsubstituted 3-7 membered heteroaryl groups, wherein the substituents of the 3-7 membered heterocyclic group and the 3-7 membered heteroaryl group are independently selected from halogens, OH, C. 1-6 Alkyl, C 1-6 One, two, or three of the alkyl halide, =O, and =S.

[0242] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of LG can be combined with any technical solution or any combination thereof of L1, L2, L3, L4, etc. This invention aims to include combinations of all these technical solutions; due to space limitations, they will not be listed one by one.

[0243] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from compounds of formula (II), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0244] (II)

[0245] R1 is selected from OH and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0246] It is CR5, where R5 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Halogenated alkenyl; or C 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 A arylene or a 5-10 heteroarylene, which may be further substituted with 1, 2, 3, 4, 5 or more R... replace;

[0247] S1 and S2 are each independently selected from chemical bonds, -O-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -SS-, -NHC(O)O-, -NHC(O)NH-, -OC(O)O-, -OC(O)NH-, -C(O)NHO-, -C(O)NHS-, -NHCH(CZ3)-, -NHCOC(R) )2CH2-、C 1-6 Alkylene, C 2-6 alkenyl;

[0248] G1 does not exist or is selected from , or R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 The haloalkenyl group, or R2 and R3, can form a C2 group with the carbon atom to which they are attached. 3-6 cycloalkyl;

[0249] G2 does not exist, or is selected from C. 1-4 Alkyl groups, amino acid groups, or -AYB;

[0250] A does not exist, or it is selected from C. 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 The A is a 5-10 arylene or heteroarylene, wherein the A may optionally be surrounded by 1, 2, 3, 4, 5 or more Rs. replace;

[0251] Y does not exist or is selected from -O- or -NR. a -、-C 0-6 Alkylene-OC 0-6 Alkylene-, C 1-6 Alkylene or C 1-6 Alkyl halide, wherein the Y is optionally substituted with one, two, three, four, five or more R#;

[0252] R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0253] B does not exist or C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by 1, 2, 3, 4, 5 or more R. replace;

[0254] R Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, nitro, -NR b R c -C(O)CZ3, -OR d CN, halogen or =O;

[0255] R a R b R c and R d Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0256] Each Z is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0257] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from compounds of formula (IIIa), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0258] (IIIa)

[0259] R1, R5, S1, A, Y, and B are as defined in this paper;

[0260] Preferably,

[0261] S1 is selected from chemical bonds, -NH-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl;

[0262] R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0263] R5 represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0264] A does not exist, or is selected from C. 3-10 5-10 membered heterocyclic alkyl groups, C 6-10 Arenes or 5-10 quinone heteroaryl compounds;

[0265] Y is selected from -O- and -C. 0-4 Alkylene-OC0-4 Alkylene-, C 1-6 Alkylene or C 1-6 Halogenated alkylene;

[0266] The Y may be optionally replaced by one, two, or three R#;

[0267] R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0268] B does not exist, or is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 The aryl group or a 5-10 heteroaryl group, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 R groups. replace;

[0269] The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0270] Preferably,

[0271] S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl;

[0272] R1 is OH or C 1-4 Alkoxy;

[0273] R5 represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0274] A does not exist, or is selected from C. 6-10 Arenes or 5-10 quinone heteroaryl compounds;

[0275] Y is selected from -O-, -OCH2-, -CH2O-, or C. 1-4 Alkylene;

[0276] The Y can be optionally replaced by one or two R#;

[0277] R# is selected from H, halogen, NH2, OH, CN, or C. 1-4 alkyl;

[0278] B is selected from C. 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by one, two or three Rs. replace;

[0279] The R Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0280] More preferably,

[0281] S1 is selected from C 1-4 Alkylene or C 2-4 alkenyl groups, preferably C 1-4 Alkyl groups, such as -CH2- or -CH2CH2-;

[0282] R1 is OH;

[0283] R5 is H;

[0284] A is absent, or is selected from 5-6 member heteroaryl groups (e.g. );

[0285] Y is either -O- or -CH(NH2)-CH2;

[0286] B is C 6-10 Aryl, such as phenyl, wherein the B may optionally be surrounded by one or two R replace;

[0287] The R Selected from H or C 1-4 alkyl;

[0288] More preferably, Selected from compounds of formula (IIIa-1) or (IIIa-2), or their pharmaceutically acceptable salts, tautomers, or stereoisomers:

[0289] (IIIa-1) (IIIa-2)

[0290] in,

[0291] Y' is a trivalent group formed by the connection of LG with L1 through Y;

[0292] B' is a divalent group formed by the connection of LG with L1 via B;

[0293] S1, A, Y, B, R1, and R5 are as defined above;

[0294] Preferably, Y is C replaced by NH2. 1-4 Alkylene, Y is attached to L1 via NH2, for example, Y' is ;

[0295] Preferably, B is selected from C. 3-10Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 The arylene or 5-10 heteroarylene, such as phenylene, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 Rs. Instead, the R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups.

[0296] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein R1 is OH, S1 is -CH=CH-, -CH2CH2- or -CH2-, A is selected from 5-6-membered heteroaryl or phenylene, Y is -O-, and B is selected from 5-6-membered heteroaryl or phenylene.

[0297] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from compounds of formula (IIIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0298] (IIIb)

[0299] in It is C 5-6 Cycloalkylene, phenylene, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group, which may be further reacted with one or more R replace;

[0300] R2, R3, and R4 are each independently selected from hydrogen or halogen;

[0301] R R1, S1, S2, and B are as defined in this paper.

[0302] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from compounds of formula (IIIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0303] (IIIb)

[0304] R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0305] R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6Haloalkenyl;

[0306] Selected from C 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 arylene or 5-10 quinone heteroarylene, the Can be optionally assigned to 1, 2 or 3 Rs replace;

[0307] S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl;

[0308] S2 is selected from -NH-, -C(O)-, -OC(O)-, -C(O)O-, -NHC(O)-, -C(O)NH-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl;

[0309] B is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 The aryl group or a 5-10 heteroaryl group, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 R groups. replace;

[0310] The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0311] Preferably,

[0312] R1 is OH or C 1-6 Alkoxy;

[0313] R2, R3, and R4 are each independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0314] Selected from C 6-10 Arenes or 5-10 quinone heteroaryl compounds;

[0315] S1 is selected from chemical bonds, C 1-6 Alkylene or C 2-6 alkenyl;

[0316] S2 is selected from -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl;

[0317] B is selected from C. 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by one, two or three Rs. replace;

[0318] The R Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0319] More preferably,

[0320] R1 is OH;

[0321] R2, R3, and R4 are each independently selected from halogens or C. 1-4 Alkyl groups, such as F or CH3;

[0322] Selected from 5-6-membered heteroaryl or phenylene groups;

[0323] S1 is a chemical bond;

[0324] S2 is selected from -NHC(O)-, -C(O)NH-, C 1-4 Alkylene or C 2-4 Alkenyl groups, preferably -C(O)NH- or -CH2-;

[0325] B is selected from 5-6-membered heteroaryl or phenyl groups, wherein B may optionally be converted by one or two R groups. replace;

[0326] The R Selected from H or C 1-4 alkyl;

[0327] More preferably, Selected from compounds of formula (IIIb-1), or their pharmaceutically acceptable salts, tautomers, or stereoisomers:

[0328] (IIIb-1)

[0329] in,

[0330] B' is a divalent group formed by the connection of LG with L1 via B;

[0331] S1, S2, R1, R2, R3, R4 and B are as defined above;

[0332] Preferably, B' is selected from C. 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10Aryl or 5-10-membered heteroaryl, such as 5-6-membered heteroaryl or phenyl.

[0333] The B' can be optionally represented by one, two, three, four, or five R's. replace;

[0334] The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups.

[0335] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from compounds of formula (IIIa), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0336] (IIIa)

[0337] S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl;

[0338] R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0339] R5 represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0340] A does not exist;

[0341] Y is selected from -O- and -C. 0-4 Alkylene-OC 0-4 alkylene- or -C 1-6 alkylene-;

[0342] The Y may be optionally replaced by one, two, or three R#;

[0343] R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0344] B is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0345] Preferably,

[0346] S1 is selected from -C 1-6 alkylene- or -C2-6 alkenyl-;

[0347] R1 is OH or C 1-4 Alkoxy;

[0348] R5 represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups;

[0349] A does not exist;

[0350] Y is selected from -O- or -C 1-4 alkylene-;

[0351] The Y can be optionally replaced by one or two R#;

[0352] R# is selected from H, halogen, NH2, OH or CN;

[0353] B is selected from C. 6-10 Aryl or 5-10 heteroaryl groups;

[0354] More preferably,

[0355] S1 is selected from C 1-4 Alkyl groups, such as -CH2- or -CH2CH2-;

[0356] R1 is OH;

[0357] R5 is H;

[0358] A does not exist;

[0359] Y is C 1-4 Alkylene, optionally substituted with H, halogen, NH2, OH or CN, for example -CH(NH2)-CH2-;

[0360] B is C 6-10 Aryl groups, such as phenyl groups;

[0361] More preferably, Selected from compounds of formula (IIIa-1), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof:

[0362] (IIIa-1)

[0363] in,

[0364] Y' is a trivalent group formed by the connection of LG with L1 through Y;

[0365] S1, A, Y, B, R1, and R5 are as defined above;

[0366] Preferably, Y is C replaced by NH2. 1-4Alkylene, Y is attached to L1 via NH2, for example, Y' is .

