Carbohydrate-oligonucleotide conjugates, pharmaceutical compositions and therapeutic applications

Abstract

The present invention provides carbohydrate-oligonucleotide conjugates, such as compounds as shown in Formula (I), and pharmaceutical compositions thereof. The present invention also provides methods of their therapeutic application for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition. [Case 1] JPEG2025531341000223.jpg15169

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) Pursuant to Title 35, U.S. Code, Section 119(a), this application claims priority to International Application No. PCT / CN2022 / 119522, filed September 19, 2022, and International Application No. PCT / CN2023 / 095768, filed May 23, 2023, the disclosures of each of the foregoing applications being incorporated herein by reference in their entirety.

[0002] The present invention provides carbohydrate-oligonucleotide conjugates and pharmaceutical compositions thereof, and further provides methods of using these conjugates to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition. (Reference to sequence listing)

[0003] This specification is accompanied by a 23,144 byte sequence listing, 413A003WO01_SEQLIST_ST26.XML, created on September 16, 2023, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0004] Therapeutic oligonucleotides, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are designed to regulate the expression of disease genes. (Roberts et al., Nature Review Drug Discovery, 2020, No. 19, pp. 673-694) ASOs are single-stranded oligonucleotides that specifically bind to target mRNAs through Watson-Crick base pairing, thereby regulating the production of disease-causing proteins. (Dhuri et al., J. Clin. Med. 2020, No. 9, pp. 2004) siRNAs are double-stranded RNA molecules that induce gene silencing by targeting and degrading complementary mRNAs. Of the two strands of siRNA, one is the antisense strand (also called the guide strand) and the other is the sense strand (also called the passenger strand). Shukla et al., ChemMedChem. 2010, No. 5, pp. 328-349 (Shukla et al., ChemMedChem. 2010, No. 5, pp. 328-349). To silence a target gene, siRNA first binds to the RNA-induced silencing complex (RISC). Hammond et al., Nature. 2000, No. 404, pp. 293-296 (Hammond et al., Nature. 2000, No. 404, pp. 293-296). Within the RISC, the two strands of the siRNA are separated, and the antisense strand and RISC form an activated RISC, which binds to and cleaves the target mRNA molecule. Nykanen et al., Cell, 2001, No. 107, pp. 309-321; Martinez et al., Cell, 2002, No. 110, pp. 563-574 (Nykanen et al., Cell 2001, 107, 309-21; Martinez et al., Cell 2002, 110, pp. 563-574). This gene silencing process proceeds through sequence-specific hybridization of guide RNA to the mRNA target site, bringing RISC into proximity with the target mRNA molecule, which is then cleaved by the RISC nuclease Argonaute2 (Ago2).Liu et al., Science, 2004, Vol. 305, pp. 1437-1441; Rand et al., Proc. Natl. Acad. Sci. USA 2004, Vol. 101, pp. 14385-14389; Rivas et al., Nature, Structural and Molecular Biology, 2005, Vol. 12, pp. 340-349 (Liu et al., Science 2004, Vol. 305, pp. 1437-1441; Rand et al., Proc. Natl. Acad. Sci. USA 2004, Vol. 101, pp. 14385-14389; Rivas et al., Nat. Struct. Mol. Biol. 2005, Vol. 12, pp. 340-349). This catalytic process leads to the selective reduction of specific mRNA molecules, which are then recovered for subsequent rounds of RISC, resulting in reduced expression of the target gene.

[0005] In general, therapeutic oligonucleotides are specific and efficient in regulating disease-related genes (Hu et al., Signal. Transduct. Target Ther. 2020, 5, 101; Alshaer et al., Eur. J. Pharmacol. 2021, 905, 174178). However, their therapeutic applications are limited by poor cellular uptake and susceptibility to degradation by nucleases. Roberts et al., Nature Review Drug Discovery, 2020, No. 19, pp. 673-694; Gagliardi and Ashizawa, Biomedicines, 2021, No. 9, p. 433; Friedrich and Aigner, BioDrugs, 2022, pp. 1-23. Therefore, there is a need for therapeutic oligonucleotides with pharmacological properties suitable for therapeutic applications. Summary of the Invention [Problem to be solved by the invention]

[0006] [Means for solving the problem]

[0007] The present invention provides a carbohydrate-oligonucleotide conjugate comprising an asialoglycoprotein receptor (ASGPR) binding group and two oligonucleotides.

[0008] The present invention further provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker or first and second bivalent linkers, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence and an end of the second sense or antisense sequence via the trivalent linker, or the ASGPR binding group is connected to an end of the first sense or antisense sequence via the first bivalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to an end of the second sense or antisense sequence via the second bivalent linker.

[0009] The present invention also provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence and an end of the second sense or antisense sequence via the trivalent linker.

[0010] The present invention also provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence via the first bivalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to an end of the second sense or antisense sequence via a second bivalent linker.

[0011] The present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker or first and second bivalent linkers, wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide and one end of the second single-stranded oligonucleotide via the trivalent linker, or the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide via the first bivalent linker, and the other end of the first single-stranded oligonucleotide is connected to one end of the second single-stranded oligonucleotide via a second bivalent linker.

[0012] The present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first single-stranded oligonucleotide and an end of the second single-stranded oligonucleotide via the trivalent linker.

[0013] The carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and first and second bivalent linkers, wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide via the first bivalent linker, and the other end of the first single-stranded oligonucleotide is connected to one end of the second single-stranded oligonucleotide via the second bivalent linker.

[0014] The present invention provides a pharmaceutical composition, which comprises a carbohydrate-oligonucleotide conjugate provided by the present invention and a pharmaceutically acceptable excipient.

[0015] The present invention provides a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a carbohydrate-oligonucleotide conjugate provided by the present invention. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows the effect of GalNAc-siRNA complexes on hPCSK9 and mANGPTL3 protein levels in hPCSK9-UTR mice. [Figure 2] 1 shows the effect of GalNAc-siRNA complexes on LDL-C and TG levels in hPCSK9-UTR mice. [Figure 3] 1 shows the effect of GalNAc-siRNA complexes on C3, C5, and CFB protein levels in mice. [Figure 4] 1 shows the effect of GalNAc-siRNA complex A18f on HBsAg levels in the plasma of HBV-infected mice. [Figure 5] 1 shows the effect of GalNAc-siRNA complex A18f on the number of HBV-infected mice with HBsAb levels in plasma exceeding 10 mIV / mL. [Figure 6]1 shows the effect of GalNAc-siRNA complex A18f on HBV DNA levels in the plasma of HBV-infected mice. DETAILED DESCRIPTION OF THE INVENTION

[0017] Embodiment 1. A carbohydrate-oligonucleotide conjugate comprising one ASGPR binding group and two oligonucleotides.

[0018] Embodiment 2. The carbohydrate-oligonucleotide conjugate of embodiment 1, comprising one ASGPR binding group, two oligonucleotides, and one trivalent linker.

[0019] Embodiment 3. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 2, comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence and an end of the second sense or antisense sequence via the trivalent linker.

[0020] Embodiment 4. In the carbohydrate-oligonucleotide conjugate of embodiment 2 or 3, the ASGPR binding group is connected to the 5'-end of the first sense or antisense sequence and the 5'-end of the second sense or antisense sequence via a trivalent linker.

[0021] Embodiment 5. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 5'-end of the first sense sequence and the 5'-end of the second sense sequence via a trivalent linker.

[0022] Embodiment 6. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 3'-end of the first sense sequence and the 5'-end of the second sense sequence via a trivalent linker.

[0023] Embodiment 7. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 3'-end of the first sense sequence and the 3'-end of the second sense sequence via a trivalent linker.

[0024] Embodiment 8. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 5'-end of the first antisense sequence and the 5'-end of the second antisense sequence via a trivalent linker.

[0025] Embodiment 9. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 3'-end of the first antisense sequence and the 5'-end of the second antisense sequence via a trivalent linker.

[0026] Embodiment 10. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is connected to the 3'-end of the first antisense sequence and the 3'-end of the second antisense sequence via a trivalent linker.

[0027] Embodiment 11 The carbohydrate-oligonucleotide conjugate of embodiment 1, comprising one ASGPR binding group, two oligonucleotides, and two bivalent linkers.

[0028] Embodiment 12. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 11 further comprises an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence via the first bivalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to an end of the second sense or antisense sequence via a second bivalent linker.

[0029] Embodiment 13 The carbohydrate-oligonucleotide conjugate of any one of embodiments 3 to 10 and 12, wherein the first oligonucleotide duplex structure is a double-stranded siRNA.

[0030] Embodiment 14. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3-10, 12, and 13, wherein each strand of the first oligonucleotide double-stranded structure independently comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0031] Embodiment 15 The carbohydrate-oligonucleotide conjugate of any one of embodiments 3-10 and 12-14, wherein the second oligonucleotide duplex structure is a double-stranded siRNA.

[0032] Embodiment 16. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3-10 and 12-15, wherein each strand of the second oligonucleotide double-stranded structure independently comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0033] Embodiment 17 The carbohydrate-oligonucleotide conjugate of embodiment 14 or 16, wherein each nucleotide is independently a natural nucleotide or a modified nucleotide.

[0034] Embodiment 18. The carbohydrate-oligonucleotide conjugate of embodiment 14, 16, or 17, wherein each nucleotide is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine, or 2'-O-methyluridine.

[0035] Embodiment 19 The carbohydrate-oligonucleotide conjugate of any one of embodiments 14 and 16-18, wherein each strand has one or more phosphate linking groups, each group independently substituted with phosphorothioate or phosphorodithioate.

[0036] Embodiment 20. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 2, further comprising an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker, wherein the ASGPR binding group is connected to the end of the first single-stranded oligonucleotide and the end of the second single-stranded oligonucleotide via the trivalent linker.

[0037] Embodiment 21 In the carbohydrate-oligonucleotide conjugate of embodiment 20, the ASGPR binding group is connected to the 5'-end of the first single-stranded oligonucleotide and the 5'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0038] Embodiment 22 In the carbohydrate-oligonucleotide conjugate of embodiment 20, the ASGPR binding group is connected to the 3'-end of the first single-stranded oligonucleotide and the 5'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0039] Embodiment 23 In the carbohydrate-oligonucleotide conjugate of embodiment 20, the ASGPR binding group is connected to the 3'-end of the first single-stranded oligonucleotide and the 3'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0040] Embodiment 24. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 11, further comprising an ASGPR binding group, first and second single-stranded oligonucleotides, and first and second bivalent linkers, wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide via the first bivalent linker, and the other end of the first single-stranded oligonucleotide is connected to one end of the second single-stranded oligonucleotide via a second bivalent linker.

[0041] Embodiment 25 The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 24, wherein the first single-stranded oligonucleotide is a single-stranded RNA.

[0042] Embodiment 26 The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 25, wherein the first single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

[0043] Embodiment 27 The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 26, wherein the second single-stranded oligonucleotide is a single-stranded RNA.

[0044] Embodiment 28 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 20 to 27, wherein the second single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

[0045] Embodiment 29 The carbohydrate-oligonucleotide conjugate of embodiment 26 or 28, wherein each nucleotide is independently a natural nucleotide or a modified nucleotide.

[0046] Embodiment 30 The carbohydrate-oligonucleotide conjugate of embodiment 26, 28, or 29, wherein each nucleotide is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine, or 2'-O-methyluridine.

[0047] Embodiment 31 The carbohydrate-oligonucleotide conjugate of any one of embodiments 26 and 28-30, wherein each single-stranded oligonucleotide has one or more phosphate linking groups independently replaced with phosphorothioate or phosphorodithioate.

[0048] Embodiment 32 The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 31, wherein the single-stranded oligonucleotide is an ASO sequence or a sense or antisense sequence of an siRNA.

[0049] Embodiment 33 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 1 to 32, wherein the ASGPR binding group comprises about 1 to about 10 N-acetylgalactosamines.

[0050] Embodiment 34 The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 33, wherein the ASGPR binding group comprises about 1, about 2, about 3, about 4, or about 5 N-acetylgalactosamines.

[0051] Embodiment 35 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 1 to 34, wherein the ASGPR binding group comprises about 2, about 3, or about 4 N-acetylgalactosamines.

[0052] Embodiment 36 The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 35, wherein the ASGPR binding group has the structure of formula (AI): [ka] or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, or mixture of two or more tautomers thereof, wherein E a and b are, respectively, (i) b is an integer of 1, and E a is a bond, CH2 or NH; (ii) b is an integer of 2, and Ea is a trivalent linker; or (iii) b is an integer of 3, and E a is a tetravalent linker; Each L a is an independent linker.

[0053] Embodiment 37 The carbohydrate-oligonucleotide conjugate of embodiment 36, wherein b is an integer of 2 and E a is a trivalent linker.

[0054] Embodiment 38 The carbohydrate-oligonucleotide conjugate of embodiment 37, wherein E a is CH.

[0055] Embodiment 39 The carbohydrate-oligonucleotide conjugate of embodiment 37, wherein E a is N.

[0056] Embodiment 40 The carbohydrate-oligonucleotide conjugate of embodiment 36, wherein b is an integer of 3 and E a is a tetravalent linker.

[0057] Embodiment 41 The carbohydrate-oligonucleotide conjugate of embodiment 40, wherein E a is C.

[0058] Embodiment 42 The carbohydrate-oligonucleotide conjugate of any one of embodiments 36 to 41, wherein each L a independently -Z n -(R n -Z n ) z - a linker having the structure: Each R n is independently C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z nare independently bonds, -C(O)-, -C(O)O-, and -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -C(R 1a )=NO-, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)NR 1b - and; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, each Q being selected from the group consisting of: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b ) OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR bR c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c and -S(O)NR b R c and each group in (b) is further selected independently from one or more (in one embodiment, one, two, three, or four) substituents Q a and each R in (c) a , R b , R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three or four) substituents Q a optionally replaced by; Here, each Q a are (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f Rg , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g and -S(O)NR f R g and each R in (c) is independently selected from e , R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and Rg together with the N atom attached to them form a heterocyclyl.

[0059] Embodiment 43 The carbohydrate-oligonucleotide conjugate of embodiment 42, wherein each R n is independently C 1-10 Alkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q.

[0060] Embodiment 44. The carbohydrate-oligonucleotide conjugate of embodiment 42 or 43, wherein each R n are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl or 1,2,3-triazoldiyl, pyrrolidinediyl or piperidinediyl, each optionally substituted with one, two or three substituents Q.

[0061] Embodiment 45 The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 44, wherein each R n is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,3-diyl, or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q.

[0062] Embodiment 46 The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 45, wherein each Z n are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH₃)=NO—, —O—, —OP(O₂)O—, —OP(O₂)S—, —NH—, —N(CH₃)—, —S—, or —S(O)₂—.

[0063] Embodiment 47. The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 46, wherein each Z n are independently a bond, —C(O)NH—, —O—, —OP(O2)O—, —OP(O2)S—, or —NH—.

[0064] Embodiment 48 The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 47, wherein z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0065] Embodiment 49 The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 48, wherein z is an integer of 0, 1, 2, 3, 4, or 5.

[0066] Embodiment 50. The carbohydrate-oligonucleotide conjugate of any one of embodiments 36 to 42, wherein each L a is independent [ka] is.

[0067] Embodiment 51 The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 35, wherein the ASGPR binding group has the structure of formula (AV): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof; E b and c are, respectively, (i) c is an integer of 1, and E b is a bond; (ii) c is an integer of 2, and E b is a trivalent linker; or (iii) c is an integer of 3, and E b is a tetravalent linker; E c and d are, respectively, (i) d is an integer of 1, and E c is a bond; (ii) d is an integer of 2, and E c is a trivalent linker; or (iii) d is an integer of 3, and E c is a tetravalent linker; G is a trivalent linker; Each L b and L c are each an independent bivalent linker.

[0068] Embodiment 52 The carbohydrate-oligonucleotide conjugate of embodiment 51, wherein c is an integer equal to 1 and E b is a bond.