[0367] In one specific embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from any SORT1 ligand in Table 1 of the specification:

[0368] Table 1. SORT1 ligands of the present invention

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein the LG is selected from... , , , , or ;

[0381] Preferably, the Selected from , , , , or .

[0382] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the LG is selected from any SORT1 ligand in Table 2 of the specification.

[0383] In one implementation, the LG is .

[0384] In one specific embodiment, the present invention relates to the above-described oligonucleotide, wherein the LG is selected from any SORT1 ligand in Table 2:

[0385] Table 2. SORT1 ligands of the present invention

[0386]

[0387]

[0388]

[0389]

[0390]

[0391] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein L1, L2, L3, and L4 are each independently absent or include chemical bonds, -OC 0-6 Alkylene-, -SC 0-6 Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links;

[0392] Preferably, the substituents of L1, L2, L3, and L4 are each independently selected from hydrogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

[0393] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein...

[0394] The L1 is selected from chemical bonds, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -C 1-6 alkylene- or -C 2-6 alkenyl-;

[0395] Preferably, L1 is selected from chemical bonds, -O-, -C(O)-, or -C. 1-6 alkylene-;

[0396] More preferably, L1 is -O- or -C(O)-.

[0397] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotides, wherein...

[0398] The L1 is selected from chemical bonds, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 alkylene-, -C 1-6 alkylene- or -C 2-6 alkenyl-;

[0399] Preferably, L1 is selected from chemical bonds, -O-, -C(O)-C. 0-6 alkylene- or -C 1-6 alkylene-;

[0400] More preferably, L1 is -O- or -C(O)-C 0-4 Alkylene, such as -O-, -C(O)- or -C(O)CH2-.

[0401] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein the L2 is an optionally substituted alkyl linker or an optionally substituted heteroalkyl linker;

[0402] Preferably, L2 is an optionally substituted alkyl linker, such as -C 1-22 Alkylene, preferably -C 1-10 Alkylene-, wherein the L2 is optionally surrounded by one, two, or three atoms selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0403] Preferably, L2 is an optionally substituted PEG linker, preferably a PEG linker with a length of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units, wherein L2 is optionally connected by one, two or three elements selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6Substituents of haloalkyl groups;

[0404] Preferably, L2 is -C 0-4 Alkylene-(O-CH2CH2) n -C 0-4 Alkylene or -C 0-4 Alkylene-(CH2CH2-O) n -C 0-4 Alkylene, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein L2 is optionally surrounded by one, two or three atoms selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0405] Preferably, L2 is , , Where n2 and n5 are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 5 or 6.

[0406] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein L3 is a chemically bonded or optionally substituted 5-26 member heteroaryl linker;

[0407] Preferably, the L3 includes The L3 is optionally selected by one, two, or three elements chosen from H, halogens, OH, and C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0408] Preferably, L3 is .

[0409] In one specific embodiment, the present invention relates to the above-mentioned oligonucleotide, wherein L4 is a chemical bond or optionally substituted heteroalkyl linker;

[0410] Preferably, the L4 is selected from compounds of formula (IV) or pharmaceutically acceptable salts thereof:

[0411] (IV)

[0412] in,

[0413] The L4 is through L 4a Connected to L3;

[0414] X is selected from O or S;

[0415] L 4a Selected from chemical bonds, -O-, or -C(O)-;

[0416] L4b Selected from -C 1-6 alkylene- or -C 1-6 Halogenated alkylene-, the L 4b Optionally selected by one, two, or three elements: halogen, OH, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0417] L 4c Selected from -O-, -S-, -C(O)-, -C(O)NH- or -NHC(O)-;

[0418] L 4d Selected from -C 1-22 alkylene-, the -C 1-22 In the alkylene group, any one, two, or three carbon atoms are independently substituted by a 3-7 membered heterocyclic group selected from O, S, N, substituted or unsubstituted, or substituted or unsubstituted 3-7 membered heteroaryl group;

[0419] The substituents of the 3-7 membered heterocyclic group and the 3-7 membered heteroaryl group are independently selected from halogens, OH, C. 1-6 Alkyl, C 1-6 One, two, or three of the alkyl halide, =O, =S;

[0420] Preferably,

[0421] X is selected from O or S;

[0422] L 4a Selected from -O- or -C(O)-, preferably -C(O)-;

[0423] L 4b Selected from -C 1-4 Alkyl-, for example -CH2CH2-;

[0424] L 4c Selected from -C(O)NH- or -NHC(O)-;

[0425] L 4d Selected from -C 1-18 Alkylene-, more preferably -C 1-10 alkylene-, the -C 1-18 alkylene- or -C 1-10 In the alkylene group, any one, two, or three carbon atoms are optionally and independently substituted by a 3-7 membered heteroaryl group selected from O, S, N, or substituted or unsubstituted, wherein the -C 1-10 Alkylenes are preferred to be unsubstituted;

[0426] The substituents of the 3-7 membered heteroaryl group are selected from halogens, OH, and C. 1-6 Alkyl, C 1-6One, two, or three of the alkyl halide, =O, =S;

[0427] More preferably, L4 is selected from the following structures or pharmaceutically acceptable salts thereof: or , where X is selected from O or S, and n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0428] In one specific embodiment, the present invention relates to the above-described oligonucleotides, wherein L1, L2, L3, and L4 together form the following structure or a salt thereof:

[0429] , , , , , , ,

[0430] or , where X is 0 or S, n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n3 is any integer selected from 0 to 22.

[0431] In one specific embodiment, the present invention relates to the above-described oligonucleotides, wherein LG, L1, L2, L3, and L4 together form the following structure or a salt thereof:

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] in This indicates the remaining portion linked to the oligonucleotide.

[0438] In one specific embodiment, the present invention relates to double-stranded RNA having a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the antisense strand contains a sequence sufficiently complementary to the sense strand and the target mRNA, wherein the sense strand and / or antisense strand contains one or more compounds of formula (I), (II), (IIIa), (IIIb) or (IIIc) as described herein, or pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

[0439] In one specific embodiment, the present invention relates to the above-described double-stranded RNA, wherein the compound of formula (I), (II), (IIIa), (IIIb) or (IIIc) is coupled to the positive strand, preferably to the 5' end of the positive strand, coupled to the 3' end of the positive strand, or coupled to both the 5' and 3' ends of the positive strand.

[0440] In one specific embodiment, the present invention relates to the above-mentioned double-stranded RNA comprising two compounds of formula (I), (II), (IIIa), (IIIb) or (IIIc) respectively coupled to the 5' and 3' ends of the positive strand.

[0441] In one specific embodiment, the present invention relates to the above-mentioned double-stranded RNA, wherein the double-stranded RNA is a small interfering RNA (siRNA) or a short hairpin RNA (shRNA), preferably used to suppress genes expressed outside the liver.

[0442] In one specific embodiment, the present invention relates to the above-mentioned double-stranded RNA, wherein the gene expressed outside the liver is expressed in one or more tissues selected from the group consisting of: eye, central nervous system, lung, muscle, kidney, fat, spleen and tumor, wherein the muscle is preferably the quadriceps femoris or heart, and the fat is preferably subcutaneous fat or gonadal fat.

[0443] In one specific embodiment, the present invention relates to a compound of formula (V), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0444] (V)

[0445] Wherein LG, L1 and L2 are as defined herein, and PG is a protection base.

[0446] In one specific embodiment, the present invention relates to the compound of formula (V) described above, wherein the PG is selected from hydroxyl protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-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), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), bis-p-methoxytriphenylmethyl (DMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzylmethyl (PMBM), 4,4'-dimethoxytriphenylmethyl, -P(OCH2CH2CN)(N(iPr)2) or -C(O)CH2CH2C(O)OH.

[0447] In one specific embodiment, the present invention relates to a compound of formula (V), wherein the PG is -N3.

[0448] This invention specifically relates to the following technical solutions:

[0449] Technical Solution A1. An oligonucleotide comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0450] (I)

[0451] LG is the SORT1 ligand, and L1, L2, L3, and L4 are each independent entities, chemical bonds, or linkers.

[0452] Technical solution A2. The oligonucleotide described in technical solution A1, wherein the LG can represent a compound of formula (II):

[0453] (II)

[0454] Where R1 is a hydroxyl group or C 1-4 Alkoxy;

[0455] It is -CR5-, where R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C2-4 alkenyl or C 2-4 Haloalkenyl; or a 5-6 membered cycloalkyl, aryl, heteroaryl or heterocyclic group containing 0-3 heteroatoms, or an 8-10 membered bicyclic heterocyclic or heteroaryl group containing 1-2 heteroatoms, which may be further reacted with one or more R replace;

[0456] S1 and S2 are each independently selected from chemical bonds, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -SS-, -NHC(O)O-, -NHC(O)NH-, -OC(O)O-, -OC(O)NH-, -C(O)NHO-, -C(O)NHS-, -NHCH(CZ3)-, -NHCOC(R) )2CH2-、C 1-4 Alkylene, C 2-4 alkenyl;

[0457] G1 does not exist or is selected from , or R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl or C 2-4 The haloalkenyl group, or R2 and R3, can form a C2 group with the carbon atom to which they are attached. 3-6 cycloalkyl;

[0458] G2 does not exist or is selected from C. 1-4 Alkyl or -AYB;

[0459] A is a 5-6 membered cycloalkyl, aryl, heteroaryl, or heterocyclic group containing 0-3 heteroatoms, or an 8-10 membered bicyclic heterocyclic or heteroaryl group containing 1-2 heteroatoms, wherein A may optionally be converted by one or more R replace;

[0460] Y does not exist or is selected from -O-, -OCH2-, -CH2O-, -CH2-, -NR a -or -CH(NH2)-;

[0461] B may be absent or contain 0-4 heteroatoms of a 5-6 aryl or heteroaryl group, wherein B may optionally be converted by one or more R groups. replace;

[0462] The R Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, nitro, -NR b R c-C(O)CZ3, -OR d Halogen or =O;

[0463] The R a R b R c and R d Each is independently selected from hydrogen and C. 1-4 Alkyl or C 1-4 Alkoxy;

[0464] Z is a halogen.

[0465] Technical solution A3. The oligonucleotide of technical solution A2, wherein LG can represent a compound of formula III:

[0466] (III)

[0467] R1, R5, S1, A, Y, and B are as defined in technical solution A2.

[0468] Technical solution A4. The oligonucleotide described in technical solution A3, wherein R1 is hydrogen, S1 is -CH=CH-, -CH2CH2- or -CH2-, A is a 5-6 aryl or heteroaryl containing 0-3 heteroatoms, Y is -O-, and B is a 5-6 aryl or heteroaryl containing 0-3 heteroatoms.

[0469] Technical solution A5. The oligonucleotide described in technical solution A4, wherein the LG is selected from any SORT1 ligand in Table 1 of the specification.

[0470] Technical solution A6. The oligonucleotide described in technical solution A5, wherein the LG is .

[0471] Technical solution A7. The oligonucleotide of technical solution A1, wherein the LG is selected from any SORT1 ligand in Table 2 of the specification.

[0472] Technical solution A8. The oligonucleotide described in any one of technical solutions A1-A7, wherein L1, L2, L3 and L4 are each independently absent, chemically bonded or optionally substituted alkyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, oxygen, optionally substituted nitrogen, amide, phosphodiester bond or thiophosphate bond.

[0473] Technical solution A9. The oligonucleotide described in technical solution A8, wherein L1 is a chemical bond or oxygen, preferably oxygen.

[0474] Technical solution A10. The oligonucleotide described in technical solutions A8 or A9, wherein L2 is an optionally substituted PEG linker, preferably a PEG linker with a length of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units.

[0475] Technical solution A11. The oligonucleotide of any one of technical solutions A8-A10, wherein L2 is an optionally substituted alkyl linker or an optionally substituted heteroalkyl linker, preferably... Where n5 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 5.

[0476] Technical solution A12. The oligonucleotide of any one of technical solutions A8-A11, wherein L3 is an optionally substituted heteroaryl linker, preferably... .

[0477] Technical solution A13. The oligonucleotide of any one of technical solutions A8-A12, wherein L4 is an optionally substituted heteroalkyl linker, preferably in the following form or a salt thereof: or , where n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0478] Technical solution A14. The oligonucleotide of any one of technical solutions A8-A13, wherein L1, L2, L3 and L4 together form the following structure or a salt thereof:

[0479] , , , , , , or , where X is 0 or S, n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n3 is any integer from 0 to 22.

[0480] Technical solution A15. The oligonucleotide of any one of technical solutions A8-A14, wherein LG, L1, L2, L3 and L4 together form the following structure or a salt thereof:

[0481]

[0482]

[0483] in This indicates the remaining portion linked to the oligonucleotide.

[0484] Technical Solution A16. A double-stranded RNA having a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the antisense strand contains a sequence sufficiently complementary to the sense strand and the target mRNA, wherein the sense strand and / or antisense strand contains one or more compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, wherein the compounds of formula (I), (II) or (III) are as defined in any one of technical solutions A1-A15.

[0485] Technical Solution A17. The double-stranded RNA of Technical Solution 16, wherein the compound of formula (I), (II) or (III) is coupled to the positive strand, preferably coupled to the 5' end of the positive strand, coupled to the 3' end of the positive strand, or coupled to both the 5' and 3' ends of the positive strand.

[0486] Technical solution A18. The double-stranded RNA of technical solution 16 comprises two compounds of formula (I), (II) or (III), respectively coupled to the 5' and 3' ends of the positive strand.

[0487] Technical solution A19. The present invention also provides a compound of formula (IV).

[0488] (IV)

[0489] Wherein LG, L1 and L2 are as defined above, and PG is a protection base.

[0490] Technical solution A20. The compound described in technical solution A19, wherein the PG is selected from hydroxyl protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloro Ethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), bis-p-methoxytriphenylmethyl (DMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzylmethyl (PMBM), 4,4'-dimethoxytriphenylmethyl, -P(OCH2CH2CN)(N(iPr)2) or -C(O)CH2CH2C(O)OH.

[0491] Technical solution A21. The compound described in technical solution A19, wherein the PG is -N3.

[0492] Technical solution A22. A cell comprising the double-stranded RNA described in any one of technical solutions A16-A18.

[0493] Technical Solution A23. A pharmaceutical composition comprising double-stranded RNA as described in any one of Technical Solutions A16-A18 or cells as described in Technical Solution A22, and optionally a pharmaceutically acceptable carrier or excipient.

[0494] Technical Solution A24. A kit comprising double-stranded RNA as described in any one of Technical Solutions A16-A18 or cells as described in Technical Solution A22.

[0495] This invention specifically relates to the following technical solutions:

[0496] B1. An oligonucleotide comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0497] (I)

[0498] LG is the SORT1 ligand, and L1, L2, L3, and L4 are each independent entities, chemical bonds, or linkers.

[0499] B2. The oligonucleotide described in technical solution B1, wherein the LG can represent a compound of formula (II):

[0500] (II)

[0501] Where R1 is a hydroxyl group or C 1-4 Alkoxy;

[0502] It is -CR5-, where R5 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl or C 2-4 Haloalkenyl; or a 5-6 membered cycloalkyl, aryl, heteroaryl or heterocyclic group containing 0-3 heteroatoms, or an 8-10 membered bicyclic heterocyclic or heteroaryl group containing 1-2 heteroatoms, which may be further reacted with one or more R replace;

[0503] S1 and S2 are each independently selected from chemical bonds, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -SS-, -NHC(O)O-, -NHC(O)NH-, -OC(O)O-, -OC(O)NH-, -C(O)NHO-, -C(O)NHS-, -NHCH(CZ3)-, -NHCOC(R) )2CH2-、C 1-4 Alkylene, C 2-4 alkenyl;

[0504] G1 does not exist or is selected from , or R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl or C 2-4 The haloalkenyl group, or R2 and R3, can form a C2 group with the carbon atom to which they are attached. 3-6 cycloalkyl;

[0505] G2 does not exist, or is selected from C. 1-4 Alkyl groups, amino acid groups, or -AYB;

[0506] A is a 5-6 membered cycloalkyl, aryl, heteroaryl, or heterocyclic group containing 0-3 heteroatoms, or an 8-10 membered bicyclic heterocyclic or heteroaryl group containing 1-2 heteroatoms, wherein A may optionally be converted by one or more R replace;

[0507] Y does not exist or is selected from -O-, -OCH2-, -CH2O-, -CH2-, -NR a -or -CH(NH2)-;

[0508] B may be absent or contain 0-4 heteroatoms of a 5-6 aryl or heteroaryl group, wherein B may optionally be converted by one or more R groups. replace;

[0509] The R Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, nitro, -NR b R c -C(O)CZ3, -OR d Halogen or =O;

[0510] The R a R b R c and R d Each is independently selected from hydrogen and C. 1-4 Alkyl or C 1-4 Alkoxy;

[0511] Z is a halogen.

[0512] B3. The oligonucleotide of technical solution B2, wherein the LG can represent a compound of formula (IIIa):

[0513] (IIIa)

[0514] R1, R5, S1, A, Y, and B are as defined in technical solution B2.

[0515] B4. The oligonucleotide described in technical solution B3, wherein R1 is hydrogen, S1 is -CH=CH-, -CH2CH2- or -CH2-, A is a 5-6 aryl or heteroaryl containing 0-3 heteroatoms, Y is -O-, and B is a 5-6 aryl or heteroaryl containing 0-3 heteroatoms.