[0069] Embodiment 53 The carbohydrate-oligonucleotide conjugate of embodiment 51, wherein c is an integer of 2 and E b is a trivalent linker.

[0070] Embodiment 54 The carbohydrate-oligonucleotide conjugate of embodiment 53, wherein E b teeth, [ka] is.

[0071] Embodiment 55 The carbohydrate-oligonucleotide conjugate of any one of embodiments 51 to 53, wherein d is an integer of 2 and E c is a trivalent linker.

[0072] Embodiment 56 The carbohydrate-oligonucleotide conjugate of embodiment 55, wherein E c teeth [ka] is.

[0073] Embodiment 57. The carbohydrate-oligonucleotide conjugate of any one of embodiments 51 to 56, wherein each L b and L c independently structure-Z n -(R n -Z n ) z - a linker of Each R n is independently C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z n are independently bonds, -C(O)-, -C(O)O-, and -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -C(R 1a )=NO-, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)NR 1b - and; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, each Q independently being (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl; (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SRa 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR b )OR c 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c および-S(O)2NR b R cand each group in (b) is further selected from one or more (in one embodiment, one, two, three, or four) substituents Q a and each R in (c) a , R b , R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three or four) substituents Q a optionally replaced by; Here, each Q a are independently (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NR e S(O)NR f R g 、-NR e S(O)2NR f R g 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR f R gand -S(O)NR f R g (c) each R e , R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom attached to them form a heterocyclyl.

[0074] Embodiment 58 The carbohydrate-oligonucleotide conjugate of embodiment 57, wherein each R n is independently C 1-10 Alkylene, C 6-14 aryl, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q;

[0075] Embodiment 59. The carbohydrate-oligonucleotide conjugate of embodiment 57 or 58, wherein each R n are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazoldiyl, pyrrolidinediyl, or piperidinediyl, each optionally substituted with one, two, or three substituents Q.

[0076] Embodiment 60. The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 59, wherein each R nis independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,3-diyl, or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q.

[0077] Embodiment 61. The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 60, wherein each Z n are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH₃)═NO—, —O—, —OP(O₂)O—, —OP(O₂)S—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-.

[0078] Embodiment 62. The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 61, wherein each Z n are independently a bond, —C(O)NH—, —O—, —OP(O2)O—, —OP(O2)S—, or —NH—.

[0079] Embodiment 63 The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 62, wherein z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0080] Embodiment 64 The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 63, wherein z is an integer of 0, 1, 2, 3, 4, or 5.

[0081] Embodiment 65. The carbohydrate-oligonucleotide conjugate of embodiment 51 or 57, wherein L b and L c are each independently [ka] is.

[0082] Embodiment 66 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 1 to 35, wherein the ASGPR binding group has the following structure: [ka] JPEG2025531341000009.jpg205169 JPEG2025531341000010.jpg238169 JPEG2025531341000011.jpg229169 JPEG2025531341000012.jpg237169 JPEG2025531341000013.jpg188169 JPEG2025531341000014.jpg219169 .

[0083] Embodiment 67. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 10, 13 to 23, and 25 to 66, wherein the trivalent linker is independently [ka] a linker having the structure: M is (i) N or CH; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl; Each R n is independently C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z nare independently bonds, -C(O)-, -C(O)O-, and -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -C(R 1a )=NO-, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)NR 1b - and; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, each Q independently being (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR b ) OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NRb R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c and -S(O)NR b R c and each group in (b) is further selected from one or more (in one embodiment, one, two, three, or four) substituents Q a and each R in (c) a , R b , R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three or four) substituents Q a optionally replaced by; Here, each Q a are independently (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR fR g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g and -S(O)NR f R g (c) each R e , R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and Rg together with the N atom attached to them form a heterocyclyl.

[0084] Embodiment 68 The carbohydrate-oligonucleotide conjugate of embodiment 67, wherein M is N.

[0085] Embodiment 69 The carbohydrate-oligonucleotide conjugate of embodiment 67, wherein M is CH or C(CH3).

[0086] Embodiment 70. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 69, wherein each R n is independently C 1-10 Alkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q.

[0087] Embodiment 71 The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 70, wherein each R n are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, phendiyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothienediyl, or tetrahydropyrandiyl, each optionally substituted with one, two, or three substituents Q.

[0088] Embodiment 72 The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 71, wherein each R nare independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, 1-acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0089] Embodiment 73. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 72, wherein each Z n are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —C(CH₃)═NO—, —O—, —OC(O)NH—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-.

[0090] Embodiment 74. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 73, wherein each Z n are independently a bond, —C(O)—, —C(O)NH—, —C(CH3)═NO—, —O—, —NH—, —P(O2)O—, —P(O)(S)O—, or —S—.

[0091] Embodiment 75 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 67 to 74, wherein each z is independently an integer of 0, 1, 2, 3, 4, or 5.

[0092] Embodiment 76 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 67 to 75, wherein each z is independently an integer of 0, 1, 2, 3, or 4.

[0093] Embodiment 77. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 10, 13 to 23, and 25 to 67, wherein the trivalent linker specifically has the following structure: [ka] JPEG2025531341000017.jpg218169 JPEG2025531341000018.jpg237169 JPEG2025531341000019.jpg207169 JPEG2025531341000020.jpg141169 is.

[0094] Embodiment 78. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 11-19, and 24-66, wherein each bivalent linker is independently -Z n -(R n -Z n ) z - is a linker having the structure Each R n is independently C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; each Z n are independently bonds, -C(O)-, -C(O)O-, and -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -C(R 1a )=NO-, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR1a C(O)S-, -NR 1a C(NR 1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)NR 1b - and; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene is optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q, each Q independently being (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NRb R c 、-C(O)SR a 、-C(NR a )NR b R c 、-C(S)R a 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR b )OR c 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR aS(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c and -S(O)NR b R c and each group in (b) is further selected from one or more (in one embodiment, one, two, three, or four) substituents Q a and each R in (c) a , R b , R c and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three or four) substituents Q a is replaced by; Here, each Q a are independently (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e、-C(O)OR e 、-C(O)NR f R g 、-C(O)SR e 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OP(O)(OR f )OR g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)Rh , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g and -S(O)NR f R g and each R in (c) is selected from e , R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom attached to them form a heterocyclyl.

[0095] Embodiment 79. The carbohydrate-oligonucleotide conjugate of embodiment 78, wherein each R n is independently C 1-10 Alkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q.

[0096] Embodiment 80. The carbohydrate-oligonucleotide conjugate of embodiment 78 or 79, wherein each R n is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazoldiyl, or pyrrolidinediyl, each optionally substituted with one, two, or three substituents Q.

[0097] Embodiment 81. The carbohydrate-oligonucleotide conjugate of any one of embodiments 78 to 80, wherein each R n are independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, 1-acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0098] Embodiment 82. The carbohydrate-oligonucleotide conjugate of any one of embodiments 78 to 81, wherein each Z n are independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -C(CH3)=NO-, -O-, -OC(O)NH-, -NH-, -N(CH3)-, -P(O2)O-, -P(O)(S)O-, -S- or -S(O)2-.

[0099] Embodiment 83. The carbohydrate-oligonucleotide conjugate of any one of embodiments 78 to 82, wherein each Z n are independently a bond, —C(O)—, —C(O)NH—, —C(CH3)═NO—, —O—, —NH—, —P(O2)O—, —P(O)(S)O—, or —S—.

[0100] Embodiment 84 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 78 to 83, wherein each z is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0101] Embodiment 85 The carbohydrate-oligonucleotide conjugate of any one of Embodiments 78 to 84, wherein each z is independently an integer of 0, 1, 2, 3, 4, or 5.

[0102] Embodiment 86 The carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 11-19, 24-66, and 78, wherein each bivalent linker is independently a linker having the following structure: [ka] .

[0103] Embodiment 87 The carbohydrate-oligonucleotide conjugate of embodiment 1, wherein the structure is: [ka] JPEG2025531341000023.jpg220169 JPEG2025531341000024.jpg231169 JPEG2025531341000025.jpg219169 JPEG2025531341000026.jpg226169 JPEG2025531341000027.jpg225169 JPEG2025531341000028.jpg236169 JPEG2025531341000029.jpg196169 and; Here, each 3'-siRNA independently represents an siRNA having one of its 3'-ends linked to a trivalent linker; each 5'-siRNA represents an siRNA having one of its 5'-ends linked to a trivalent linker; and 5'-ssDNA represents a single-stranded DNA, the 5'-end of which is linked to a trivalent linker.

[0104] Embodiment 88 The carbohydrate-oligonucleotide conjugate of embodiment 1, wherein the structure is: [ka] and Here, 3'-siRNA represents an siRNA, one of whose 3'-ends is linked to a first bivalent linker and one of whose 5'-ends is linked to a second bivalent linker; 5'-siRNA represents an siRNA, one of whose 5'-ends is linked to a second bivalent linker.

[0105] Embodiment 89. In the carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 19 and 33 to 88, the oligonucleotide is an oligonucleotide double-stranded structure, and this double-stranded structure comprises a pair of sequences consisting of the nucleotide sequences set forth in the following SEQ ID NOs: SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:24.

[0106] Embodiment 90 The carbohydrate-oligonucleotide conjugate of embodiment 1, wherein the structure is: [ka] JPEG2025531341000032.jpg220169 JPEG2025531341000033.jpg231169 JPEG2025531341000034.jpg219169 JPEG2025531341000035.jpg225169 JPEG2025531341000036.jpg225169 JPEG2025531341000037.jpg236169 JPEG2025531341000038.jpg199169 and; Here, each 3'-ssRNA independently represents a single-stranded RNA, the 3'-terminus of which is linked to a trivalent linker; each 5'-ssRNA independently represents a single-stranded RNA, the 5'-terminus of which is linked to a trivalent linker; and each 5'-ssDNA independently represents a single-stranded RNA, the 5'-terminus of which is linked to a trivalent linker.

[0107] Embodiment 91 The carbohydrate-oligonucleotide conjugate of embodiment 1, wherein the structure is: [ka] and Here, 3'-ssRNA refers to a single-stranded RNA, the 3'-end of which is linked to a first bivalent linker and the 5'-end of which is linked to a second bivalent linker; and 5'-ssRNA refers to a single-stranded RNA, the 5'-end of which is linked to a second bivalent linker.

[0108] Embodiment 92. In the carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 2, 20-86, 90 and 91, each oligonucleotide independently comprises a nucleotide sequence set forth in any one of SEQ ID NO:1-SEQ ID NO:25.

[0109] Embodiment 93. A pharmaceutical composition comprising the carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 92 and a pharmaceutically acceptable excipient.

[0110] Embodiment 94 The pharmaceutical composition of embodiment 93, wherein the composition is a unitary dosage form.

[0111] Embodiment 95 The pharmaceutical composition of embodiment 93 or 94, wherein the composition is in a parenteral or intravenous dosage form.

[0112] Embodiment 96 The pharmaceutical composition of embodiment 95, wherein the composition is formulated into an intravenous dosage form. The present invention provides a carbohydrate-oligonucleotide conjugate, the conjugate comprising an asialoglycoprotein receptor (ASGPR) binding group and two oligonucleotides. (Detailed explanation)

[0113] To facilitate understanding of the present invention, several terms are defined below.

[0114] Generally, the terms used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0115] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0116] The terms "treatment," "treating," and "method of treatment" include reducing or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or reducing or eliminating the cause of the disorder, disease, or condition itself.

[0117] The terms "prevention," "preventing," and "prophylactic treatment" include methods of delaying the onset and / or eliminating a disorder, disease, or condition and / or its associated symptoms, methods of preventing a subject from contracting a disorder, disease, or condition, or methods of reducing a subject's risk of contracting a disorder, disease, or condition.

[0118] The terms "alleviating" and "alleviating" refer to slowing and / or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also refer to reducing side effects associated with the active ingredient. Also, the beneficial effects a subject derives from a prophylactic or therapeutic agent may not result in a cure of the disorder, disease, or condition.

[0119] The term "contact" or "contacting" refers to contacting a therapeutic agent with a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue, thereby producing a physiological and / or chemical effect. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule ex vivo, and the effect of the therapeutic agent on the biological molecule is determined. In another embodiment, a therapeutic agent is contacted with cells in cell culture (ex vitro), and the effect of the therapeutic agent on the cells is determined. In yet another embodiment, contacting a therapeutic agent with a biological molecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biological molecule, cell, or tissue contacted.

[0120] The term "therapeutically effective amount" or "effective amount" refers to a dose of a compound that, when administered at this dose, is sufficient to prevent the onset of the disorder, disease, or condition being treated, or to alleviate to some extent one or more of its symptoms. The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound that is sufficient to elicit the biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0121] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable," meaning compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of a subject (e.g., a human) without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy,23rd ed.;Adejare Ed.;Academic Press,2020;Handbook of Pharmaceutical Excipients,9th ed.;Sheskey et al.,Eds.;Pharmaceutical Press,2020;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Synapse Information Resources,2007;Pharmaceutical Please refer to Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015.

[0122] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0123] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkyl refers to a hydrocarbon radical having 1 to 20 (C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6 Alkyl is also referred to as “lower alkyl.” Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (including all isomers such as n-propyl, isopropyl, etc.), butyl (including all isomers such as n-butyl, isobutyl, sec-butyl, tert-butyl, etc.), pentyl (including all isomers such as n-pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl, etc.), and hexyl (including all isomers such as n-hexyl, isohexyl, sec-hexyl, etc.).

[0124] In the present invention, the terms "alkylene" and "alkanediyl" are used interchangeably to refer to a straight-chain or branched-chain saturated divalent hydrocarbon radical, where the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkanediyl refers to a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkanediyl refers to a hydrocarbon radical having 1 to 30 (C 1-30 ), 1~20(C 1-20 ), 1~15(C 1-15), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) straight-chain saturated divalent hydrocarbon radical having 3 to 30 (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6 Alkanediyls are also called "lower alkanediyls." Examples of alkanediyl include, but are not limited to, methanediyl, ethanediyl (including all isomers such as ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomers such as propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomers such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomers such as pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomers such as hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of alkanediyl include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, and -C(O)(CH2). 10 These include, but are not limited to, -, -C(O)CHC(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0125] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon radical containing in the backbone one or more heteroatoms, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl refers to a linear saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, heteroalkyl is a hydrocarbon radical having 1 to 20 (C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6 Heteroalkyl is also referred to as "lower heteroalkyl." Examples of heteroalkyl include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0126] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein and refer to a linear or branched saturated divalent hydrocarbon radical containing in its backbone one or more heteroatoms, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Heteroalkylene refers to a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, heteroalkylene is a hydrocarbon radical having 1 to 20 (C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) straight-chain saturated divalent hydrocarbon radical having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6 Heteroalkylene is also referred to as "lower heteroalkylene." Examples of heteroalkylene include -CHO-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH) 10 Examples of substituted heteroalkylene include, but are not limited to, -O-, -CHOCH-, -CHCHO-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -CHNH-, -CHNHCH-, -CHCHNH-, -CHS-, -CHSCH-, or -CHCHS-. Examples of substituted heteroalkylene include, but are not limited to, -C(O)CHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, 10 These include, but are not limited to, O-, -C(O)CHOCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -CHNHC(O)CH-, or -CHCHC(O)NH-.

[0127] The term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical, which in one embodiment contains 1, 2, 3, or 4 carbon-carbon double bonds, and in another embodiment contains 1 carbon-carbon double bond. The alkenyl may be optionally substituted with one or more substituents Q as described herein. As will be understood by those of skill in the art, the term "alkenyl" includes radicals having the "cis" or "trans" configuration, or a mixture thereof, or includes radicals having the "Z" or "E" configuration, or a mixture thereof. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkenyl refers to a hydrocarbon radical having 2 to 20 (C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6 ) straight-chain monovalent hydrocarbon radical having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 (Alkenyl) is a branched-chain monovalent hydrocarbon radical having 1 to 3 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl (including all isomers such as propen-1-yl, propen-2-yl, allyl), and butenyl (including all isomers such as buten-1-yl, buten-2-yl, buten-3-yl, 2-buten-1-yl).

[0128] The terms "alkenylene" and "alkenediyl" are used interchangeably herein and refer to a straight- or branched-chain divalent hydrocarbon radical containing one or more carbon-carbon double bonds, in one embodiment containing 1, 2, 3, or 4 carbon-carbon double bonds, and in another embodiment containing one carbon-carbon double bond. The alkenediyl may be optionally substituted with one or more substituents Q as described herein. As will be understood by those skilled in the art, the term "alkenediyl" includes radicals having the "cis" or "trans" configuration, or mixtures thereof, or includes radicals having the "Z" or "E" configuration, or mixtures thereof. For example, C 2-6 Alkenediyl refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkenediyl refers to a hydrocarbon radical having 2 to 30 (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6 ) straight-chain divalent hydrocarbon radical having 3 to 30 (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6) carbon atoms. Examples of alkenediyls include ethenediyl (including all isomers such as ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (1-propene-1,1-diyl, 1-propene-1,2-diyl, 1-propene-1,3-diyl, etc.), butenediyl (including all isomers of 1-butene-1,1-diyl, 1-butene-1,2-diyl, 1-butene-1,4-diyl, etc.), pentenediyl (including all isomers of 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, 1-pentene-1,5-diyl, etc.), and hexenediyl (including all isomers of 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,5-diyl, 1-hexene-1,6-diyl, etc.).

[0129] The terms "heteroalkenylene" and "heteroalkenediyl" are used interchangeably herein and refer to a straight- or branched-chain divalent hydrocarbon radical containing one or more carbon-carbon double bonds, in one embodiment 1, 2, 3, or 4 carbon-carbon double bonds, and in another embodiment 1 carbon-carbon double bond. The hydrocarbon chain then contains one or more heteroatoms, each independently selected from O, S, and N. Heteroalkenylene may be optionally substituted with one or more substituents Q as described herein. As will be appreciated by those skilled in the art, the term "heteroalkenylene" includes radicals having the "cis" or "trans" configuration, or a mixture thereof, or the "Z" or "E" configuration, or a mixture thereof. For example, C 2-6 Heteroalkenylene means a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene is a heterocyclic group having 2 to 20 (C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6) straight-chain divalent hydrocarbon radical having 3 to 20 (C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 -CH=CHCH2-, -CH=CHCHO-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0130] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more carbon-carbon triple bonds, although in one embodiment, 1, 2, 3, or 4 carbon-carbon triple bonds, and in another embodiment, 1 carbon-carbon triple bond. An alkynyl group does not contain a carbon-carbon double bond. An alkynyl may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, alkynyl is a cyclic alkyl group having 2 to 20 (C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6 ) straight-chain monovalent hydrocarbon radical having 4 to 20 (C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ), or 4 to 6 (C 4-6) carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomers such as 1-propynyl (-C≡CCH) and propargyl (-CHC≡CH)), butynyl (including all isomers such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomers such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers such as 1-hexyn-1-yl and 2-hexyn-1-yl).

[0131] The terms "alkynylene" and "alkynediyl" are used interchangeably herein and refer to a straight or branched chain divalent hydrocarbon radical containing one or more carbon-carbon triple bonds, but in one embodiment containing 1, 2, 3, or 4 carbon-carbon triple bonds, and in another embodiment containing one carbon-carbon triple bond. An alkynylene group does not contain a carbon-carbon double bond. An alkynediyl may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, alkynediyl refers to a hydrocarbon radical having 2 to 30 (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6 ) straight-chain divalent hydrocarbon radical having 4 to 30 (C 4-30 ), 4~20(C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ), or 4 to 6 (C 4-6) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomers such as 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomers such as 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomers such as 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomers such as 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).

[0132] The terms "heteroalkynylene" and "heteroalkynediyl" are used interchangeably herein and refer to a straight- or branched-chain divalent hydrocarbon radical containing one or more carbon-carbon triple bonds, but in one embodiment containing 1, 2, 3, or 4 carbon-carbon triple bonds, and in another embodiment containing one carbon-carbon triple bond, and one or more heteroatoms independently selected from O, S, and N in the backbone. A heteroalkynylene group does not contain a carbon-carbon double bond. A heteroalkynylene may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, heteroalkynylene is a heteroalkynylene having 2 to 30 (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2 to 6 (C 2-6 ) straight-chain divalent hydrocarbon radical having 4 to 30 (C 4-30 ), 4~20(C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ), or 4 to 6 (C 4-6) carbon atoms. Examples of heteroalkynylene groups include, but are not limited to, -C≡CCH2O-, -C≡CCH2S-, or -C≡CCH2NH-.

[0133] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical, optionally substituted with one or more substituents Q as described herein. In one embodiment, a cycloalkyl is a saturated or unsaturated, but not aromatic, and / or bridged or unbridged, and / or fused bicyclic group. In certain embodiments, a cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. In one embodiment, a cycloalkyl is monocyclic. In another embodiment, a cycloalkyl is bicyclic. In yet another embodiment, a cycloalkyl is tricyclic. In yet another embodiment, a cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0134] As used herein, the terms "cycloalkylene" and "cycloalkanediyl" refer to a cyclic divalent hydrocarbon radical, optionally substituted with one or more substituents Q as defined herein, and can be used interchangeably. In one embodiment, the cycloalkanediyl group may be saturated or unsaturated, but not aromatic, and / or bridged, and / or unbridged, and / or fused bicyclic groups. In certain embodiments, the cycloalkanediyl group is a cyclic group having 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkanediyl groups include cyclopropanediyl (including all isomers such as cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomers such as cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomers such as cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomers such as cyclohexane-1,1-diyl, cyclohexane-1,2-diyl and cyclohexane-1,3-diyl), and the like. cyclohexane-1,4-diyl, cyclohexanediyl, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohexane-1,4-diyl), cycloheptanediyl (including all isomers such as cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (including all isomers such as decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantodiyl (including all isomers such as adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0135] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical containing at least one aromatic carbocyclic ring. In certain embodiments, an aryl group is a monovalent aromatic hydrocarbon radical having 6 to 20 (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbocycles, where one ring is aromatic and the other rings can be saturated, partially unsaturated, or aromatic. Examples include dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, an aryl is monocyclic. In another embodiment, an aryl is bicyclic. In yet another embodiment, an aryl is tricyclic. In yet another embodiment, an aryl is polycyclic. In certain embodiments, an aryl may be optionally substituted with one or more substituents Q as described herein.

[0136] As used herein, the terms "arylene" and "arenediyl" refer to a divalent monocyclic aromatic hydrocarbon radical or a divalent polycyclic aromatic hydrocarbon radical containing at least one aromatic hydrocarbon ring, and can be used interchangeably. In certain embodiments, an arylene is a divalent aromatic hydrocarbon radical having 6 to 20 (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10Examples of arylene groups include phenylene (including all isomers such as phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomers such as naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomers such as fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulenylene (including all isomers such as azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), anthrylene (including all isomers such as anthra-1,2-diyl, anthra-1,3-diyl, and anthra-1, Arylene includes, but is not limited to, phenanthrylene (including all isomers such as phenanthri-1,2-diyl, phenanthri-1,3-diyl, and phenanthri-1,8-diyl), pyrenylene (including all isomers such as pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomers such as biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (including all isomers such as terphen-2,3-diyl, terphen-3,4'-diyl, and terphen-4,4'-diyl). Arylene also refers to a bicyclic or tricyclic carbocyclic ring, where one ring is aromatic and the other ring can be saturated, partially unsaturated, or aromatic. Examples include dihydronaphthylene (including all isomers such as dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomers such as indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanylene (including all isomers such as indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), and tetrahydronaphthylene (tetralinylene) (including all isomers such as tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl).In certain embodiments, arylene may be optionally substituted with one or more substituents Q as described herein.

[0137] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, an aralkyl is a monovalent alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomers such as 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomers such as 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, aralkyls may be optionally substituted with one or more substituents Q as described herein.

[0138] The term "aralkylene" or "arylalkylene" refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene is a divalent alkyl group having 7 to 30 (C 7-30 ), 7~20(C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomers such as phenylmethodiyl), phenylethylene (including all isomers such as 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (including all isomers such as 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, aralkylene may be optionally substituted with one or more substituents Q as described herein.

[0139] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, within the ring. In the case of a heteroaryl group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not connected to the rest of the molecule through the non-aromatic heterocyclic ring. Each ring of the heteroaryl may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, a heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomers of furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomers of furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), and imidazopyridinyl (including all isomers of furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl). [1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl, including all isomers thereof), imidazothiazolyl (including all isomers thereof, such as imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and all its isomers), oxazolopyridinyl (including all its isomers such as oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all its isomers such as pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl (q In another embodiment, heteroaryl is a tricyclic heteroaryl. Examples of heteroaryl include, but are not limited to, thiadiazolopyrimidyl (including all isomers such as [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomers such as thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In another embodiment, heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl (1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,Examples of heteroaryl include, but are not limited to, 10-phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0140] As used herein, the terms "heteroarylene" and "heteroarenediyl" refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group containing at least one aromatic ring, and may be used interchangeably, where the at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N within the ring. In the case of a heteroarylene group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of the molecule through the non-aromatic heterocyclic ring. Each ring of the heteroarylene group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolidinyl, thienediyl, tetrazolidinyl, triazinediyl, and triazolediyl. Examples of bicyclic heteroarylene groups include benzofurandiyl, benzimidazolediyl, benzoisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothienediyl, benzotriazolediyl, benzoxazolediyl, furopyridinediyl (furo[2,3-b]pyridinediyl, furo[2,3-c]pyridinediyl, furo[3,2-b]pyridinediyl, furo[ 3,2-c]pyridinediyl, furo[3,4-b]pyridinediyl, and furo[3,4-c]pyridinediyl, including all isomers thereof), imidazopyridinediyl (including all isomers thereof, such as imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl, and imidazo[4,5-c]pyridinediyl), imidazothiazoldiyl (including all isomers thereof, such as imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothienediyl (i.e., benzo[c]thienediyl), isoindolediyl, isoquinolinediyl, naphthyridinediyl (including all isomers of 1,5-naphthyridinediyl, 1,6-naphthyridinediyl, 1,7-naphthyridinediyl, and 1,8-naphthyridinediyl), oxazolopyridinediyl (including all isomers of oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl, and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purindiyl Examples of thiadiazolopyrimidinediyl include, but are not limited to, pyrrolopyridinediyl (including all isomers of pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2-b]pyridinediyl, and pyrrolo[3,2-c]pyridinediyl), quinolinediyl, quinoxalinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomers of [1,2,5]thiadiazolo[3,4-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl), and thienopyridinediyl (including all isomers of thieno[2,3-b]pyridinediyl, thieno[2,3-c]pyridinediyl, thieno[3,2-b]pyridinediyl, and thieno[3,2-c]pyridinediyl). Examples of tricyclic heteroarylene groups include acridinediyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,Examples of heteroarylenes include, but are not limited to, 10-phenanthrolinediyl (including all isomers thereof, such as 10-phenanthrolinediyl), phenanthridinediyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazinediyl, and xanthendiyl. In certain embodiments, heteroarylenes may be optionally substituted with one or more substituents Q as described herein.

[0141] The terms "heterocyclyl" or "heterocyclic" refer to a monovalent non-aromatic monocyclic ring system or monovalent polycyclic ring system containing at least one non-aromatic ring, where one or more non-aromatic ring atoms are heteroatoms, each heteroatom being independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In heterocyclyl groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heterocyclyl group is not attached to the rest of the molecule through a heteroaromatic ring. In certain embodiments, a heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl can be attached to any heteroatom or carbon atom of the main structure to form a stable compound.Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomers of 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrofuryl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyri Examples of heterocyclyl include, but are not limited to, imidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclyl may be optionally substituted with one or more substituents Q as described herein.

[0142] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, where one or more non-aromatic ring atoms are heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms. In heterocyclylene groups containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heterocyclylene group is attached to the remainder of the molecule through at least one bond in the non-aromatic heterocyclic ring. In certain embodiments, heterocyclylene groups have 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclylene may be attached at any heteroatom or carbon atom of the main structure which results in the creation of a stable compound.Examples of such heterocyclic groups include azepinediyl, benzodioxanediyl, benzodioxoldiyl, benzofuranonediyl, chromandiyl, decahydroisoquinolinediyl, dihydrobenzofurandiyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomers of 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl, and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofuldiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dioxolanediyl, 1,4-dihydrobenzo[d][1,3]oxazinediyl, These include, but are not limited to, dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolinediyl, isochromandiyl, isoindolinediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolinediyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofuldiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothienediyl, thiamorpholinediyl, thiazolidinediyl, thiochromandiyl, tetrahydroquinolinediyl, and 1,3,5-trithianediyl. In certain embodiments, heterocyclylene may be optionally substituted with one or more substituents Q as described herein.

[0143] "Halogen," "halide," or "halo" refers to fluorine, chlorine, bromo, and / or iodo.

[0144] The term "optionally substituted" means that a group or substituent, such as an alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, can be substituted with one or more (in one embodiment, 1, 2, 3, or 4) substituents Q. Each substituent can be any of, for example, (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO), and oxo (=O); (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which may further contain any one or more (in one embodiment, 1, 2, 3, or 4) substituents Q a and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b Rc , -OP(O)(OR b ) OR c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -P(O)R b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c , where each R is independently selected from a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q a or (iii) R b and R c together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three or four) substituents Q a As used herein, any group that can be substituted is "optionally substituted."

[0145] In one embodiment, each Q a are (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NRf R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OP(O)(OR f ) OR g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -P(O)R f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g and -S(O)NR f R g and each R in (c) is independently selected from e, R f , R g and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom attached to them form a heterocyclyl.

[0146] In certain embodiments, "optically active" and "enantiomeric activity" refer to a collection of molecules having an enantiomeric excess of about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In certain embodiments, an optically active compound contains about 95% or greater of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the mixture of enantiomers under consideration. In certain embodiments, an optically active compound contains about 98% or greater of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the mixture of enantiomers under consideration. In certain embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the mixture of enantiomers under consideration.

[0147] When describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the compound's chiral centers. The prefixes (+) and (-) are used to denote the compound's optical rotation, i.e., the direction in which the plane of polarized light is rotated by the optically active compound. The prefix (-) denotes that the compound has levorotatory power, meaning that the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) denotes that the compound has dextrorotatory power, meaning that the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation (+) and (-) has no bearing on the absolute configuration (R and S) of the compound.

[0148] The terms "substantially pure" and "substantially homogeneous," in the case of a substance, mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties (e.g., enzymatic and biological activity) of the substance. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a population of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound (including a single enantiomer, a racemic mixture, or a mixture of enantiomers), as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular rare isotope, molecules containing an atom other than the designated isotope at the designated position are impurities to the isotopically enriched compound. Thus, for a deuterated compound having an atom designated as deuterium at a particular position, a compound containing protium at the same position is an impurity.

[0149] For divalent groups described herein, the direction of the divalent group does not imply orientation. For example, unless a specific direction is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-. Carbohydrate-oligonucleotide conjugates

[0150] In one embodiment, the invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group and two oligonucleotides.

[0151] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, two oligonucleotides, and a trivalent linker.

[0152] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, two oligonucleotides, and two bivalent linkers.

[0153] In certain embodiments, the two oligonucleotides are identical. In certain embodiments, the two oligonucleotides are different.

[0154] In certain embodiments, each of the two oligonucleotides is a single-stranded oligonucleotide. In certain embodiments, each of the two oligonucleotides is a double-stranded oligonucleotide.