[0516] B5. The oligonucleotide of technical solution B2, wherein the LG can be represented as a compound of formula (IIIb):

[0517] (IIIb)

[0518] in It is a 5-6 membered cycloalkyl, aryl, heteroaryl, or heterocyclic group containing 0-3 heteroatoms, which can be further reacted with one or more R... replace;

[0519] R R1, S1, S2, and B are as defined in technical solution B2.

[0520] B6. The oligonucleotide of technical solution B2, wherein the LG can be represented as a compound of formula (IIIc):

[0521] (IIIc)

[0522] Wherein Aa represents an amino acid group, preferably a natural amino acid group, and more preferably a natural amino acid group. ,

[0523] R1, R5, and S1 are as defined in technical solution B2.

[0524] B7. The oligonucleotide of any one of technical solutions B3-B6, wherein the LG is selected from any SORT1 ligand in Table 1 of the specification.

[0525] B8. The oligonucleotide described in technical solution B7, wherein the LG is or .

[0526] B9. The oligonucleotide described in technical solution B1, wherein the LG is selected from any SORT1 ligand in Table 2 of the specification.

[0527] B10. The oligonucleotide described in any one of technical solutions B1-B9, wherein L1, L2, L3 and L4 are each independently free of chemical bonds, -C(O)-, optionally substituted alkyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, oxygen, optionally substituted nitrogen, amide, phosphodiester bonds or thiophosphate bonds.

[0528] B11. The oligonucleotide of technical solution B9, wherein L1 is a chemical bond, -C(O)- or oxygen, preferably -C(O)- or oxygen.

[0529] B12. The oligonucleotide of technical solution B10 or B11, wherein L2 is an optionally substituted PEG linker, preferably a PEG linker with a length of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units.

[0530] B13. The oligonucleotide of any one of technical solutions B10-B12, wherein L2 is an optionally substituted alkyl linker or an optionally substituted heteroalkyl linker, preferably... Where n5 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 5.

[0531] B14. The oligonucleotide of any one of technical solutions B10-B13, wherein L3 is an optionally substituted heteroaryl linker, preferably... .

[0532] B15. The oligonucleotide of any one of technical solutions B10-B14, wherein L4 is an optionally substituted heteroalkyl linker, preferably the following structure or a salt thereof: or , where n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0533] B16. The oligonucleotide of any one of technical solutions B10-B15, wherein L1, L2, L3 and L4 together form the following structure or a salt thereof:

[0534] , , , , , , , or , where X is 0 or S, n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n3 is any integer from 0 to 22.

[0535] B17. The oligonucleotide of any one of technical solutions B10-B16, wherein LG, L1, L2, L3 and L4 together form the following structure or a salt thereof:

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] in This indicates the remaining portion linked to the oligonucleotide.

[0542] B18. A double-stranded RNA having a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the antisense strand contains a sequence sufficiently complementary to the sense strand and the target mRNA, wherein the sense strand and / or antisense strand comprises one or more compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, wherein the compounds of formula (I), (II) or (III) are as defined in any one of claims B1-B17.

[0543] B19. The double-stranded RNA of technical solution B17, wherein the compound of formula (I), (II) or (III) is coupled to the positive strand, preferably to the 5' end of the positive strand, coupled to the 3' end of the positive strand, or coupled to both the 5' and 3' ends of the positive strand.

[0544] B20. The double-stranded RNA of technical solution B18 comprises two compounds of formula (I), (II) or (III), respectively coupled to the 5' and 3' ends of the positive strand.

[0545] B21. The present invention also provides a compound of formula (IV).

[0546] (IV)

[0547] Wherein LG, L1 and L2 are as defined above, and PG is a protection base.

[0548] B22. The compound described in technical solution B21, wherein the PG is selected from hydroxyl protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloro Ethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), bis-p-methoxytriphenylmethyl (DMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzylmethyl (PMBM), 4,4'-dimethoxytriphenylmethyl, -P(OCH2CH2CN)(N(iPr)2) or -C(O)CH2CH2C(O)OH.

[0549] B23. The compound described in technical solution B21, wherein the PG is -N3.

[0550] B24. A cell comprising double-stranded RNA as described in any one of technical solutions B18-B20.

[0551] B25. A pharmaceutical composition comprising double-stranded RNA as described in any one of technical solutions B18-B20 or cells as described in technical solution B24, and optionally a pharmaceutically acceptable carrier or excipient.

[0552] B26. A kit comprising double-stranded RNA as described in any one of technical solutions B18-B20 or cells as described in technical solution B24.

[0553] Example

[0554] The following embodiments are provided for the purpose of illustrating various embodiments of the invention, but are not intended to limit the invention in any way. These embodiments and the methods described herein represent preferred embodiments and are exemplary, not intended to be limiting of the scope of the invention. Variations and other uses will be apparent to those skilled in the art within the spirit of the invention as defined by the claims.

[0555] The siRNA sequence used in this invention is as follows:

[0556]

[0557] The meanings of the abbreviations in this article are as follows:

[0558] The distributions A, U, G, and C represent naturally occurring adenine ribonucleotides, uracil ribonucleotides, guanine ribonucleotides, and cytosine ribonucleotides.

[0559] The 'm' indicates that the nucleotide adjacent to it on the left is a nucleotide modified with 2'-OCH3. For example, Am, Um, Gm, and Cm represent A, U, G, and C modified with 2'-OCH3.

[0560] The 'f' indicates that the nucleotide adjacent to it on the left is a 2'-F modified nucleotide. For example, Af, Uf, Gf, and Cf represent 2'-F modified A, U, G, and C, respectively.

[0561] “s” or “s-” indicates that the two adjacent nucleotides and / or delivery carriers are linked by a phosphate thioester.

[0562] VP indicates that the nucleotide adjacent to its right is a vinylphosphonate-modified nucleotide, which is well known in the art, and can be found in, for example, PCT publications WO2011139702, WO2013033230 and WO2019105419.

[0563] SL1 indicates

[0564]

[0565] SL2 indicates

[0566]

[0567] SL3 indicates

[0568]

[0569] SL4 indicates

[0570]

[0571] SL5 indicates

[0572]

[0573] SL6 indicates

[0574]

[0575] Example 1: Preparation of compound DE1

[0576]

[0577] 1. Preparation of compound 1c

[0578]

[0579] At 0 °C, a solution of compound 1a (500 mg, 2.84 mmol) in dichloromethane (5 mL) was added dropwise to a mixture of compound 1b (412 mg, 2.84 mmol) and triethylamine (0.98 mL, 7.1 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, the residue was separated by reversed-phase C18 column chromatography (water / acetonitrile = 2:1) to obtain compound 1c (426 mg, yield 52.6%).

[0580] m / z: ES + [M + H] + 284.7

[0581] 1H NMR (400 MHz, DMSO-d6) δ 8.85 – 8.79 (m, 2H), 8.26 (dd, J = 8.3,2.5 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 4.44 (td, J = 7.9, 4.8 Hz, 1H), 1.79 –1.69 (m, 2H), 0.92 (s, 9H).

[0582] 2. Preparation of compound 1e

[0583]

[0584] Cesium carbonate (1.14 g, 3.51 mmol) was added to a mixture of compounds 1c (200 mg, 0.7 mmol) and 1d (116 mg, 1.1 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 110 °C for 3 hours. After the reaction mixture was cooled to room temperature, acetic acid was added to neutralize the pH to 5. The residue was concentrated under reduced pressure and separated by reversed-phase C18 column chromatography (water / acetonitrile = 2:1) to obtain compound 1e (74 mg, yield 52.6%).

[0585] m / z: ES + [M + H] + 359.8

[0586] 3. Preparation of compound DE1

[0587]

[0588] Potassium carbonate (85 mg, 0.6 mmol) was added to a mixture of compounds 1e (74 mg, 0.2 mmol) and 1f (95 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at 100 °C for 18 hours. After the reaction solution was cooled to room temperature, acetic acid was added to neutralize the pH to 5. The residue was concentrated under reduced pressure and separated by reversed-phase C18 column chromatography (water / acetonitrile = 1:1) to obtain the title compound DE1 (18 mg, yield 13.5%).

[0589] m / z: ES- [MH]- 646.3

[0590] 1H NMR (400 MHz, DMSO-d6) δ 8.66 – 8.57 (m, 2H), 8.25 (dd, J = 8.7, 2.5 Hz, 1H), 7.13 – 6.96 (m, 5H), 4.47 (td, J = 8.6, 3.4 Hz, 1H), 4.14 – 4.08(m, 2H), 3.78 – 3.73 (m, 2H), 3.63 – 3.49 (m, 18H), 3.38 (dd, J = 5.6, 4.3Hz, 2H), 1.83 – 1.69 (m, 2H), 0.92 (s, 9H).

[0591] Example 2 Preparation of compound DE2

[0592]

[0593] 1. Preparation of compound 2c

[0594]

[0595] Potassium carbonate (179 mg, 1.3 mmol) was added to a mixture of compounds 2a (200 mg, 0.43 mmol) and 2b (143 mg, 1.3 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 110 °C for 18 hours. After the reaction solution was cooled to room temperature, acetic acid was added to neutralize the pH to 5. The residue was concentrated under reduced pressure and then separated by reversed-phase C18 column chromatography (water / acetonitrile = 1:1) to obtain compound 2c (110 mg, yield 63.5%).

[0596] m / z: ES + [M + H] + 400.1

[0597] 1 H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 7.09 (t, J = 8.1 Hz,1H), 6.52 (t, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.2, 2.4 Hz, 3H), 4.13 – 4.08(m, 2H), 3.82 – 3.79 (m, 2H), 3.72 – 3.62 (m, 18H), 3.37 (t, J = 5.1 Hz, 2H).

[0598] 2. Preparation of compound DE2

[0599]

[0600] Cesium carbonate (269 mg, 0.83 mmol) was added to a mixture of N,N-dimethylformamide (1 mL) containing compounds 2c (110 mg, 0.28 mmol) and 2d (i.e., compound 1e, 78 mg, 0.28 mmol), and the mixture was stirred at 110 °C for 16 hours. After the reaction mixture was cooled to room temperature, acetic acid was added to neutralize the pH to 5. The residue was concentrated under reduced pressure and then separated by reversed-phase C18 column chromatography (water / acetonitrile = 3:2) to obtain compound DE2 (50.7 mg, yield 28.4%).

[0601] m / z: ES- [MH]- 646.3

[0602] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.4 Hz, 1H), 8.39 (d, J =8.5 Hz, 1H), 8.26 (dd, J = 8.7, 2.5 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.05(d, J = 8.6 Hz, 1H), 6.83 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.76 (t, J = 2.3Hz, 1H), 6.74 – 6.70 (m, 1H), 4.36 (td, J = 8.9, 2.7 Hz, 1H), 4.10 – 4.06 (m,2H), 3.75 – 3.71 (m, 2H), 3.61 – 3.50 (m, 18H), 3.38 (dd, J = 5.6, 4.3 Hz, 2H), 1.80 – 1.62 (m, 2H), 0.90 (s, 9H).

[0603] Example 3 Preparation of compound DE3

[0604]

[0605] DE3 was synthesized using the same method as DE2, except that compound 1b was replaced by compound (S)-2-amino-5,5-dimethylhexanoic acid.

[0606] Example 4 Preparation of compound DE4

[0607]

[0608] 1. Preparation of compound 3b

[0609]

[0610] Under a nitrogen atmosphere, compound 3a (10 g, 81.887 mmol) and imidazole (11.15 g, 163.773 mmol) were dissolved in dichloromethane (100 mL), and tert-butyldimethylchlorosilane (13.58 g, 90.075 mmol) was added in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water, the organic phase was separated, washed with water and saturated brine, dried, filtered, concentrated under reduced pressure, and the crude product was dissolved in methanol (100 mL) and cooled to 0°C. o After step C, sodium borohydride (0.5 g, 12 mmol) was added in batches. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with water and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography to obtain compound 3b (13.6 g, yield 69.67%).

[0611] 2. Preparation of compound 3c

[0612]

[0613] Under a nitrogen atmosphere, compound 3b (13 g, 54.530 mmol), triethylamine (6.62 g, 65.436 mmol), and 4-N,N-dimethylpyridine (0.67 g, 5.453 mmol) were dissolved in dichloromethane (50 mL), and the reaction solution was cooled to 5 °C. o C. Add p-toluenesulfonyl chloride (11.44 g, 59.983 mmol) in batches, controlling the temperature to not exceed 5°C. o C, after addition, slowly raise to room temperature and stir overnight. After the reaction is complete, wash twice each with 1M hydrochloric acid aqueous solution, water, and saturated saline solution, then dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is separated and purified by rapid column chromatography (ethyl acetate = 100%) to obtain compound 3c (5 g, yield 23.36%).

[0614] 3. Preparation of compound 3e

[0615]

[0616] Under a nitrogen atmosphere, sodium hydroxide (31.86 mg, 0.797 mmol) was added to a 5 mL solution of compound 3d (104.22 mg, 0.531 mmol) in N,N-dimethylformamide under an ice-water bath. After reacting at room temperature for 0.5 hours, the solution was cooled again to 0 °C. oC, then compound 3c (200 mg, 0.531 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction mixture was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (0-40% EtOAc, in PE) to obtain compound 3e (78 mg, 0.258 mmol).

[0617] 1 H NMR (400 MHz, Chloroform-d) δ 7.10 – 7.02 (m, 2H), 6.71 (s, 1H), 6.69 – 6.63 (m, 2H), 5.62 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 – 1.30 (m,12H).

[0618] 4. Preparation of compound 3f

[0619]

[0620] Potassium carbonate (107.64 mg, 0.780 mmol) was added to a 2 mL solution of N,N-dimethylformamide containing compounds 3e (78.62 mg, 0.260 mmol) and 1f (120 mg, 0.260 mmol). The reaction mixture was kept at room temperature (110 °C). o The mixture was stirred overnight at C. The reaction solution was then purified by reversed-phase rapid column chromatography (0-60% ACN in water) to obtain a colorless oily intermediate 3f (61 mg, yield 39.65%).

[0621] LC-MS: [M+H] + 591.82.

[0622] 5. Preparation of compound DE4

[0623]

[0624] Lithium hydroxide (5.44 mg, 0.227 mmol) was added to tetrahydrofuran (2 mL) and water (1 mL) containing compound 3f (61 mg, 0.103 mmol). The reaction mixture was stirred overnight at room temperature. After neutralization with acetic acid, the mixture was purified by reversed-phase rapid column chromatography (0-40% ACN in water) to obtain compound DE4 (34 mg, yield 58.51%).

[0625] LC-MS: [M+H]+ 563.9.

[0626] Example 5 Preparation of compound DE5

[0627]

[0628] 1. Preparation of compound 5d

[0629]

[0630] Compound 5b (0.64 g, 2.14 mmol) and N-methylmorpholine (0.94 mL, 8.58 mmol) were dissolved in THF (4.50 mL), and the reaction mixture was cooled to 0 °C. o C. Compound 5c (0.43 g, 3.21 mmol) was added to the reaction system. 25 o Compound 5a (0.45 g, 2.14 mmol) was added at C. At 25°C... o The reaction was carried out at C for 1 hour. EtOAc (5 mL) was added to the reaction solution, followed by washing with 1M HCl aqueous solution (5.00 mL), saturated NaHCO3 aqueous solution (5.00 mL), and brine (5.00 mL). The organic phase was dried over Na2SO4, filtered, concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate) to give compound 5d (0.73 g, yield: 73.0%).

[0631] m / z: ES+ [M+H] + 455.2

[0632] 1 H NMR (400 MHz, CDCl3) δ 7.36-7.20 (m, 10H), 6.22-6.20 (d, J=7.6 Hz,1H), 4.52-4.44 (m, 2H), 3.71 (s, 3H), 3.17-3.02 (m, 2H), 1.79-1.56 (m, 2H), 1.10-0.99 (m, 2H), 0.83 (s, 9H).

[0633] 2. Preparation of compound 5e

[0634]

[0635] Pd / C (0.73 g) was dissolved in MeOH (73.0 mL), and compound 5d (0.73 g, 1.60 mmol) was added to the reaction system. The reaction was carried out under a hydrogen atmosphere at 25 °C. oThe reaction was carried out at C for 2 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate) to give compound 5e (0.37 g, yield: 66.8%).

[0636] m / z: ES+ [M+H] + 321.2

[0637] 1 H NMR (400 MHz, CDCl3) δ 7.80-7.78 (d, J=8.0 Hz,1H), 7.38-7.27 (m,5H), 4.63-4.58 (m, 1H), 3.78 (s, 3H), 3.72-3.69 (m, 1H), 3.53 (s, 1H), 3.31-3.26 (m, 1H), 2.83-2.77 (m, 1H), 1.85-1.84 (m, 1H), 1.65-1.64 (m, 1H), 1.21-1.13 (m, 2H), 0.92 (s, 9H).

[0638] 3. Preparation of 5g of compound

[0639]

[0640] To a DMF (1 mL) solution of compound 5f (104.6 mg, 0.31 mmol), HATU (154.2 mg, 0.41 mmol) and DIEA (0.16 mL, 0.94 mmol) were added. After stirring at room temperature for 15 minutes, compound 5e (100 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solution was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and the crude product was subjected to reversed-phase column chromatography (eluent: water and acetonitrile) to give compound 5 g (44 mg, yield: 22%).

[0641] m / z: ES+ [M+H] + 637.57

[0642] 4. Preparation of compound DE5

[0643]

[0644] Triethylamine (0.06 mL, 0.41 mmol) and LiBr (119.8 mg, 1.38 mmol) were added to a solution of 5 g (44 mg, 0.07 mmol) of the compound in acetonitrile (1 mL) and water (0.04 mL). The mixture was stirred at 40 °C for 12 hours. The reaction solution was concentrated, and the crude product was subjected to reversed-phase column chromatography (eluent: water and acetonitrile) to give compound DE5 (25 mg, yield: 58%).