[0155] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker or first and second bivalent linkers, wherein the ASGPR-binding group is connected to an end of the first sense or antisense sequence and an end of the second sense or antisense sequence via the trivalent linker, or the ASGPR-binding group is connected to an end of the first sense or antisense sequence via the first bivalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to an end of the second sense or antisense sequence via the second bivalent linker.

[0156] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first sense or antisense sequence and an end of the second sense or antisense sequence via the trivalent linker.

[0157] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first sense sequence and an end of the second sense sequence via the trivalent linker.

[0158] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first antisense sequence and an end of the second sense sequence via the trivalent linker.

[0159] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first sense sequence and an end of the second antisense sequence via the trivalent linker.

[0160] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to an end of the first antisense sequence and an end of the second antisense sequence via the trivalent linker.

[0161] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR-binding group is connected to the 5'-end of the first sense or antisense sequence and the 5'-end of the second sense or antisense sequence via the trivalent linker.

[0162] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to the 5'-end of the first sense sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0163] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to the 5'-end of the first antisense sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0164] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR-binding group is connected to the 5'-end of the first sense sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0165] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR-binding group is connected to the 5'-end of the first antisense sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0166] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first sense or antisense sequence and the 5'-end of the second sense or antisense sequence via the trivalent linker.

[0167] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to the 3'-end of the first sense sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0168] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first antisense sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0169] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to the 3'-end of the first sense sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0170] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first antisense sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0171] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first sense or antisense sequence and the 3'-end of the second sense or antisense sequence via the trivalent linker.

[0172] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR binding group is connected to the 3'-end of the first sense sequence and the 3'-end of the second sense sequence via the trivalent linker.

[0173] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first antisense sequence and the 3'-end of the second sense sequence via the trivalent linker.

[0174] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first sense sequence and the 3'-end of the second antisense sequence via the trivalent linker.

[0175] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising first sense and antisense sequences, a second oligonucleotide double-stranded structure comprising second sense and antisense sequences, and a trivalent linker, wherein the ASGPR-binding group is connected to the 3'-end of the first antisense sequence and the 3'-end of the second antisense sequence via the trivalent linker.

[0176] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to an end of the first sense or antisense sequence via the first bivalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to an end of the second sense or antisense sequence via a second bivalent linker.

[0177] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR binding group is connected to an end of the first sense sequence via the first bivalent linker, and one of the remaining ends of the first sense sequence is connected to an end of the second sense sequence via a second bivalent linker.

[0178] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to an end of the first antisense sequence via the first bivalent linker, and one of the remaining ends of the first antisense sequence is connected to an end of the second sense sequence via a second bivalent linker.

[0179] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to an end of the first sense sequence via the first bivalent linker, and one of the remaining ends of the first sense sequence is connected to an end of the second antisense sequence via a second bivalent linker.

[0180] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to an end of the first antisense sequence via the first bivalent linker, and one of the remaining ends of the first antisense sequence is connected to an end of the second antisense sequence via a second bivalent linker.

[0181] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to the 5'-end of the first sense or antisense sequence via the first bivalent linker, and the 3'-end of the first sense or antisense sequence is connected to the 5'-end of the second sense or antisense sequence via the second bivalent linker.

[0182] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to the 5'-end of the first sense sequence via the first bivalent linker, and the 3'-end of the first sense sequence is connected to the 5'-end of the second sense sequence via the second bivalent linker.

[0183] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to the 5'-end of the first antisense sequence via the first bivalent linker, and the 3'-end of the first antisense sequence is connected to the 5'-end of the second sense sequence via the second bivalent linker.

[0184] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to the 5'-end of the first sense sequence via the first bivalent linker, and the 3'-end of the first sense sequence is connected to the 5'-end of the second antisense sequence via the second bivalent linker.

[0185] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR-binding group, a first oligonucleotide double-stranded structure comprising a first sense and antisense sequence, a second oligonucleotide double-stranded structure comprising a second sense and antisense sequence, and first and second bivalent linkers, wherein the ASGPR-binding group is connected to the 5'-end of the first antisense sequence via the first bivalent linker, and the 3'-end of the first antisense sequence is connected to the 5'-end of the second antisense sequence via the second bivalent linker.

[0186] In certain embodiments, each oligonucleotide double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention is independently a double-stranded oligodeoxyribonucleotide or oligoribonucleotide.In certain embodiments, each oligonucleotide double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention is independently a double-stranded oligodeoxyribonucleotide.In certain embodiments, each oligonucleotide double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention is independently a double-stranded oligoribonucleotide.In certain embodiments, each oligonucleotide double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention is independently an siRNA.

[0187] In certain embodiments, each strand of the first oligonucleotide duplex structure in the carbohydrate-oligonucleotide conjugates provided by the present invention independently contains about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex structure in the carbohydrate-oligonucleotide conjugates provided by the present invention independently contains about 10 to about 50 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex structure in the carbohydrate-oligonucleotide conjugates provided by the present invention independently contains about 10 to about 30 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex structure in the carbohydrate-oligonucleotide conjugates provided by the present invention independently contains about 15 to about 25 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex structure in the carbohydrate-oligonucleotide conjugates provided by the present invention independently contains about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0188] In certain embodiments, each strand of the second oligonucleotide duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently contains about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently contains about 10 to about 50 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently contains about 10 to about 30 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently contains about 15 to about 25 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently contains about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0189] In certain embodiments, the first oligonucleotide duplex structure is a double-stranded siRNA. In certain embodiments, each strand of the first siRNA duplex structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, each strand of the first siRNA duplex structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 10 to about 50 nucleotides. In certain embodiments, each strand of the first siRNA duplex structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 10 to about 30 nucleotides. In certain embodiments, each strand of the first siRNA duplex structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 15 to about 25 nucleotides. In certain embodiments, each strand of the first siRNA double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0190] In certain embodiments, the second oligonucleotide duplex structure is a double-stranded siRNA. In certain embodiments, each strand of the second siRNA duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, each strand of the second siRNA duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently comprises about 10 to about 50 nucleotides. In certain embodiments, each strand of the second siRNA duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently comprises about 10 to about 30 nucleotides. In certain embodiments, each strand of the second siRNA duplex structure in the carbohydrate-oligonucleotide complexes provided by the present invention independently comprises about 15 to about 25 nucleotides. In certain embodiments, each strand of the second siRNA double-stranded structure in the carbohydrate-oligonucleotide complex provided by the present invention independently comprises about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0191] In certain embodiments, each nucleotide in each strand of the first siRNA double-stranded structure is independently natural nucleotide or modified nucleotide.In certain embodiments, natural nucleotide includes adenylic acid (a), cytidylic acid (c), guanylic acid (g) and uridylic acid (u).In certain embodiments, modified nucleotide means that the nucleotide that is modified occurs in the nucleic acid base, sugar group and / or phosphate linkage group of nucleotide. Examples of modified nucleotides include, but are not limited to, 2'-fluoroadenosine (fA), 2'-fluorocytidine (fC), 2'-fluoroguanosine (fG), 2'-fluorouridine (fU), 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), 2'-deoxycytidine (dC), 2'-deoxythymidine (dT), 2'-O-methyladenosine (A), 2'-O-methylcytidine (C), 2'-O-methylguanosine (G), or 2'-O-methyluridine (U). In certain embodiments, each nucleotide in each strand of the first siRNA double-stranded structure is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine or 2'-O-methyluridine.In certain embodiments, each strand of the first siRNA double-stranded structure has one or more phosphate linkages replaced with phosphorothioate or phosphorodithioate.

[0192] In certain embodiments, each nucleotide in each strand of the second siRNA double-stranded structure is independently natural nucleotide or modified nucleotide.In certain embodiments, each nucleotide in each strand of the second siRNA double-stranded structure is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine or 2'-O-methyluridine.In certain embodiments, each strand of the second siRNA double-stranded structure has one or more phosphate binding groups replaced with phosphorothioate or phosphorodithioate.

[0193] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker or first and second bivalent linkers, wherein the ASGPR binding group is connected to one end of the first oligonucleotide and one end of the second oligonucleotide via the trivalent linker, or the ASGPR binding group is connected to one end of the first oligonucleotide via the first bivalent linker and the other end of the first oligonucleotide is connected to one end of the second oligonucleotide via the second bivalent linker.

[0194] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker, wherein the ASGPR binding group is connected to the 5'-end of the first oligonucleotide and the 5'-end of the second oligonucleotide via the trivalent linker.

[0195] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker, wherein the ASGPR binding group is connected to the 3'-end of the first oligonucleotide and the 5'-end of the second oligonucleotide via the trivalent linker.

[0196] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and a trivalent linker, wherein the ASGPR binding group is connected to the 3'-end of the first oligonucleotide and the 3'-end of the second oligonucleotide via the trivalent linker.

[0197] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and first and second bivalent linkers, wherein the ASGPR binding group is connected to one end of the first oligonucleotide via the first bivalent linker, and the other end of the first oligonucleotide is connected to one end of the second oligonucleotide via the second bivalent linker.

[0198] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and first and second bivalent linkers, wherein the ASGPR binding group is connected to the 5'-end of the first oligonucleotide via the first bivalent linker, and the 3'-end of the first oligonucleotide is connected to the 5'-end of the second oligonucleotide via the second bivalent linker.

[0199] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, first and second single-stranded oligonucleotides, and first and second bivalent linkers, wherein the ASGPR binding group is connected to the 3'-end of the first oligonucleotide via the first bivalent linker, and the 5'-end of the first oligonucleotide is connected to the 3'-end of the second oligonucleotide via the second bivalent linker.

[0200] In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide complex provided by the present invention is independently a single-stranded oligodeoxyribonucleotide or oligoribonucleotide.In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide complex provided by the present invention is independently a single-stranded oligodeoxyribonucleotide.In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide complex provided by the present invention is independently a single-stranded oligoribonucleotide.In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide complex provided by the present invention can independently be ASO, miRNA, mRNA, or tRNA.

[0201] In certain embodiments, the first single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention is a ribonucleotide. In certain embodiments, the first single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, the first single-stranded oligonucleotide comprises about 10 to about 50 nucleotides. In certain embodiments, the first single-stranded oligonucleotide comprises about 10 to about 30 nucleotides. In certain embodiments, the first single-stranded oligonucleotide comprises about 15 to about 25 nucleotides. In certain embodiments, the first single-stranded oligonucleotide comprises about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0202] In certain embodiments, the second single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention is a ribonucleotide. In certain embodiments, the second single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides. In certain embodiments, the second single-stranded oligonucleotide comprises about 10 to about 50 nucleotides. In certain embodiments, the second single-stranded oligonucleotide comprises about 10 to about 30 nucleotides. In certain embodiments, the second single-stranded oligonucleotide comprises about 15 to about 25 nucleotides. In certain embodiments, the second single-stranded oligonucleotide comprises about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0203] In certain embodiments, each nucleotide in the first single-stranded oligonucleotide is independently natural nucleotide or modified nucleotide.In certain embodiments, each nucleotide in the first single-stranded oligonucleotide is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine or 2'-O-methyluridine.In certain embodiments, one or more phosphate linking groups in the first single-stranded oligonucleotide are replaced with phosphorothioate or phosphorodithioate.

[0204] In certain embodiments, each nucleotide in the second single-stranded oligonucleotide is independently natural nucleotide or modified nucleotide.In certain embodiments, each nucleotide in the second single-stranded oligonucleotide is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine or 2'-O-methyluridine.In certain embodiments, one or more phosphate linkage groups of the second single-stranded oligonucleotide are replaced with phosphorothioate or phosphorodithioate.

[0205] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the invention, the ASGPR binding group comprises one or more molecules, each molecule independently having the following structure: [ka] ; Here, each R as are independently -OH, -NHC(O)H, or -NHCO(CH2) a CH3 and a is an integer of 0, 1, 2, 3, or 4.

[0206] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises one or more N-acetylgalactosamines (GalNAc). In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 1 to about 10 or about 1 to about 6 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 1 to about 10 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 1 to about 6 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 1, about 2, about 3, about 4, or about 5 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 1 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 2 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 3 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 4 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises about 5 GalNAc.

[0207] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group has the structure of formula (AI): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers, where E a and b are, respectively, (i) b is an integer of 1, and E a is a bond; (ii) b is an integer of 2, and E a is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; or (iii) b is an integer of 3, and E a is (i) C; or (ii) tetravalent C 1-6 Alkenyl, tetravalent C 3-10 Cycloalkyl, tetravalent C 6-14 aryl, tetravalent heteroaryl, or tetravalent heterocyclyl, each of which is substituted with one or more substituents Q; Each L a is an independent linker.

[0208] In one embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-II): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers, where E a is a bond and L a is the linker.

[0209] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-III): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers, where E a is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; and each L a are independently linkers.

[0210] In certain embodiments, in formula (A-III), E a is CH or N. In certain embodiments, in formula (A-III), E a is CH. In certain embodiments, in formula (A-III), E a is N.

[0211] In certain embodiments, in formula (A-III), E a is trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III), E a is trivalent C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III), E a is CR m where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in formula (A-III), E is aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more Q. a is CR m where R m is C 1-6 alkyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-III), E a is trivalent C 1-6 alkenyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III), E a is trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III), E a is trivalent C 6-14 aryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III), E a is a trivalent heteroaryl, each optionally substituted with one or more substituents Q.

[0212] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-IV): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers thereof, where E a is (i) C; or (ii) tetravalent C 1-6 Alkenyl, tetravalent C 3-10 Cycloalkyl, tetravalent C 6-14 aryl, tetravalent heteroaryl, or tetravalent heterocyclyl, each of which is substituted with one or more substituents Q; and each La are independently linkers.

[0213] In certain embodiments, in formula (A-IV), E a is C. In certain embodiments, in formula (A-IV), E a is tetravalent C 1-6 alkenyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-IV), E a is tetravalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-IV), E a is tetravalent C 6-14 aryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-IV), E a is a tetravalent heteroaryl, each optionally substituted with one or more substituents Q.

[0214] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group is [ka] JPEG2025531341000046.jpg207169 JPEG2025531341000047.jpg112169 is.

[0215] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group is [ka] JPEG2025531341000049.jpg121169 is.

[0216] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group is [ka] is.

[0217] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group has the structure of formula (AV): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers, where E b and c are, respectively, (i) c is an integer of 1, and E b is a bond; (ii) c is an integer of 2, and E b is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C (1-6) Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; or (iii) c is an integer of 3, and E b is (i) C; or (ii) tetravalent C 1-6 Heteroalkyl, tetravalent C 1-6 Alkenyl, tetravalent C 3-10 Cycloalkyl, tetravalent C 6-14 aryl, tetravalent heteroaryl, or tetravalent heterocyclyl, each of which is substituted with one or more substituents Q; E c and d are, respectively, (i) d is an integer of 1, and E c is a bond; (ii) d is an integer of 2, and E c is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; or (iii) d is an integer of 3, and E c is (i) C; or (ii) tetravalent C 1-6 Heteroalkyl, tetravalent C 1-6 Alkenyl, tetravalent C 3-10 Cycloalkyl, tetravalent C 6-14 aryl, tetravalent heteroaryl, or tetravalent heterocyclyl, each of which is substituted with one or more substituents Q; G is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; and Each L b and L c are each independently a linker.

[0218] In one embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-VI): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; E bis (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; E c is a bond, G is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; Each L b and L c is an independent linker.

[0219] In certain embodiments, in formula (A-VI), E b is CH or N. In certain embodiments, in formula (A-VI), E b is CH. In certain embodiments, in formula (A-VI), E b is N.

[0220] In certain embodiments, in formula (A-VI), E b is trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b are trivalent C groups each substituted with one or more substituents Q 1-6 In certain embodiments, in formula (A-VI), E b is CRm where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-VI), E b is CR m where R m is C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is C(CH). In certain embodiments, in formula (A-VI), E b is trivalent C 1-6 heteroalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is trivalent C 1-6 alkenyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is trivalent C 6-14 aryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is a trivalent heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), E b is a trivalent heterocyclyl, each of which is optionally substituted with one or more substituents Q.

[0221] In certain embodiments, in formula (A-VI), G is CH or N. In certain embodiments, in formula (A-VI), G is CH. In certain embodiments, in formula (A-VI), G is N.

[0222] In certain embodiments, in formula (A-VI), G is a trivalent C 1-6 Alkyl, C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 In certain embodiments, in formula (A-VI), G is a trivalent C 1-6 alkyl, each of which may be substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), G is CR m where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in formula (A-VI), G is CR m where R m is C 1-6 In certain embodiments, in formula (A-VI), G is C(CH). In certain embodiments, in formula (A-VI), G is trivalent C(CH). 1-6 In certain embodiments, in formula (A-VI), G is a trivalent C 1-6 alkenyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VI), G is a trivalent C 6-14aryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is a trivalent heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is a trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0223] In certain embodiments, in formula (A-VI), E b is CH or N; G is CH or N.

[0224] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-VII): [ka] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers, wherein: E b and E c are each independently (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; G is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q; Each L b and Lc are independent linkers.

[0225] In certain embodiments, in formula (A-VII), E b is CH or N. In certain embodiments, in formula (A-VII), E b In certain embodiments, in formula (A-VII), E b is N.

[0226] In certain embodiments, in formula (A-VII), E b is trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is trivalent C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is CR m where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-VII), E b is CR m where R m is C 1-6 alkyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-VII), E b is C(CH). In certain embodiments, in formula (A-VII), E b is trivalent C 1-6Heteroalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is trivalent C 1-6 alkenyl, each of which may be substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is trivalent C 6-14 aryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is a trivalent heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E b is a trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0227] In certain embodiments, in formula (A-VII), E c is CH or N. In certain embodiments, in formula (A-VII), E c In certain embodiments, in formula (A-VII), E c is N.

[0228] In certain embodiments, in formula (A-VII), E c is trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is trivalent C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is CR m where R m is C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-VII), E c is CR m where R m is C 1-6 alkyl, each of which is optionally substituted with one or more Q. In certain embodiments, in formula (A-VII), E c is C(CH). In certain embodiments, in formula (A-VII), E c is trivalent C 1-6 Heteroalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is trivalent C 1-6 alkenyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is trivalent C 6-14 aryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is a trivalent heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), E c is a trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0229] In certain embodiments, G in formula (A-VII) is CH or N. In certain embodiments, G in formula (A-VII) is CH. In certain embodiments, G in formula (A-VII) is N.

[0230] In certain embodiments, in formula (A-VII), G is a trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C (6-14) In certain embodiments, in formula (A-VII), G is a trivalent C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), G is CR m where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in formula (A-VII), G is CR m where R m is C 1-6 In certain embodiments, in formula (A-VII), G is C(CH). In certain embodiments, in formula (A-VII), G is trivalent C(CH). 1-6 In certain embodiments, in formula (A-VII), G is a trivalent C 1-6 alkenyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), G is a trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), G is a trivalent C 6-14aryl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), G is a trivalent heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-VII), G is a trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0231] In certain embodiments, in formula (A-VII), E b is CH or N, E c is CH or N; G is CH or N.

[0232] In certain embodiments, in any of formulas (AV) to (A-VII), E b teeth, [ka] is. In certain embodiments, in any of formulas (AV) to (A-VII), E b teeth [ka] is.

[0233] In certain embodiments, in any of formulas (AV) to (A-VII), E c teeth, [ka] In certain embodiments, in formula (AV) or (A-VII), E c is N, [ka] is.

[0234] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group is [ka] JPEG2025531341000059.jpg219169 JPEG2025531341000060.jpg66169 is.

[0235] In certain embodiments, in any of formulas (AI) to (A-IV), each L a is independently a cleavable or non-cleavable linker. In certain embodiments, in any of Formulas (AI) through (A-IV), each L a are each independently cleavable linkers. In certain embodiments, in any of formulas (AI) to (A-IV), each L a is an independently non-cleavable linker.

[0236] In certain embodiments, in any of formulas (AI) to (A-IV), each L a are each independently a cleavable linker that is sensitive to acidic pH. In certain embodiments, in any of formulas (AI) to (A-IV), each L( a ) is independently a cleavable linker comprising a reducible disulfide. In certain embodiments, in any of Formulas (AI) through (A-IV), each L a are independently linkers cleavable by glutathione. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently enzymatically cleavable linkers. In certain embodiments, in any of formulas (AI) through (A-IV), each L a are independently protease-cleavable linkers. In certain embodiments, in any of formulas (AI) to (A-IV), each L aare linkers cleavable by lysosomal proteases. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently linkers cleavable by cathepsin B. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently galactosidase-cleavable linkers. In certain embodiments, in any of formulas (AI) through (A-IV), each L a are independently β-galactosidase-cleavable linkers. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are linkers that are independently cleaved by glucuronidase. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently linkers cleaved by β-glucuronidase. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently glucuronidase-cleavable linkers. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently β-glucuronidase-cleavable linkers. In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independently phosphatase-cleavable linkers.

[0237] In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently cleavable linkers that are sensitive to acidic pH. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently cleavable linkers comprising a reducible disulfide. In certain embodiments, in any of formulas (AV) through (A-VII), each L b and L care independently linkers cleavable by glutathione. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently enzymatically cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently protease-cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently cleavable by a lysosomal protease. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently linkers cleavable by cathepsin B. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently galactosidase-cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently β-galactosidase-cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently glucuronidase-cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently β-glucuronidase cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently glucuronidase-cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L care independently β-glucuronidase cleavable linkers. In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independently phosphatase-cleavable linkers.

[0238] In certain embodiments, in any of formulas (AI) to (A-IV), each L a independently -Z n -(R n -Z n ) z - a linker having the structure: Each R n independently, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q; each Z n are independently a bond, -C(O)-, -C(O)O-, or -C(O)NR 1b -, -C(O)S-, -C(NR 1a )NR 1b -, -C(S)-, -C(S)O-, -C(S)NR 1b -, -C(R 1a )=NO-, -O-, -OC(O)O-, -OC(O)NR 1b -, -OC(O)S-, -OC(NR 1a )NR 1b -, -OC(S)O-, -OC(S)NR 1b -, -OP(O2)-, -OP(O)(S)-, -OP(O2)O-, -OP(O)(S)O-, -OP(O2)S-, -OS(O)-, -OS(O)2-, -OS(O)NR 1b -,-OS(O)2NR 1b -, -NR 1b -, -NR 1a C(O)NR 1b -, -NR 1a C(O)S-, -NR 1a C(NR1d )NR 1b -, -NR 1a C(S)NR 1b -, -NR 1a S(O)NR 1b -, -NR 1a S(O)NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)NR 1b - and; Each R 1a , R 1b , R 1c and R 1d are independently (i) hydrogen or deuterium; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0239] In certain embodiments, each L in any of formulas (AV)-(A-VII) b independently -Z n -(R n -Z n ) z -, where each R n , Z n , and z are as defined herein.

[0240] In certain embodiments, each L in any of formulas (AV)-(A-VII) c independently -Z n -(R n -Z n ) z -, where each R n , Zn , and z are as defined herein.

[0241] In certain embodiments, each R n independently C 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q; each Z n are independently a bond, -C(O)-, or -C(O)NR 1b -, -OC(NR 1a )NR 1b -, -O-, -OC(O)NR 1b -, -OP(O2)-, -OP(O)(S)-, -NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR 1b and z is an integer of 0, 1, 2, 3, 4, 5, or 6; where each R 1a , R 1b and R 1d is as defined herein.

[0242] In certain embodiments, each R n independently C 1-10 Alkylene, C 2-10 Alkynylene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene, each of which is substituted with one or more substituents Q; each Z n are independently a bond, -C(O)-, or -C(O)NR 1b -, -O-, -OC(O)NR 1b -, -OP(O2)-, -OP(O)(S)-, -NR 1b -, -P(O2)O-, -P(O)(S)O-, -S(O)2-, or -S(O)2NR 1b z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; 1a , R 1b and R1d is as defined herein.

[0243] In certain embodiments, each R n are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, propynediyl, pentynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinediyl, azetidinediyl, 1,3-dioxanediyl, pyrrolidinediyl, piperazinediyl, piperidinediyl, or 3,9-diazaspiro[5. 5]undecanediyl, each of which is substituted with one or more substituents Q. In certain embodiments, each R nare independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, diyl, ethyne-1,2-diyl, propyne-1,3-diyl, 1-pentyne-1,5-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, cycloheptane-1,4-diyl, bicyclo[2.2.2]octane-1,4-diyl, phen-1 ,3-diyl, phen-1,4-diyl, pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, pyrazolidine-1,3-diyl, pyrazolidine-1,4-diyl, azetidine-1,3-diyl, 1,3-dioxane-2,5-diyl, pyrrolidine-1,3-diyl, piperazine-1,4-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, or 3,9-diazaspiro[5.5]-undecane-3,9-diyl, each optionally substituted with one or more substituents Q.

[0244] In certain embodiments, each R n is independently methanediyl, cyclopropylmethanediyl, ethanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, ethynediyl, propynediyl, pentynediyl, azetidinediyl, pyrrolidinediyl, piperazinediyl, or piperidinediyl. nare independently methanediyl, cyclopropylmethanediyl, ethane-1,2-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, ethyne-1,2-diyl, propyne-1,3-diyl, 1-pentyne-1,5-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperazine-1,4-diyl, or piperidine-1,4-diyl.

[0245] In certain embodiments, each R n independently C 1-10 Alkylene, C 6-14 arylene, or heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each R n is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, or 1,2,3-triazoldiyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, each R n is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, or 1,2,3-triazole-1,4-diyl, each optionally substituted with one or more substituents Q.

[0246] In certain embodiments, each Z n is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH═NO—, —O—, —OP(O₂)—, —OP(O)(S)—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-. In certain embodiments, each Z n are independently a bond, —C(O)NH—, —O—, —OP(O2)—, —OP(O)(S)—, —NH—, —P(O2)O—, or —P(O)(S)O—.

[0247] In certain embodiments, z is the integer 0. In certain embodiments, z is the integer 1. In certain embodiments, z is the integer 2. In certain embodiments, z is the integer 3. In certain embodiments, z is the integer 4. In certain embodiments, z is the integer 5. In certain embodiments, z is the integer 6. In certain embodiments, z is the integer 7. In certain embodiments, z is the integer 8. In certain embodiments, z is an integer of 0, 1, 2, 3, 4, or 5.

[0248] In certain embodiments, each R n are independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, propynediyl, pentynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, phendiyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinediyl, azetidinediyl, 1,3-dioxanediyl, pyrrolidinediyl, piperazinediyl, piperidinediyl, or 3,9-diazaspiro[5. 5]undecanediyl, each of which may be substituted with one or more substituents Q. n are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH═NO—, —O—, —OP(O₂)—, —OP(O)(S)—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-; and z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0249] In certain embodiments, each R nare independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl, tridecane-1,13-diyl, diyl, ethyne-1,2-diyl, propyne-1,3-diyl, 1-pentyne-1,5-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,3-diyl, cycloheptane-1,4-diyl, bicyclo[2.2.2]octane-1,4-diyl, phen-1 ,3-diyl, phen-1,4-diyl, pyrazole-1,3-diyl, pyrazole-1,4-diyl, imidazole-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, pyrazolidine-1,3-diyl , pyrazolidine-1,4-diyl, azetidine-1,3-diyl, 1,3-dioxane-2,5-diyl, pyrrolidine-1,3-diyl, piperazine-1,4-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, or 3,9-diazaspiro[5.5]-undecane-3,9-diyl, each optionally substituted with one or more substituents Q. Each Z n teeth, independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH₃)═NO—, —O—, —OP(O₂)—, —OP(O)(S)—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-; and z is an integer of 0, 1, 2, 3, 4, or 5.

[0250] In certain embodiments, each R nis independently methanediyl, cyclopropylmethanediyl, ethanediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, ethynediyl, propynediyl, pentynediyl, azetidinediyl, pyrrolidinediyl, piperazinediyl, or piperidinediyl. n are independently a bond, —C(O)—, —C(O)NH—, —C(CH₃)═NO—, —O—, —OP(O₂)—, —OP(O)(S)—, —NH—, —N(CH₃)—, —S—, or —S(O)₂—; and z is an integer of 0, 1, 2, 3, 4, or 5.

[0251] In certain embodiments, each R n are independently methanediyl, cyclopropylmethanediyl, ethane-1,2-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, ethyne-1,2-diyl, propyne-1,3-diyl, 1-pentyne-1,5-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperazine-1,4-diyl, or piperidine-1,4-diyl. n are independently a bond, —C(O)—, —C(O)NH—, —C(CH₃)═NO—, —O—, —OP(O₂)—, —OP(O)(S)—, —NH—, —N(CH₃)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-; and z is an integer of 0, 1, 2, 3, 4, or 5.

[0252] In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independent of each other: [ka] .

[0253] In certain embodiments, in any of formulas (AI) to (A-IV), each L a are independent: [ka] .

[0254] In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independent: [ka] .

[0255] In certain embodiments, in any of formulas (AV) to (A-VII), each L b and L c are independent: [ka] .

[0256] In certain embodiments, the trivalent linkers in the carbohydrate-oligonucleotide conjugates provided by the present invention are linkers that independently have the structure: [ka] where M is (i) N or CH; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl, or trivalent heterocyclyl, each of which is optionally substituted with one or more substituents Q; Each R n , Z n and z is as defined herein.

[0257] In certain embodiments, M is N or CH. In certain embodiments, M is N. In certain embodiments, M is CH.

[0258] In certain embodiments, M is a trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 In certain embodiments, M is a trivalent C 1-6 alkyl, each optionally substituted with one or more substituents Q. In certain embodiments, M is CR m where R m is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, M is CR m where R m is C 1-6 In certain embodiments, M is alkyl, each optionally substituted with one or more Q. In certain embodiments, M is C(CH). In certain embodiments, M is trivalent C 1-6 In certain embodiments, M is a trivalent C 1-6 alkenyl, each optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 6-14 In certain embodiments, M is aryl, each optionally substituted with one or more substituents Q. In certain embodiments, M is trivalent heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, M is trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0259] In certain embodiments, each R n independently C 1-10 Alkylene, C 6-14 arylene, heteroarylene, or heterocyclyl, each substituted with one or more substituents Q. In certain embodiments, each R n is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothienediyl, or tetrahydropyrandiyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, each R n is independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,2-diyl, 2,5-dioxopyrrolidine-1,3-diyl, tetrahydrothien-2,5-diyl, or tetrahydropyran-1,3-diyl. n are independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phenyl-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0260] In certain embodiments, each Z n is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —C(CH═NO—, —O—, —OC(O)NH—, —NH—, —N(CH═)—, —OP(O₂)—, —OP(O)(S)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂—. In certain embodiments, each Z nare independently a bond, —C(O)—, —C(O)NH—, —C(CH3)═NO—, —O—, —NH—, —O—P(O2)—, —P(O2)O—, —P(O)(S)O—, or —S—.

[0261] In certain embodiments, each z is independently an integer of 0, 1, 2, 3, 4, or 5. In certain embodiments, each z is independently an integer of 0, 1, 2, 3, or 4. In certain embodiments, each z is independently an integer of 0, 1, 2, or 3.

[0262] In certain embodiments, each R n is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothienediyl, or tetrahydropyrandiyl, each optionally substituted with one, two, or three substituents Q. Each Z n is independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —C(CH═NO—, —O—, —OC(O)NH—, —NH—, —N(CH═)—, —OP(O₂)—, —OP(O)(S)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂—; and each z is independently an integer of 0, 1, 2, 3, 4, or 5.