[0645] m / z: ES+ [M+H] + 623.64

[0646] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.29 – 7.13 (m, 5H), 4.59 (ddd, J = 9.8, 8.4, 4.1Hz, 1H), 4.13 (td, J = 8.0, 5.1 Hz, 1H), 3.63 – 3.37 (m, 22H), 3.01 (dd, J =13.9, 4.1 Hz, 1H), 2.72 (dd, J = 13.9, 9.9 Hz, 1H), 2.28 (t, J = 6.7 Hz, 2H),1.78 – 1.49 (m, 2H), 1.29 – 1.12 (m, 2H), 0.86 (s, 9H).

[0647] Example 6 Preparation of compound DE6

[0648]

[0649] 1. Preparation of compound 6c

[0650]

[0651] Compound 6a (0.20 g, 0.69 mmol, synthetic method can be found in, for example, intermediate Z49 of WO2014114779A1) was dissolved in DCM (1.50 mL), and then compound 6b (0.12 g, 0.69 mmol), DIEA (0.34 mL, 2.08 mmol), and HBTU (0.28 g, 0.76 mmol) were added to the reaction solution. The mixture was then heated to 25 °C. oAfter reacting at C for 16 hours, water (2 mL) was added, and DCM (2 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether and ethyl acetate) to give compound 6c (110 mg, yield 34.6%).

[0652] 1 H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.29 (s, 1H), 8.07-8.01 (m,2H), 7.77-7.75 (m, 1H), 7.35 (s, 1H), 2.40 (s, 1H), 1.38 (s, 9H).

[0653] 2. Preparation of compound DE6

[0654]

[0655] To a 2 mL solution of compound 6c (70 mg, 0.15 mmol) in 1,4-dioxane, BrettPhosPd G3 (13.8 mg, 0.015 mmol), BrettPhos (8.2 mg, 0.015 mmol), cesium carbonate (149 mg, 0.46 mmol), and compound 6d (70.27 mg, 0.229 mmol) were added. The mixture was purged three times with nitrogen, stirred at 120 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was subjected to column chromatography (dichloromethane:methanol = 1:0 to 10:1) to give compound DE6 (10.1 mg, yield: 9.1%).

[0656] m / z: ES+ [M+H] + 629.44

[0657] 1 H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 11.25 (s, 1H), 8.13 – 7.74(m, 3H), 7.65 (s, 1H), 6.67 (d, J = 2.1 Hz, 1H), 4.21 – 4.16 (m, 2H), 3.78(t, J = 4.5 Hz, 2H), 3.63 – 3.47 (m, 16H), 3.39 (t, J = 5.0 Hz, 2H), 2.35 (s,3H), 1.29 – 1.12 (m, 2H).

[0658] Example 7: Coupling of compound DE1 with nucleic acid chains

[0659] Conjugation at the ends of nucleic acid strands The methods are well known in the art, see, for example, WO2023196342A1, WO2023168296A2 or WO2023154896A2.

[0660] Similar methods can be used to couple compounds DE2, DE3, DE4, DE5, and DE6 to nucleic acid chains.

[0661]

[0662]

[0663] 1. Preparation of compound 7b

[0664]

[0665] Take the ammonia solution of compound 7a (3.65 g, 0.5 mmol) after ammonia deprotection, concentrate to dryness, and add acetic acid / water solution dropwise to compound 3a (3.65 g, 0.5 mmol) at low temperature. After the addition is complete, stir at room temperature for 1 hour, add methyl tert-butyl ether as a precipitating agent, wash, and obtain compound 7b (3.16 g, 90% yield). Without further purification, it is used directly in the next step.

[0666] m / z: ES+ [M+H]+7013

[0667] 2. Preparation of compound 7c

[0668]

[0669] The starting material compound 7b (2.1 g, 0.3 mmol) was dissolved in sodium bicarbonate aqueous solution to prepare a DBCO-NHS active ester (1.21 g, 3 mmol, 10 eq) N,N-dimethylformamide solution. The two were mixed, and the reaction was monitored by HPLC or LCMS. Acetonitrile was added as a precipitating reagent to obtain the crude product. The product compound 7c (1.2 g, yield 54.8%) was purified by HPLC with an anion exchange packing material.

[0670] m / z: ES + [M + H] + 7300

[0671] 3. Coupling of compound 7c with compound DE1

[0672]

[0673] A solution of compound DE1 (10 mg) in DMF (0.3 mL) was added to a water (1 mL) solution of compound 7c (30 mg). The mixture was stirred at room temperature for one hour. After the reaction was complete, reverse-phase C8 column chromatography (water (10 mM TEAA) / acetonitrile: 1:1) was performed to obtain the product compound DE1-7c.

[0674] m / z: ES-[MH]-7948

[0675] Example 8: Pharmacological Validation of the Compound

[0676] Experimental methods

[0677] Male SD rats (8-10 weeks old) were randomly divided into two groups: a solvent (i.e., aCSF) control group (n=3 per group) and compound group (n=5 per group). The compound was prepared using sterile artificial cerebrospinal fluid at a concentration of 30 mg / mL. After anesthesia, the corresponding compound was administered via intrathecal injection (L4-L6 level) at a dose of 0.9 mg / rat (30 µL / rat).

[0678] On day 14 after drug administration, the animals were euthanized by CO2, and the following tissues were rapidly isolated and removed: brainstem, hippocampus, and frontal cortex. After the samples were removed, they were placed in 5-10 times the volume of RNAlater and incubated overnight at 2-8°C, and then transferred to -80°C for storage for subsequent detection of rSOD1 mRNA.

[0679] RNA was extracted from tissues using a nucleic acid extractor (Hangzhou Aosheng, Auto-pure96) according to the protocol of the high-throughput tissue RNA extraction kit (Shanghai Fushen Biotechnology, FSF0035-TS); reverse transcription was performed using the PrimeScript™ II 1st Strand cDNA Synthesis Kit (Takara, 6210B); and quantitative real-time PCR was performed using a 20 μL system of TaqMan™ Fast Advanced Master Mix (ABI, 4444965) (ABI, QuantStudio3). Primers are shown in the table below.

[0680] Table 3. Primer Information

[0681]

[0682] Data statistics and analysis

[0683] Calculate 2 -△△Ct The values ​​were converted into percentages to obtain the residual inhibition rate, as shown in the table below;

[0684] △△Ct=[(Ct experimental group target gene - Ct experimental group internal reference) - (Ct control group target gene - Ct control group internal reference)].

[0685] The target gene is rSOD1, and the internal reference gene is rGAPDH.

[0686] Table 4. Inhibitory activity of the compounds of the present invention against SOD1 mRNA in different brain regions of SD rats.

[0687]

[0688]

[0689] Example 9: Peripheral drug delivery bioactivity test

[0690] Experimental methods

[0691] C57BL / 6 (male, 6-8 weeks old) mice were randomly divided into two groups: a solvent control group (n=3 per group) and a compound group (n=3 per group). The compound was prepared using physiological saline at a concentration of 5 mg / mL. The corresponding compound was administered subcutaneously at a dose of 5 mg / kg.

[0692] On day 14 or 28 post-drug administration, animals were euthanized with CO2, and the following tissues were rapidly isolated and removed: subcutaneous fat, gonadal fat, quadriceps femoris muscle, heart, liver, kidney, lung, spleen, and brain. After sample removal, the samples were divided into two portions, flash-frozen in liquid nitrogen, and then transferred to -80°C for storage for subsequent detection of mSOD1-mRNA levels.

[0693] Tissue RNA extraction was performed using a nucleic acid extractor (Hangzhou Aosheng, Auto-pure96) following the instructions of the High-Throughput Tissue RNA Extraction Kit (Shanghai Fushen Biotechnology, FSF0035-TS). (Special note: For adipose tissue: Transfer the adipose tissue to a 2mL centrifuge tube pre-filled with zirconium beads, add 1mL Trizol (Takara, 9108), and homogenize thoroughly using a tissue homogenizer (-5℃, 60Hz, 15min). After homogenization, centrifuge at high speed (12000 rpm) for 3 minutes, carefully discard the upper oil phase with a pipette tip, and then centrifuge again at high speed (12000 rpm) for 3 minutes. Use 350µL of tissue lysis supernatant for RNA extraction. For non-adipose tissue, follow the kit instructions.) Reverse transcription was performed using the PrimeScript™ II 1st Strand cDNASynthesis Kit (Takara, 6210B); TaqMan™ Fast Advanced Master Mix was also used. A 20 μL volume of (ABI, 4444965) was used for real-time PCR (ABI, QuantStudio3). The primers used are as follows:

[0694] Table 5. Primer Information

[0695]

[0696] Data statistics and analysis

[0697] Calculate 2 -△△Ct The values ​​were converted into percentages to obtain the residual inhibition rate, as shown in the table below;

[0698] △△Ct=[(Ct experimental group target gene - Ct experimental group internal reference) - (Ct control group target gene - Ct control group internal reference)].

[0699] The target gene is mSOD1, and the internal reference gene is mGAPDH.