[0263] In certain embodiments, each R n is independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, tetrahydrothien-2,5-diyl, or tetrahydropyran-1,3-diyl; and each Z nis independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —C(CH═NO—, —O—, —OC(O)NH—, —NH—, —N(CH═)—, —OP(O₂)—, —OP(O)(S)—, —P(O₂)O—, —P(O)(S)O—, —S—, or —S(O)₂-; and each z is independently an integer of 0, 1, 2, 3, or 4.

[0264] In certain embodiments, each R n is independently methanediyl, ethane-1,2-diyl, acetamidoethane-1,2-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl; and each Z n is independently a bond, —C(O)—, —C(O)NH—, —C(CH₃)═NO—, —O—, —NH—, —O₂P(O₂)O—, —P(O₂)O—, —P(O)(S)O—, or —S—; and each Z is independently an integer of 0, 1, 2, or 3.

[0265] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention has the following structure: [ka] JPEG2025531341000067.jpg218169 JPEG2025531341000068.jpg204169 .

[0266] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention has the following structure: [ka] .

[0267] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention has the following structure: [ka] .

[0268] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable or non-cleavable linker. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable linker. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a non-cleavable linker.

[0269] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable linker that is sensitive to acidic pH. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable linker containing a reducible disulfide. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by glutathione. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by an enzyme. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by a protease. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by a lysosomal protease. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by cathepsin B. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by galactosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by β-galactosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by glucuronidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by β-glucuronidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by glucuronidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker cleavable by β-glucuronidase.In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by phosphatase.Example linkers that can be applied to the carbohydrate-oligonucleotide conjugate provided by the present invention include but are not limited to those disclosed in Beck et al., Nat.Rev.Drug Discov.2017,16,317-37; Bargh et al., Chem.Soc.Rev.2019,48,4361-74.The disclosures of these documents are incorporated herein by reference in their entirety.

[0270] In certain embodiments, each bivalent linker in a carbohydrate-oligonucleotide conjugate provided by the present invention is independently -Z n -(R n -Z n ) z -, where each R n , Z n and z is as defined herein.

[0271] In certain embodiments, each bivalent linker in a carbohydrate-oligonucleotide conjugate provided herein independently has the following structure: [ka] .

[0272] In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is an independently cleavable or non-cleavable linker.In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is an independently cleavable linker.In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is an independently non-cleavable linker.

[0273] In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable linker that is sensitive to acidic pH. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a cleavable linker that contains a reducible disulfide. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that is cleavable by glutathione. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that is cleavable by an enzyme. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that is cleavable by a protease. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that is cleavable by a lysosomal protease. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that is cleavable by cathepsin B. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is independently cleavable by galactosidase. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is independently cleavable by β-galactosidase. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is independently cleavable by glucuronidase. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is independently cleavable by β-glucuronidase. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is independently cleavable by glucuronidase.In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that can be independently cleaved by β-glucuronidase. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugates provided by the present invention is a linker that can be independently cleaved by phosphatase. Exemplary linkers that can be used in the carbohydrate-oligonucleotide conjugates provided by the present invention include, but are not limited to, those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74. The disclosures of these linkers are incorporated herein by reference in their entirety.

[0274] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate having the structure of formula (I): [ka] where: R 1 is the ASGPR binding group; R 2 and R 3 are each independently an oligonucleotide; L 1 , L 2 , L 3a and L 3c are each an independent linker; L 3b is (i) a bond; or (ii) heteroarylene or heterocyclylene, each substituted with one or more substituents Q; and M is (i) N or CH; or (ii) trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14aryl, trivalent heteroaryl, or trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0275] In certain embodiments, in formula (I), L 3b is a bond. In certain embodiments, in formula (I), L 3b is heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is heteroarylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a monocyclic heteroarylene, each of which may be optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a 5- or 6-membered heteroarylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a 5-membered heteroarylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b and is [1,2,3]triazolediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b and R is [1,2,3]triazole-1,4-diyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a 6-membered heteroarylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a bicyclic heteroarylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a tricyclic heteroaryl, each substituted with one or more substituents Q.

[0276] In certain embodiments, in formula (I), L 3bis heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a monocyclic heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a bicyclic heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is 4,5,6,7,8,9-hexahydrocycloocta[d][1,2,3]triazolediyl or 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinediyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is 4,5,6,7,8,9-hexahydrocycloocta[d][1,2,3]triazole-1,6-diyl, 4,5,6,7,8,9-hexahydrocycloocta[d]-[1,2,3]triazole-1,7-diyl, or 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine-1,7-diyl, each substituted with one or more substituents Q.

[0277] In certain embodiments, in formula (I), L 3b is a tricyclic heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is 1,5a,6,6a-tetrahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazolediyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is 1,5a,6,6a-tetrahydro-cyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-1,6-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a tetracyclic heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3bis 8,9-dihydrodibenzo[b,f][1,2,3]triazolo[4,5-d]azocindiyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is 8,9-dihydrodibenzo[b,f]-[1,2,3]triazolo[4,5-d]azocine-1,8-diyl or 8,9-dihydrodibenzo[b,f]-[1,2,3]triazolo-[4,5-d]azocine-3,8-diyl, each substituted with one or more substituents Q.

[0278] In certain embodiments, in formula (I), L 3b teeth, [ka] is.

[0279] In certain embodiments, in formula (I), L 3b teeth, [ka] is.

[0280] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate having the structure of formula (II): [ka] where R 1 , R 2 , R 3 , L 1 , L 2 , L 3a , L3c and M are each as defined herein.

[0281] In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group according to the present invention. In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (AI). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (A-II). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (A-III). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (A-IV). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (AV). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group shown in formula (A-VI). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR-binding molecule shown in formula (A-VII).

[0282] In certain embodiments, in formula (I) or (II), R 1 teeth, [ka] is.

[0283] In certain embodiments, in formula (I) or (II), R 2 is an oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligodeoxyribonucleotide or oligoribonucleotide. In certain embodiments, in formula (I) or (II), R 2is a single-stranded oligodeoxyribonucleotide (ssDNA). In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligoribonucleotide (ssRNA). In certain embodiments, in formula (I) or (II), R 2 is an ASO, miRNA, mRNA, or tRNA.

[0284] In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:5, or SEQ ID NO:9.

[0285] In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide, and contains one nucleotide sequence selected from SEQ ID NO: 1 to SEQ ID NO: 25. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:25. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, or SEQ ID NO: 23. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:9, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:19, or SEQ ID NO:23.

[0286] In certain embodiments, in formula (I) or (II), R 2 is a double-stranded oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 2 is a double-stranded oligodeoxyribonucleotide or oligoribonucleotide. In certain embodiments, in formula (I) or (II), R 2 is a double-stranded oligodeoxyribonucleotide. In certain embodiments, in formula (I) or (II), R 2 is a double-stranded oligoribonucleotide.

[0287] In certain embodiments, in formula (I) or (II), R 2 is an siRNA. In certain embodiments, in formula (I) or (II), R 2 is an siRNA and comprises a pair of nucleotide sequences of SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, or SEQ ID NO: 11 and SEQ ID NO: 12. In certain embodiments, in formula (I) or (II), R 2 is an siRNA comprising a pair of nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:5 and SEQ ID NO:6, or SEQ ID NO:9 and SEQ ID NO:10.

[0288] In certain embodiments, in formula (I) or (II), R 2 is an siRNA. In certain embodiments, in formula (I) or (II), R 2 is an siRNA and comprises a pair of nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:24. In certain embodiments, in formula (I) or (II), R 2is an siRNA and comprises the paired nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:19 and SEQ ID NO:20, or SEQ ID NO:23 and SEQ ID NO:24.

[0289] In certain embodiments, in formula (I) or (II), R 3 is an oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligodeoxyribonucleotide or oligoribonucleotide. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligodeoxyribonucleotide. In certain embodiments, in formula (I) or (II), R 3 is an ASO, miRNA, mRNA, or tRNA. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 11. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:3, SEQ ID NO:7, or SEQ ID NO:11.

[0290] In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide and comprises any one of the nucleotide sequences of SEQ ID NO: 1 to SEQ ID NO: 25. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:25. In certain embodiments, in formula (I) or (II), R 3is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, or SEQ ID NO: 23. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, or SEQ ID NO: 25. In certain embodiments, in formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:11, SEQ ID NO:17, SEQ ID NO:19, or SEQ ID NO:21.

[0291] In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide according to the present invention. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligodeoxyribonucleotide or oligoribonucleotide. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligodeoxyribonucleotide. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligoribonucleotide.

[0292] In certain embodiments, in formula (I) or (II), R 3 is an siRNA. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide and comprises a pair of nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, or SEQ ID NO:11 and SEQ ID NO:12. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide comprising the paired nucleotide sequences of SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:7 and SEQ ID NO:8, or SEQ ID NO:11 and SEQ ID NO:12.

[0293] In certain embodiments, in formula (I) or (II), R 3 is an siRNA. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide and comprises the paired nucleotide sequences SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:24. In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide and comprises the paired nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, or SEQ ID NO:21 and SEQ ID NO:22.

[0294] In certain embodiments, in formula (I) or (II), L 1 is a linker as defined herein. In certain embodiments, in formula (I) or (II), L 1 Ha-Z n -(R n -Z n ) z -, where each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 1 is -NHC(O)(CH2) e C(O)NH—, where e is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In certain embodiments, in formula (I) or (II), L 1 is -NHC(O)(CH2) e C(O)NH—, where e is an integer of 3, 6, or 10. In certain embodiments, in formula (I) or (II), L 1is —NHC(O)(CH)C(O)NH—. In certain embodiments, in formula (I) or (II), L 1 is —NHC(O)(CH)C(O)NH—. In certain embodiments, in formula (I) or (II), L 1 is -NHC(O)(CH2) 10 In certain embodiments, in formula (I) or (II), L 1 teeth, [ka] is.

[0295] In certain embodiments, in formula (I) or (II), L 2 is a linker as defined herein. In certain embodiments, in formula (I) or (II), L 2 Ha-Z n -(R n -Z n ) z -, where each R n , Z n and z is as defined herein. In certain embodiments, in formula (I) or (II), L 2 Ha-(CH2) f C(O)NH(CH2) g OP(O2)-, where f is an integer of 1, 2, 3, 4, 5, or 6; and g is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in formula (I) or (II), L 2 is —(CH)NHC(O)(CH)OP(O)—, or —NHC(O)(CH)OP(O)—. In certain embodiments, in formula (I) or (II), L 2 is —(CH 2 )NHC(O)(CH 2 ) 6 OP(O 2 )—. In certain embodiments, in formula (I) or (II), L 2 is -NHC(O)(CH2)6OP(O2)-.

[0296] In certain embodiments, in formula (I) or (II), L 2is a linker comprising -O-, -S-, or -N(H)-. In certain embodiments, in formula (I) or (II), L 2 is C 6-14 A linker comprising an arylene or heterocyclylene, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene or monocyclic heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene, 5-membered or 6-membered heterocyclylene, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene, pyrrolidinediyl, tetrahydrothienediyl, tetrahydropyrandiyl, or piperidinediyl, each substituted with one or more substituents Q.

[0297] In certain embodiments, in formula (I) or (II), L 2 is -X(CH2) h X-, where each X is independently -O-, -S-, or -N(H)-; and h is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, in formula (I) or (II), L 2 is -X(CH2) i CH(OH)(CH2) j X-, where each X is as defined herein, and i and j are each independently an integer of 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in formula (I) or (II), L 2 teeth, [ka] In certain embodiments, in formula (I) or (II), L 2 teeth, [ka] where L 2 is attached to the 5'-end of the oligonucleotide. In certain embodiments, in formula (I) or (II), L 2 teeth, [ka] In certain embodiments, in formula (I) or (II), L 2 teeth, [ka] where L 2 is attached to the 3'-end of the oligonucleotide.

[0298] In certain embodiments, in formula (I) or (II), L 2 teeth, [ka] is.

[0299] In certain embodiments, in formula (I) or (II), L 3a is a linker as defined herein. In certain embodiments, in formula (I) or (II), L 3a Ha-Z n -(R n -Z n ) z -, where each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 3a is C 1-10 Alkylene or C 7-15 aralkylene, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3a is methanediyl or phendiyl, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L3a is —(CH 2 )— or —(CH 2 )-phen-1,4-diyl, each of which is substituted with one or more substituents Q.

[0300] In certain embodiments, in formula (I) or (II), L 3a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, [ka] is.

[0301] In certain embodiments, in formula (I) or (II), L 3c is a linker as defined herein. In certain embodiments, in formula (I) or (II), L 3c is Z n -(R n -Z n ) z -, where each R n , Z n and z is as defined herein. In certain embodiments, in formula (I) or (II), L 3c teeth, -(CH2) m C(O)NH(CH2) n OP(O2)-, where m and n are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in formula (I) or (II), L 3c is -(CH2)5C(O)NH(CH2)6OP(O2)-.

[0302] In certain embodiments, in formula (I) or (II), L 3c is a linker comprising -O-, -S-, or -N(H)-. In certain embodiments, in formula (I) or (II), L 3c is C 6-14A linker comprising an arylene or heterocyclylene, each of which is substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene or monocyclic heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene, 5-membered or 6-membered heterocyclylene, each substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene, pyrrolidinediyl, tetrahydrothienediyl, tetrahydropyrandiyl, or piperidinediyl, each of which is substituted with one or more substituents Q

[0303] In certain embodiments, in formula (I) or (II), L 3c is X(CH2) p X-, where each X is independently -O-, -S-, or -N(H)-; and p is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, in formula (I) or (II), L 3c is -X(CH2) q CH(OH)(CH2) r X-, where each X is as defined herein. Further, q and r are each independently an integer of 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, in formula (I) or (II), L 3c teeth, [ka] In certain embodiments, in formula (I) or (II), L 3c teeth, [ka] where L 3cis attached to the 5'-end of the oligonucleotide. In certain embodiments, in formula (I) or (II), L 3c teeth, [ka] In certain embodiments, in formula (I) or (II), L 3c teeth, [ka] where L 3c is attached to the 3'-end of the oligonucleotide.

[0304] In certain embodiments, in formula (I) or (II), L 3c teeth, [ka] is.

[0305] In certain embodiments, in formula (I) or (II), M is N or CH. In certain embodiments, in formula (I) or (II), M is N. In certain embodiments, in formula (I) or (II), M is CH.

[0306] In certain embodiments, in formula (I) or (II), M is a trivalent C 1-6 Alkyl, trivalent C 1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 In certain embodiments, in formula (I) or (II), M is a trivalent C 1-6 alkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is CR m where R m is C 1-6 Alkyl, C1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 In certain embodiments, in formula (I) or (II), M is CR m where R m is C 1-6 In certain embodiments, in formula (I) or (II), M is C(CH). In certain embodiments, in formula (I) or (II), M is trivalent C(CH). 1-6 In certain embodiments, in formula (I) or (II), M is a trivalent C 1-6 alkenyl, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 3-10 cycloalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 6-14 aryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I) or (II), M is a trivalent heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I) or (II), M is a trivalent heterocyclyl, each optionally substituted with one or more substituents Q.

[0307] In certain embodiments, in formula (I) or (II), L 1 is -NHC(O)(CH2) e C(O)NH—, where e is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; L 2 is -(CH2) f C(O)NH(CH2) gOP(O2)-, where f is an integer of 1, 2, 3, 4, 5, or 6; g is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L 3a is methanediyl or phendiyl, each substituted with one or more substituents Q; L 3c is -(CH2) m C(O)NH(CH2) n OP(O2)-, where m and n are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; M is a trivalent C 1-6 It is alkyl.

[0308] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] JPEG2025531341000090.jpg220169 JPEG2025531341000091.jpg231169 JPEG2025531341000092.jpg217169 ; Here, each 3'-siRNA refers to an siRNA independently connected to one of its 3'-ends and a trivalent linker; and each 5'-siRNA refers to an siRNA independently connected to one of its 5'-ends and a trivalent linker.

[0309] In another embodiment, the present invention provides a carbohydrate-oligonucleotide: [ka] ; Here, 3'-siRNA refers to an siRNA having one of its 3'-ends connected to a first bivalent linker and one of its 5'-ends connected to a second bivalent linker, and 5'-siRNA refers to an siRNA having one of its 5'-ends connected to a second bivalent linker.

[0310] In another embodiment, the present invention provides a carbohydrate-oligonucleotide: [ka] JPEG2025531341000095.jpg217169 ; Here, each 5'-siRNA independently refers to an siRNA having one 5'-end connected to a trivalent linker.

[0311] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 5'-siRNA independently refers to an siRNA having one 5'-end connected to a trivalent linker.

[0312] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] Here, 5'-siRNA refers to siRNA, the 5'-end of which is connected to a trivalent linker; 5'-ssDNA refers to single-stranded DNA, the 5'-end of which is connected to a trivalent linker.

[0313] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 5'-siRNA independently refers to an siRNA having one 5'-end connected to a trivalent linker.

[0314] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 3'-siRNA independently refers to an siRNA having one of its 3'-ends connected to a trivalent linker.

[0315] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] JPEG2025531341000101.jpg220169 JPEG2025531341000102.jpg231169 JPEG2025531341000103.jpg218169 ; Here, each 3'-ssRNA independently represents a single-stranded RNA, the 3'-end of which is connected to a trivalent linker, and each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0316] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, 3'-ssRNA refers to a single-stranded RNA, the 3'-end of which is connected to a first bivalent linker and the 5'-end of which is connected to a second bivalent linker, and 5'-ssRNA refers to a single-stranded RNA, the 5'-end of which is connected to a second bivalent linker.

[0317] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] JPEG2025531341000106.jpg217169 ; Here, each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0318] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0319] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, 5'-siRNA refers to a single-stranded RNA, the 5'-end of which is connected to a trivalent linker; 5'-ssDNA refers to a single-stranded DNA, the 5'-end of which is connected to a trivalent linker.

[0320] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 5'-ssRNA independently represents a single-stranded RNA, and its 5'-end is connected to a trivalent linker.

[0321] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: [ka] ; Here, each 3'-ssRNA independently represents a single-stranded RNA, the 3'-end of which is connected to a trivalent linker.

[0322] In one embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention is any one of carbohydrate-oligonucleotide conjugates A18a-A18c.

[0323] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention is any one of carbohydrate-oligonucleotide conjugates A4a, A18a-A18h, and A19a-A29a.

[0324] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:3 and SEQ ID NO:4.

[0325] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:5 and SEQ ID NO:6, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:7 and SEQ ID NO:8.

[0326] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:9 and SEQ ID NO:10, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:11 and SEQ ID NO:12.

[0327] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:13 and SEQ ID NO:14, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:7 and SEQ ID NO:8.

[0328] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:15 and SEQ ID NO:16, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:17 and SEQ ID NO:18.

[0329] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:9 and SEQ ID NO:10, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:19 and SEQ ID NO:20.

[0330] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:19 and SEQ ID NO:20, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:21 and SEQ ID NO:22.

[0331] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second oligonucleotide duplex structure, wherein the first oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:3 and SEQ ID NO:4, and the second oligonucleotide duplex structure comprises the nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2.

[0332] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an oligonucleotide double-stranded structure and a single-stranded oligonucleotide, wherein the oligonucleotide double-stranded structure comprises the nucleotide sequences of SEQ ID NO:23 and SEQ ID NO:24, and the single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:25.

[0333] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 1 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 3.

[0334] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:5 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:7.

[0335] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:9 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:11.

[0336] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 13 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 7.

[0337] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 15 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 17.

[0338] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 9 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 19.

[0339] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 19 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 21.

[0340] In certain embodiments, the carbohydrate-oligonucleotide conjugates provided by the present invention comprise a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:3 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:1.

[0341] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second single-stranded oligonucleotide, wherein the first single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 23 and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 25. (Pharmaceutical composition)

[0342] In one embodiment, the present invention provides a pharmaceutical composition, comprising a carbohydrate-oligonucleotide conjugate provided by the present invention and a pharmaceutically acceptable excipient.

[0343] In one embodiment, the drug compositions provided by the present invention are formulated in a dosage form for parenteral administration. In another embodiment, the drug compositions provided by the present invention are formulated in a dosage form for intravenous administration. In another embodiment, the drug compositions provided by the present invention are formulated in a dosage form for intramuscular administration. In another embodiment, the drug compositions provided by the present invention are formulated in a dosage form for subcutaneous administration.

[0344] The pharmaceutical compositions provided by the present invention can be provided in unit-dosage or multi-dosage forms. As used herein, a unit-dosage form refers to a physically discrete unit suitable for administration to a subject, packaged individually as known in the art. Each unit-dosage contains a predetermined amount of an active ingredient (e.g., a carbohydrate-oligonucleotide conjugate provided by the present invention) sufficient to produce a desired therapeutic effect, along with any necessary pharmaceutical excipients. Examples of unit-dosage forms include, but are not limited to, ampoules and syringes. Unit-dosage forms can be administered individually or multiple times. A multi-dosage form is one in which multiple identical unit-dosage forms are packaged in a single container, with the separated unit-dosage forms administered as individual doses. Examples of multi-dosage forms include, but are not limited to, vials or bottles in pint or gallon sizes.

[0345] The pharmaceutical composition provided by the present invention can be administered at once or multiple times at intervals.It should be understood that the exact dosage and duration of treatment will vary depending on the age, weight, and condition of the subject being treated, and can be determined empirically using known testing protocols or by extrapolating from in vivo or in vitro test or diagnostic data.It should also be understood that for a particular individual, the specific dosage regimen will need to be adjusted over time according to the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0346] The present invention can be further understood by the following non-limiting examples. Example

[0347] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, e.g., the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not by way of limitation, the following abbreviations may be used in the examples and throughout the specification: g (gram), mg (milligram), mL (milliliter), mL (microliter), mM (millimol), mM (micromol), mmol (millimol), min (minute), h (hour), AcOH (acetic acid), DEA (diethylamine), DIPEA (N,N-diisopropylethylamine), DMSO (dimethylsulfoxide), DMTr (4,4-dimethoxytrityl), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), ETT (5-(ethylthio)tetrazole), HBTU (2-(1H-benzotriazole-1H-yl)-2H-pyrrolidone), HCl (HCl-HCl-HCl (HCl-HCl), ... -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), HOSu (N-hydroxysuccinimide), NaOAc (sodium acetate), iPr (isopropyl ether); Pfp (pentafluorophenyl); SDPD (succinimidyl 3-(2-pyridyldithio)propionate); TBAF (tetrabutylammonium fluoride); TBDPS (tert-butyldiphenylsilyl); TCEP (tris(2-carboxyethyl)phosphine); TFAPFP (pentafluorophenyl trifluoroacetate); THF (tetrahydrofuran); MS (mass spectrometry); and prep-HPLC (semi-preparative high performance liquid chromatography).

[0348] In all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise specified, all temperatures are expressed in °C (Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methods presented herein are intended to illustrate applicable chemical reactions with specific examples and are not indicative of the scope of the present disclosure. Example 1 Preparation of GalNAc-siRNA complex A1 [ka]

[0349] GalNAc-siRNA complex A1: Prepared as in Scheme 1, where R p teeth, [ka] is a group having the structure q teeth [ka] The ASGPR binding group has the structure: Each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA or an ASO sequence), and its 5'-end is linked to a trivalent linker. Each 5'-siRNA independently represents an siRNA with one of its 5'-ends linked to a trivalent linker. In Scheme 1, compound 1.2 is as described in WO2020 / 259497A1, the disclosure of which is incorporated herein by reference in its entirety. [ka] Note: Complementary ssRNA Example 2 Preparation of GalNAc-siRNA complex A2 [ka]

[0350] GalNAc-siRNA complex A2: Prepared as in Method 2. s teeth, [ka] It is a group having the structure R t teeth, [ka] The ASGPR binding group has the structure: Each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA or an ASO sequence), and its 5'-end is linked to a trivalent linker. Each 5'-siRNA independently represents an siRNA with one of its 5'-ends linked to a trivalent linker. In Scheme 2, compound 2.2 is prepared as described in WO2020 / 259497A1, the disclosure of which is incorporated herein by reference in its entirety. [ka] Note: Complementary ssRNA Example 3 Preparation of GalNAc-siRNA complex A3 [ka]

[0351] GalNAc-siRNA complex A3 was prepared according to Scheme 3, where R s and R t is performed as described in Scheme 2, where each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker, and each 5'-siRNA independently represents an siRNA whose one of its 5'-ends is linked to a trivalent linker. [ka] Note: Solid Phase Synthesis, Complementary ssRNA Example 4 GalNAc-siRNA complex A4a [ka]

[0352] The preparation of GalNAc-siRNA complex A4a was performed as shown in Schemes 4A and 4B, where R s and R t are as described in Example 2. Here, 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker, and has an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and has an antisense strand having the nucleotide sequence of SEQ ID NO: 4. [ka]

[0353] In Schemes 4A and 4B, oligonucleotides of compounds 4.2 (SEQ ID NO: 1), 4.5 (SEQ ID NO: 3), 4.9 (SEQ ID NO: 2), and 4.10 (SEQ ID NO: 4) were prepared by solid phase oligonucleotide synthesis. [ka] NOTE: Oligonucleotides, Annealing

[0354] Preparation of Compound 4.3. Compound 4.2 (210 mg, 29 μmol) was dissolved in 0.1 M Na2B4O7 aqueous solution (1 mL), and compound 4.1 (37 mg, 147 μmol) dissolved in DMSO (1 mL) was added. The reaction mixture was sonicated for 2 hours, after which NaOAc (164 mg, 2 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give compound 4.3 (150 mg) in 70% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 229 H 302 F3N 80 O 142 P 21 The calculated value for S4 was 7283.04, and the observed value was 7283.21 (MS m / z: [M+H] + Calcd for C 229 H 302 F3N 80 O 142 P 21 S47283.04;Found 7283.21).

[0355] Preparation of Compound 4.6. Compound 4.5 (280 mg, 38 μmol) was dissolved in 0.1 M Na2B4O7 aqueous solution (2.6 mL), and compound 4.4 (88 mg, 159 μmol) dissolved in DIPEA (0.5 mL) and DMSO (2.6 mL) was added. The reaction mixture was sonicated for 2 hours, followed by the addition of DEA solution (2 mL). The reaction mixture was further sonicated for 2 hours. NaOAc (467 mg, 5.7 mmol) was then added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give compound 4.6 (210 mg) in 73% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 229 H 305 F2N 66 O 151 P 21 The calculated value for S4 is 7214.96 and the measured value is 7215.17.

[0356] Preparation of Compound 4.7. Compound 4.6 (210 mg, 28 μmol) was dissolved in 0.1 M Na2B4O7 aqueous solution (3.5 mL), and compound 2.2 (332 mg, 175 μmol) dissolved in DIPEA (0.5 mL) and DMSO (4 mL) was added. The reaction mixture was sonicated for 2 hours, after which NaOAc (656 mg, 8 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give compound 4.7 (160 mg) in 62% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 307 H 428 F2N 73 O 186 P 21 The calculated value of S4 is 8933.81; the measured value is 8933.98.

[0357] Preparation of Compound 4.8. To a solution of Compound 4.3 (55 mg, 8 μmol) and Compound 4.7 (45 mg, 6 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (3 mg, 15 μmol). After stirring at 60 °C for 2 hours, NaOAc (256 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 4.8 (53 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 536 H 730 F5N 153 O 328 P 42 The calculated value for S8 is 16216.85 and the measured value is 6217.16.

[0358] Preparation of Compound B4a. To a solution (1 mL) of Compound 4.8 (53 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (29 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B4a (13.7 mg) in 17% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 518 H 712 F5N 153 O 319 P 42The calculated value of S8 is 15838.52 and the measured value is 15838.

[0359] Preparation of Compound A4a: Compound A4a was obtained by heating an aqueous solution of Compound B4a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) at 70-95°C for approximately 1-5 minutes and then cooling to room temperature. Example 5 Preparation of GalNAc-siRNA complex A5 [ka]

[0360] GalNAc-siRNA complex A5 was prepared as shown in Scheme 5, where R s and R t are as described in Example 2. Each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker. Also, each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. [ka] Note: Succinic Anhydride, Resin, Solid Phase Synthesis, Cleavage, Deprotection, Complementary ssRNA Example 6 Preparation of GalNAc-siRNA complex A6 [ka]

[0361] GalNAc-siRNA complex A6 is prepared as shown in Scheme 6, where R s and R tare as described in Example 2. 3'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence), and its 3'-end is linked to a trivalent linker. 5'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence), and its 5'-end is linked to a trivalent linker. 3'-siRNA refers to an siRNA, and one of its 3'-ends is linked to a trivalent linker. 5'-siRNA refers to an siRNA, and one of its 5'-ends is linked to a trivalent linker. [ka] Note: Succinic Anhydride, Resin, Solid Phase Synthesis, Cleavage, Deprotection, Complementary ssRNA Example 7 Preparation of GalNAc-siRNA complex A7 [ka]

[0362] GalNAc-siRNA complex A7 is prepared as shown in Scheme 7, where R s and R t are as described in Example 2. 3'-ssRNA refers to single-stranded RNA (for example, the sense or antisense sequence of siRNA, or ASO sequence), and its 3'-end is linked to a trivalent linker. 5'-ssRNA refers to single-stranded RNA (for example, the sense or antisense sequence of siRNA, or ASO sequence), and its 5'-end is linked to a trivalent linker. 3'-siRNA refers to siRNA, and one of its 3'-ends is linked to a trivalent linker. 5'-siRNA refers to siRNA, and one of its 5'-ends is linked to a trivalent linker. [ka] Note: Piperidine, complementary ssRNA Example 8 Preparation of GalNAc-siRNA complex A8 [ka]

[0363] GalNAc-siRNA complex A8 is prepared as shown in Scheme 8, where R s and R t are as described in Example 2. Each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker, and each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. [ka] Note: Complementary ssRNA Example 9 Preparation of GalNAc-siRNA complex A9 [ka]

[0364] GalNAc-siRNA complex A9 is prepared as shown in Scheme 9, where R s and R tare as described in Example 2. 3'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence), whose 3'-end is linked to a trivalent linker. 5'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence), whose 5'-end is linked to a trivalent linker. 3'-siRNA refers to an siRNA, whose one of its 3'-ends is linked to a trivalent linker. 5'-siRNA refers to an siRNA, whose one of its 5'-ends is linked to a trivalent linker. [ka] Note: Complementary ssRNA Example 10 Preparation of GalNAc-siRNA complex A10 [ka]

[0365] GalNAc-siRNA complex A10 is prepared as shown in Scheme 9, where R s and R t are as described in Example 2. Each 3'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 3'-end is linked to a trivalent linker, and each 3'-siRNA independently represents an siRNA whose one 3'-end is linked to a trivalent linker. [ka] Note: Complementary ssRNA Example 11 Preparation of GalNAc-siRNA complex A11 [ka]

[0366] GalNAc-siRNA complex A11 is prepared as shown in Scheme 11, where R s and R t are as described in Example 2. Each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker, and each 5'-siRNA independently represents an siRNA whose one of its 5'-ends is linked to a trivalent linker. [ka] Note: Complementary ssRNA Example 12 Preparation of GalNAc-siRNA complex A13 [ka]

[0367] GalNAc-siRNA complex A13 is prepared as shown in Scheme 10, where each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker, and each 5'-siRNA independently represents an siRNA whose one of its 5'-ends is linked to a trivalent linker. [ka] Note: Coupling Reagent, Complementary ssRNA Example 13 Preparation of GalNAc-siRNA complex A17 [ka]

[0368] GalNAc-siRNA complex A17 is prepared as shown in Scheme 13, where R s and R t are as described in Example 2. 3'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA or an ASO sequence) whose 3'-end is linked to a first bivalent linker and whose 5'-end is linked to a second bivalent linker; 5'-ssRNA refers to a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA or an ASO sequence) whose 5'-end is linked to a second bivalent linker; 3'-siRNA refers to an siRNA whose 3'-end is linked to a first bivalent linker. a 5'-ssRNA represents a single-stranded RNA (e.g., a sense or antisense sequence of an siRNA or an ASO sequence) and one of its 5'-ends is linked to a second bivalent linker; a 3'-siRNA represents an siRNA and one of its 3'-ends is linked to a first bivalent linker and one of its 5'-ends is linked to a second bivalent linker; a 5'-siRNA represents an siRNA and one of its 5'-ends is linked to a second bivalent linker. [ka] Note: Succinic Anhydride, Resin, Solid Phase Synthesis, Complementary ssRNA Example 14 Preparation of GalNAc-siRNA complex A18a [ka]

[0369] GalNAc-siRNA complex A18a is prepared as shown in Scheme 14, where R s and R tare as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker; 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker, and further comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2; and 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and further comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0370] Preparation of Compound 14.3. To a solution of compound 14.2 (280 mg, 38 μmol) in 0.1 M Na2B4O7 (2.6 mL) was added a solution of compound 14.1 (79 mg, 159 μmol) in DMSO (2.6 mL) with DIPEA (0.5 mL). The reaction mixture was sonicated for 2 hours, followed by the addition of DEA solution (2 mL). The reaction mixture was further sonicated for 2 hours, after which NaOAc (467 mg, 5.7 mmol) was added. The reaction mixture was centrifuged, and the precipitate was collected and dried to give compound 14.3 (250 mg) in 88% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 225 H 297 F2N 66 O 151 P 21 The calculated value for S4 is 7158.85 and the Found is 7158.92.