[0700] Table 6. Inhibitory activity of the compounds of the present invention against SOD1 mRNA in different sites of C57BL / 6 mice (expressed as residual inhibition percentage)

[0701]

[0702] While preferred embodiments of the invention have been shown and described herein, these embodiments will be apparent to those skilled in the art as provided by way of example only. Many variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein may be employed. The following claims are intended to define the scope of the invention and cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. An oligonucleotide comprising one or more compounds of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: (I) in, LG is a SORT1 ligand. A monovalent group formed by connecting L1 to any position of the SORT1 ligand; L1, L2, L3, and L4 are each independently nonexistent, chemical bonds, or linkers.

2. The oligonucleotide of claim 1, wherein the LG is selected from compounds of formula (II), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (II) R1 is selected from OH and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; It is CR5, where R5 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Halogenated alkenyl; or C 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 A arylene or a 5-10 heteroarylene, which may be further substituted with 1, 2, 3, 4, 5 or more R... replace; S1 and S2 are each independently selected from chemical bonds, -O-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -SS-, -NHC(O)O-, -NHC(O)NH-, -OC(O)O-, -OC(O)NH-, -C(O)NHO-, -C(O)NHS-, -NHCH(CZ3)-, -NHCOC(R) )2CH2-、C 1-6 Alkylene or C 2-6 alkenyl; G1 does not exist or is selected from , or R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 The haloalkenyl group, or R2 and R3, can form a C2 group with the carbon atom to which they are attached. 3-6 cycloalkyl; G2 does not exist, or is selected from C. 1-4 Alkyl groups, amino acid groups, or -AYB; A does not exist, or it is selected from C. 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 The A is a 5-10 arylene or heteroarylene, wherein the A may optionally be surrounded by 1, 2, 3, 4, 5 or more Rs. replace; Y does not exist or is selected from -O- or -NR. a -、-C 0-6 Alkylene-OC 0-6 Alkylene-, C 1-6 Alkylene or C 1-6 Alkyl halide, wherein the Y is optionally substituted with one, two, three, four, five or more R#; R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; B does not exist or C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by 1, 2, 3, 4, 5 or more R. replace; R Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, nitro, -NR b R c -C(O)CZ3, -OR d CN, halogen or =O; R a R b R c and R d Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; Each Z is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

3. The oligonucleotide of claim 2, wherein the LG is selected from compounds of formula (IIIa), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (IIIa) R1, R5, S1, A, Y, B as defined in claim 2; Preferably, S1 is selected from chemical bonds, -NH-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl; R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; R5 represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; A does not exist, or is selected from C. 3-10 5-10 membered heterocyclic alkyl groups, C 6-10 Arenes or 5-10 quinone heteroaryl compounds; Y is selected from -O- and -C. 0-4 Alkylene-OC 0-4 Alkylene-, C 1-6 Alkylene or C 1-6 Halogenated alkylene; The Y may be optionally replaced by one, two, or three R#; R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; B does not exist, or is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 The aryl group or a 5-10 heteroaryl group, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 R groups. replace; The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; Preferably, S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl; R1 is OH or C 1-4 Alkoxy; R5 represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; A does not exist, or is selected from C. 6-10 Arenes or 5-10 quinone heteroaryl compounds; Y is selected from -O-, -OCH2-, -CH2O-, or C. 1-4 Alkylene; The Y can be optionally replaced by one or two R#; R# is selected from H, halogen, NH2, OH, CN, or C. 1-4 alkyl; B is selected from C. 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by one, two or three Rs. replace; The R Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; More preferably, S1 is selected from C 1-4 Alkylene or C 2-4 alkenyl groups, preferably C 1-4 Alkyl groups, such as -CH2- or -CH2CH2-; R1 is OH; R5 is H; A is absent, or is selected from 5-6 member heteroaryl groups (e.g. ); Y is either -O- or -CH(NH2)-CH2; B is C 6-10 Aryl, such as phenyl, wherein the B may optionally be surrounded by one or two R replace; The R Selected from H or C 1-4 alkyl; More preferably, Selected from compounds of formula (IIIa-1) or (IIIa-2), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: (IIIa-1) (IIIa-2) in, Y' is a trivalent group formed by the connection of LG with L1 through Y; B' is a divalent group formed by the connection of LG with L1 via B; S1, A, Y, B, R1, and R5 are as defined above; Preferably, Y is C replaced by NH2. 1-4 Alkylene, Y is attached to L1 via NH2, for example, Y' is ; Preferably, B is selected from C. 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 The arylene or 5-10 heteroarylene, such as phenylene, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 Rs. Instead, the R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups.

4. The oligonucleotide of claim 3, wherein R1 is OH, S1 is -CH=CH-, -CH2CH2- or -CH2-, A is selected from 5-6-membered heteroaryl or phenylene, Y is -O-, and B is selected from 5-6-membered heteroaryl or phenylene.

5. The oligonucleotide of claim 2, wherein the LG is selected from compounds of formula (IIIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (IIIb) in It is C 5-6 Cycloalkylene, phenylene, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group, which may be further reacted with one or more R replace; R2, R3, and R4 are each independently selected from hydrogen or halogen; R R1, S1, S2, and B are as defined in claim 2.

6. The oligonucleotide of claim 2, wherein the LG is selected from compounds of formula (IIIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (IIIb) R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; R2, R3, and R4 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Haloalkenyl; Selected from C 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 arylene or 5-10 quinone heteroarylene, the Can be optionally assigned to 1, 2 or 3 Rs replace; S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl; S2 is selected from -NH-, -C(O)-, -OC(O)-, -C(O)O-, -NHC(O)-, -C(O)NH-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl; B is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 The aryl group or a 5-10 heteroaryl group, wherein the B may optionally be surrounded by 1, 2, 3, 4 or 5 R groups. replace; The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; Preferably, R1 is OH or C 1-6 Alkoxy; R2, R3, and R4 are each independently selected from H, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Selected from C 6-10 Arenes or 5-10 quinone heteroaryl compounds; S1 is selected from chemical bonds, C 1-6 Alkylene or C 2-6 alkenyl; S2 is selected from -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-6 Alkylene or C 2-6 alkenyl; B is selected from C. 6-10 Aryl or 5-10 heteroaryl, wherein the B may optionally be surrounded by one, two or three Rs. replace; The R Selected from H, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; More preferably, R1 is OH; R2, R3, and R4 are each independently selected from halogens or C. 1-4 Alkyl groups, such as F or CH3; Selected from 5-6-membered heteroaryl or phenylene groups; S1 is a chemical bond; S2 is selected from -NHC(O)-, -C(O)NH-, C 1-4 Alkylene or C 2-4 Alkenyl groups, preferably -C(O)NH- or -CH2-; B is selected from 5-6-membered heteroaryl or phenyl groups, wherein B may optionally be converted by one or two R groups. replace; The R Selected from H or C 1-4 alkyl; More preferably, Selected from compounds of formula (IIIb-1), or their pharmaceutically acceptable salts, tautomers, or stereoisomers: (IIIb-1) in, B' is a divalent group formed by the connection of LG with L1 via B; S1, S2, R1, R2, R3, R4 and B are as defined above; Preferably, B' is selected from C. 3-10 Cycloalkylene, 5-10 membered heterocyclic alkylene, C 6-10 Aryl or 5-10-membered heteroaryl, such as 5-6-membered heteroaryl or phenyl. The B' can be optionally represented by one, two, three, four, or five R's. replace; The R Selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups.

7. The oligonucleotide of claim 2, wherein the LG is selected from compounds of formula (IIIa), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (IIIa) S1 is selected from chemical bonds, -NH-, -O-, C. 1-6 Alkylene or C 2-6 alkenyl; R1 is OH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; R5 represents H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; A does not exist; Y is selected from -O- and -C. 0-4 Alkylene-OC 0-4 alkylene- or -C 1-6 alkylene-; The Y may be optionally replaced by one, two, or three R#; R# is selected from H, halogens, NH2, OH, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; B is selected from C. 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups; Preferably, S1 is selected from -C 1-6 alkylene- or -C 2-6 alkenyl-; R1 is OH or C 1-4 Alkoxy; R5 represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; A does not exist; Y is selected from -O- or -C 1-4 alkylene-; The Y can be optionally replaced by one or two R#; R# is selected from H, halogen, NH2, OH or CN; B is selected from C. 6-10 Aryl or 5-10 heteroaryl groups; More preferably, S1 is selected from C 1-4 Alkyl groups, such as -CH2- or -CH2CH2-; R1 is OH; R5 is H; A does not exist; Y is C 1-4 Alkylene, optionally substituted with H, halogen, NH2, OH or CN, for example -CH(NH2)-CH2-; B is C 6-10 Aryl groups, such as phenyl groups; More preferably, Selected from compounds of formula (IIIa-1), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof: (IIIa-1) in, Y' is a trivalent group formed by the connection of LG with L1 through Y; S1, A, Y, B, R1, and R5 are as defined above; Preferably, Y is C replaced by NH2. 1-4 Alkylene, Y is attached to L1 via NH2, for example, Y' is .

8. The oligonucleotide of any one of claims 1-7, wherein the LG is selected from any SORT1 ligand in Table 1 of the specification.

9. The oligonucleotide of any one of claims 1-6, wherein the LG is selected from... , , , , or ; Preferably, the Selected from , , , , or .

10. The oligonucleotide of claim 1, wherein the LG is selected from any SORT1 ligand in Table 2 of the specification.

11. The oligonucleotide of any one of claims 1-10, wherein L1, L2, L3, and L4 are each independently absent or comprise chemical bonds, -OC 0-6 Alkylene-, -SC 0-6 Alkylene-, -C(O)-C 0-6 Alkylene-,-C(O)NH-C 0-6 Alkylene-, -NHC(O)-C 0-6 Alkylene-, optionally substituted alkyl linkers, optionally substituted alkenyl linkers, optionally substituted polyethylene glycol (PEG) linkers, optionally substituted heteroalkyl linkers, optionally substituted heteroaryl linkers, optionally substituted nitrogen, amide, phosphate diester, or thiophosphate ester links; Preferably, the substituents of L1, L2, L3, and L4 are each independently selected from hydrogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, 5-10 membered heterocyclic, C 6-10 One, two, three or more of aryl and 5-10 heteroaryl groups.

12. The oligonucleotide of claim 11, wherein, The L1 is selected from chemical bonds, -C 0-6 Alkylene-OC 0-6 alkylene-, -C 0-6 Alkylene-SC 0-6 alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 alkylene-, -C 1-6 alkylene- or -C 2-6 alkenyl-; Preferably, L1 is selected from chemical bonds, -O-, -C(O)-C. 0-6 alkylene- or -C 1-6 alkylene-; More preferably, L1 is -O- or -C(O)-C 0-4 Alkylene, such as -O-, -C(O)- or -C(O)CH2-.

13. The oligonucleotide of claim 11 or 12, wherein the L2 is an optionally substituted alkyl linker or an optionally substituted heteroalkyl linker; Preferably, L2 is an optionally substituted alkyl linker, such as -C 1-22 Alkylene, preferably -C 1-10 Alkylene-, wherein the L2 is optionally surrounded by one, two, or three atoms selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Preferably, L2 is an optionally substituted PEG linker, preferably a PEG linker with a length of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units, wherein L2 is optionally connected by one, two or three elements selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Preferably, L2 is -C 0-4 Alkylene-(O-CH2CH2) n -C 0-4 Alkylene or -C 0-4 Alkylene-(CH2CH2-O) n -C 0-4 Alkylene, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein L2 is optionally surrounded by one, two or three atoms selected from H, halogen, OH, C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Preferably, L2 is , or , wherein n2 and n5 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 5 or 6.

14. The oligonucleotide of any one of claims 11-13, wherein the L3 is a chemically bonded or optionally substituted 5-26 member heteroaryl linker; Preferably, the L3 includes The L3 is optionally selected by one, two, or three elements chosen from H, halogens, OH, and C. 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; Preferably, L3 is .

15. The oligonucleotide of any one of claims 11-14, wherein the L4 is a chemically bonded or optionally substituted heteroalkyl linker; Preferably, the L4 is selected from compounds of formula (IV) or pharmaceutically acceptable salts thereof: (IV) in, The L4 is through L 4a Connected to L3; X is selected from O or S; L 4a Selected from chemical bonds, -O-, or -C(O)-; L 4b Selected from -C 1-6 alkylene- or -C 1-6 Halogenated alkylene-, the L 4b Optionally selected by one, two, or three elements: halogen, OH, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups; L 4c Selected from -O-, -S-, -C(O)-, -C(O)NH- or -NHC(O)-; L 4d Selected from -C 1-22 alkylene-, the -C 1-22 In the alkylene group, any one, two, or three carbon atoms are independently substituted by a 3-7 membered heterocyclic group selected from O, S, N, substituted or unsubstituted, or substituted or unsubstituted 3-7 membered heteroaryl group; The substituents of the 3-7 membered heterocyclic group and the 3-7 membered heteroaryl group are independently selected from halogens, OH, C. 1-6 Alkyl, C 1-6 One, two, or three of the alkyl halide, =O, =S; Preferably, X is selected from O or S; L 4a Selected from -O- or -C(O)-, preferably -C(O)-; L 4b Selected from -C 1-4 Alkyl-, for example -CH2CH2-; L 4c Selected from -C(O)NH- or -NHC(O)-; L 4d Selected from -C 1-18 Alkylene-, more preferably -C 1-10 alkylene-, the -C 1-18 alkylene- or -C 1-10 In the alkylene group, any one, two, or three carbon atoms are optionally and independently substituted by a 3-7 membered heteroaryl group selected from O, S, N, or substituted or unsubstituted, wherein the -C 1-10 Alkylenes are preferred to be unsubstituted; The substituents of the 3-7 membered heteroaryl group are selected from halogens, OH, and C. 1-6 Alkyl, C 1-6 One, two, or three of the alkyl halide, =O, =S; More preferably, L4 is selected from the following structures or pharmaceutically acceptable salts thereof: or , where X is selected from O or S, and n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

16. The oligonucleotide of any one of claims 1-15, wherein said L1, L2, L3 and L4 together form the following structure or a salt thereof: 、 、 、 、 、 、 、 or , where X is 0 or S, n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n3 is any integer selected from 0 to 22.

17. The oligonucleotide of any one of claims 10-16, wherein said LG, L1, L2, L3 and L4 together form the following structure or a salt thereof: in This indicates the remaining portion linked to the oligonucleotide.

18. A double-stranded RNA having a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the antisense strand contains a sequence sufficiently complementary to the sense strand and the target mRNA, wherein the sense strand and / or antisense strand contains one or more compounds of formula (I), (II), (IIIa) or (IIIb) as defined in any one of claims 1-17, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

19. The double-stranded RNA of claim 18, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is coupled to the positive strand, preferably to the 5' end of the positive strand, coupled to the 3' end of the positive strand, or coupled to both the 5' and 3' ends of the positive strand.

20. The double-stranded RNA of claim 18, comprising two compounds of formula (I), (II), (IIIa) or (IIIb), respectively coupled to the 5' and 3' ends of the positive strand.

21. The double-stranded RNA of any one of claims 18-20, wherein the double-stranded RNA is a small interfering RNA (siRNA) or a short hairpin RNA (shRNA), preferably used to suppress genes expressed outside the liver.

22. The double-stranded RNA of claims 18-21, wherein the gene expressed outside the liver is expressed in one or more tissues selected from the group consisting of: eye, central nervous system, lung, muscle, kidney, fat, spleen and tumor, wherein the muscle is preferably the quadriceps femoris or heart, and the fat is preferably subcutaneous fat or gonadal fat.

23. A compound of formula (V), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: (V) Wherein LG, L1 and L2 are as defined in any one of claims 1-17, and PG is a protection base.

24. The compound of claim 23, wherein the PG is selected from hydroxyl protecting groups, such as trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trimethylsilyl... Chloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, triphenylmethyl (Tr), bis-p-methoxytriphenylmethyl (DMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), p-methoxybenzylmethyl (PMBM), 4,4'-dimethoxytriphenylmethyl, -P(OCH2CH2CN)(N(iPr)2) or -C(O)CH2CH2C(O)OH.

25. The compound of claim 23, wherein the PG is -N3.

26. A cell comprising the double-stranded RNA according to any one of claims 18-22.

27. A pharmaceutical composition comprising an oligonucleotide of any one of claims 1-17, a double-stranded RNA of any one of claims 18-22, or a cell of claim 26, and optionally a pharmaceutically acceptable carrier or excipient.

28. A kit comprising the double-stranded RNA of any one of claims 18-22 or the cells of claim 26.

29. A method for administering oligonucleotides to a subject via extrahepatic delivery, wherein, The method includes administering an oligonucleotide as defined in any one of claims 1-17 to a subject, wherein the extrahepatic delivery includes delivery to one or more tissues from the group consisting of: the eye, central nervous system, lung, muscle, kidney, fat, spleen, and tumor, wherein the muscle is preferably the quadriceps femoris or heart, and the fat is preferably subcutaneous fat or gonadal fat.

30. The method of claim 29, the method comprising delivering the oligonucleotide by systemic or local administration, the local administration being any one of the following: intrathecal injection, intraocular injection, intramuscular injection, aerosol spray, and intratumoral injection.

31. A method for delivering SORT1 ligands to the brain of a subject, wherein, The method includes administering to a subject the oligonucleotide of any one of claims 1-17, the double-stranded RNA of any one of claims 18-22, the pharmaceutical composition of claim 27, or the kit of claim 28; Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to a subject via intrathecal administration; Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to the subject in a therapeutically effective amount; Preferably, the method includes delivering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to one or more brain regions selected from the striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord.

32. A method for preventing or treating a disease, comprising administering to a subject the oligonucleotide of any one of claims 1-17, the double-stranded RNA of any one of claims 18-22, the pharmaceutical composition of claim 27, or the kit of claim 28; Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to a subject via intrathecal administration; Preferably, the method includes administering the oligonucleotide, double-stranded RNA, pharmaceutical composition, or kit to the subject in a therapeutically effective amount; Preferably, the disease is selected from diseases, conditions, or symptoms related to SORT1; Preferably, the disease is selected from central nervous system (CNS) diseases, symptoms or their manifestations.

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