[0371] Preparation of Compound 14.4. Compound 14.3 (250 mg, 34 μmol) in 0.1 M Na2B4O7 aqueous solution (3.5 mL) was added to a solution of DIPEA (0.5 mL) and compound 2.2 (399 mg, 210 μmol) in DMSO (4 mL). The reaction mixture was sonicated for 2 hours, after which NaOAc (656 mg, 8 mmol) was added. The reaction mixture was then centrifuged, and the pellet was collected and dried to give compound 14.4 (270 mg) in 87% yield. Mass spectrum mass-to-charge ratio: [M+H] + C303 H 420 F2N 73 O 186 P 21 The calculated value of S4 is 8877.7 and the measured value is 8877.78.

[0372] Preparation of Compound 14.5. To a solution of Compound 4.3 (74 mg, 10 μmol) and Compound 14.4 (60 mg, 8 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (4 mg, 19 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 14.5 (65 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 532 H 722 F5N 153 O 328 P 42 The calculated value of S8 is 16160.74 and the measured value is 16161.09.

[0373] Preparation of Compound B18a. To a solution of Compound 14.5 (65 mg) in water (1 mL) was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (51 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B18a (20.5 mg) in 19% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 514 H 704 F5N 153 O 319 P 42 The calculated value for S8 is 15782.41; the observed value is 15782.53.

[0374] Preparation of Compound A18a: Compound A18a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) were heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A18a. [ka] Note: Compound, Oligonucleotide, Annealing

[0375] GalNAc-siRNA complexes A18b to A18h were prepared in the same manner as in Example 14. [ka] [Table 1]

[0376] GalNAc-siRNA complexes B18b to B18g were prepared in the same manner as in Example 14. [ka] [Table 2] Example 15 Preparation of GalNAc-siRNA complex A19a [ka]

[0377] GalNAc-siRNA conjugate A19a is prepared as shown in Scheme 15, where R s and R tare as described in Example 2, where 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1 linked at its 5'-end to a trivalent linker, and 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3 linked at its 5'-end to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, its 5'-end linked to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3 linked at its 5'-end to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 4. [ka] Note: Compound, Oligonucleotide, Annealing

[0378] Preparation of Compound 15.2. To a solution of Compound 15.1 (62 mg, 9 μmol) and Compound 4.3 (76 mg, 10 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (4 mg, 19 μmol). After stirring at 60°C for 2 hours, NaOA (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 15.2 (78 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 535 H 728 F5N 153 O 328 P 42 The calculated value of S8 is 16202.82 and the measured value is 16202.93.

[0379] Preparation of Compound B19a. To a solution of Compound 15.2 (78 mg) in water (1 mL) was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (52 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B19a (26.3 mg) in 24% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 517 H 710 F5N 153 O 319 P 42 The calculated value for S8 is 15824.49 and the measured value is 15824.72.

[0380] Preparation of Compound A19a: An aqueous solution of Compound B19a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1-5 minutes, and then cooled to room temperature to obtain Compound A19a. Example 16 Preparation of GalNAc-siRNA complex A20a [ka]

[0381] GalNAc-siRNA conjugate A20a is prepared as shown in Scheme 16, where R s and R t are as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a contains a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. It also contains an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b contains a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and it also contains an antisense strand having the nucleotide sequence of SEQ ID NO: 4. [ka] Note: Compound, Oligonucleotide, Annealing

[0382] Preparation of Compound 16.2. To a solution of Compound 16.1 (75 mg, 10 μmol) and Compound 4.3 (92 mg, 13 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (5 mg, 24 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 μmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 16.2 (67 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 539 H 736 F5N 153 O 328 P 42 The calculated value for S8 is 16258.93; the measured value is 16258.94.

[0383] Preparation of Compound B20a. To a solution (1 mL) of Compound 16.2 (67 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (51 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B20a (23.9 mg) in 18% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 521 H 718 F5N 153 O 319 P 42 The calculated value for S8 is 15880.6; the measured value is 15880.86.

[0384] Preparation of Compound A20a: Compound B20a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) were heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A20a. Example 17 Preparation of GalNAc-siRNA complex A21a [ka]

[0385] GalNAc-siRNA conjugate A21a is prepared as shown in Scheme 17, where R s and R t are as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker; 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker, and further comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and further comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0386] Preparation of Compound 17.2. To a solution (3 mL) of Compound 17.1 (80 mg, 11 μmol) and Compound 4.3 (98 mg, 14 μmol) in water, copper(I) bromide dimethyl sulfide (6 mg, 29 μmol) was added. After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 16.2 (73 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 533 H 724 F5N 153 O 328 P 42 The calculated value for S8 is 16174.77; the measured value is 16175.1. [ka] Note: Compound, Oligonucleotide, Annealing

[0387] Preparation of Compound B21a. To a solution (1 mL) of Compound 17.2 (73 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (57 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B21a (25.7 mg) in 18% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 515 H 706 F5N 153 O 319 P 42 The calculated value for S8 is 15796.44; the observed value is 15797.07.

[0388] Preparation of Compound A21a: Compound B21a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) were heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A21a. Example 18 Preparation of GalNAc-siRNA complex A22a [ka]

[0389] GalNAc-siRNA conjugate A22a is prepared as shown in Scheme 18, where R s and R tare as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, with its 5'-end linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, with its 5'-end linked to a trivalent linker; 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, with its 5'-end linked to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, with its 5'-end linked to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0390] Preparation of Compound 18.2. To a solution of Compound 18.1 (56 mg, 8 μmol) and Compound 4.3 (69 mg, 9 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (4 mg, 19 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 18.2 (76 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 535 H 728 F5N 153 O 328 P 42 The calculated value for S8 is 16202.82; the measured value is 16202.95.

[0391] Preparation of Compound B22a. To a solution (1 mL) of Compound 18.2 (76 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (66 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B22a (19.8 mg) in 20% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 517 H 710 F5N 153 O 319 P 42 The calculated value for S8 is 15824.49; the measured value is 15824.67. [ka] Note: Compound, Oligonucleotide, Annealing

[0392] Preparation of Compound A22a: An aqueous solution of Compound B22a (1 equivalent), Oligonucleotide 4.9 (1 equivalent), and Oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for approximately 1-5 minutes, and then cooled to room temperature to obtain Compound A22a. Example 19 Preparation of GalNAc-siRNA complex A23a [ka]

[0393] GalNAc-siRNA conjugate A23a is prepared as shown in Scheme 19, where R s and R t are as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2, and 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0394] Preparation of Compound 19.2. To a solution of Compound 19.1 (60 mg, 8 μmol) and Compound 4.3 (74 mg, 10 μmol) in water (3 mL), copper(I) bromide dimethyl sulfide (4 mg, 19 μmol) was added. After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 19.2 (82 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 538 H 726 F5N 153 O 328 P 42 The calculated value for S8 is 16236.84; the observed value is 16236.98.

[0395] Preparation of Compound B22a. To a solution of Compound 18.2 (82 mg) in water (1 mL) was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (56 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B23a (21.7 mg) in 20% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 520 H 708 F5N 153 O 319 P 42 The calculated value for S8 is 15858.51; the observed value is 15858.84. [ka] Note: Compound, Oligonucleotide, Annealing

[0396] Preparation of Compound A23a: An aqueous solution of Compound B23a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) was heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A23a. Example 20 Preparation of GalNAc-siRNA complex A24a [ka]

[0397] GalNAc-siRNA complex A24a is prepared as shown in Scheme 20, where R u teeth [ka] is a group having the structure R v teeth [ka] The ASGPR binding group has the structure: 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and it also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4. [ka] Note: Compound, Oligonucleotide, Annealing

[0398] Preparation of Compound 20.2. To a solution of Compound 20.1 (72 mg, 10 μmol) and Compound 4.3 (87 mg, 12 μmol) in water (3 mL), copper(I) bromide dimethyl sulfide (5 mg, 24 μmol) was added. After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 20.2 (61 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 538 H 731 F5N 156 O 331 P 42 The calculated value of S8 is 16331.9; the measured value is 16332.0.

[0399] Preparation of Compound B24a. To a solution (1 mL) of Compound 20.2 (61 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (38 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B24a (18.8 mg) in 15% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 520 H 713 F5N 156 O 322 P 42 The calculated value for S8 is 15953.56; the measured value is 15953.67.

[0400] Preparation of Compound A24a: An aqueous solution of Compound B24a (1 equivalent), Oligonucleotide 4.9 (1 equivalent), and Oligonucleotide 4.10 (1 equivalent) was heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A24a. Example 21 Preparation of GalNAc-siRNA complex A25a [ka]

[0401] GalNAc-siRNA complex A25a is prepared as shown in Scheme 21, where R x teeth, [ka] is a group having the structure R y teeth, [ka] The ASGPR binding group has the structure: 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1 and its 5'-end is linked to a trivalent linker; 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3 and its 5'-end is linked to a trivalent linker; 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1 and its 5'-end is linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2; and 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3 and its 5'-end is linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0402] Preparation of Compound 21.2. To a solution of Compound 21.1 (72 mg, 10 μmol) and Compound 4.3 (89 mg, 12 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (5 mg, 24 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 21.2 (68 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 523 H 703 F5N 154 O 329 P 42 The calculated value for S8 is 16063.5; the measured value is 16063.97.

[0403] Preparation of Compound B25a. To a solution (1 mL) of Compound 21.2 (68 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (46 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B25a (19.8 mg) in 15% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 505 H 685 F5N 154 O 320 P 42 The calculated value for S8 is 15685.16; the observed value is 15684.94.

[0404] Preparation of Compound A25a: An aqueous solution of Compound B25a (1 equivalent), Oligonucleotide 4.9 (1 equivalent), and Oligonucleotide 4.10 (1 equivalent) was heated at 70 to 95°C for about 1 to 5 minutes, and then cooled to room temperature to obtain Compound A25a. [ka] Note: Compound, Oligonucleotide, Annealing Example 22 Preparation of GalNAc-siRNA complex A26a [ka]

[0405] GalNAc-siRNA A26a is prepared as shown in Scheme 22, where R p and R qare as described in Example 1. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, its 5'-end is linked to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, its 5'-end is linked to a trivalent linker, and an antisense strand having the nucleotide sequence of SEQ ID NO: 4. [ka] Note: Compound, Oligonucleotide, Annealing

[0406] Preparation of Compound 22.2. To a solution of Compound 22.1 (72 mg, 10 μmol) and Compound 4.3 (94 mg, 13 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (5 mg, 24 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 22.2 (68 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 508 H 684 F5N 151 O 317 P 42 The calculated value for S8 is 15630.17; the measured value is 15630.67.

[0407] Preparation of Compound B26a. To a solution (1 mL) of Compound 22.2 (68 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (49 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B26a (26.7 mg) in 20% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 496 H 672 F5N 151 O 311 P 42 The calculated value for S8 is 15377.95; the observed value is 15378.25.

[0408] Preparation of Compound A26a: An aqueous solution of Compound B26a (1 equivalent), Oligonucleotide 4.9 (1 equivalent), and Oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for approximately 1-5 minutes, and then cooled to room temperature to obtain Compound A26a. Example 23 Preparation of GalNAc-siRNA complex A27a [ka]

[0409] GalNAc-siRNA conjugate A27a is prepared as shown in Scheme 23, where R p and R q are as described in Example 1. 5'-ssRNA-a comprises the nucleotide sequence of SEQ ID NO: 1, with its 5'-end linked to a trivalent linker. 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, with its 5'-end linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 1, with its 5'-end linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b comprises a sense strand having the nucleotide sequence of SEQ ID NO: 3, with its 5'-end linked to a trivalent linker. It also comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0410] Preparation of Compound 23.2. To a solution of Compound 23.1 (68 mg, 9 μmol) and Compound 4.3 (89 mg, 12 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (5 mg, 24 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 23.2 (72 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 511 H 690 F5N 151 O 317 P 42 The calculated value for S8 is 15672.25; the observed value is 15672.31. [ka] Note: Compound, Oligonucleotide, Annealing

[0411] Preparation of Compound B27a. To a solution (1 mL) of Compound 23.2 (72 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (56 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B27a (25.4 mg) in 20% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 499 H 678 F5N 151 O 311 P 42 The calculated value for S8 is 15420.03; the measured value is 15420.46.

[0412] Preparation of Compound A27a: An aqueous solution of Compound B27a (1 equivalent), oligonucleotide 4.9 (1 equivalent), and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1-5 minutes, and then cooled to room temperature to obtain Compound A27a. Example 24 Preparation of GalNAc-siRNA complex A28a [ka]

[0413] GalNAc-siRNA conjugate A28a is prepared as shown in Scheme 24, where R p and R q are as described in Example 1. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker. 5'-ssRNA-b has the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a contains a sense strand having the nucleotide sequence of SEQ ID NO: 1, and its 5'-end is linked to a trivalent linker, and further contains an antisense strand having the nucleotide sequence of SEQ ID NO: 2. 5'-siRNA-b contains a sense strand having the nucleotide sequence of SEQ ID NO: 3, and its 5'-end is linked to a trivalent linker, and further contains an antisense strand having the nucleotide sequence of SEQ ID NO: 4.

[0414] Preparation of Compound 24.2. To a solution of Compound 24.1 (75 mg, 9 μmol) and Compound 4.3 (97 mg, 13 μmol) in water (3 mL) was added copper(I) bromide dimethyl sulfide (5 mg, 24 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 24.2 (81 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 515 H 698 F5N 151 O 317 P 42 The calculated value for S8 is 15728.36; the measured value is 15730.0.

[0415] Preparation of Compound B28a. To a solution (1 mL) of Compound 24.2 (81 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (64 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B28a (29.3 mg) in 21% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 503 H 686 F5N 151 O 311 P 42 The calculated value for S8 is 15476.14; the observed value is 15475.88. [ka] Note: Compound, Oligonucleotide, Annealing

[0416] Preparation of Compound A28a: An aqueous solution of Compound B28a (1 equivalent), Oligonucleotide 4.9 (1 equivalent), and Oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for approximately 1-5 minutes, and then cooled to room temperature to obtain Compound A28a. Example 25 Preparation of GalNAc-siRNA complex A29a [ka]

[0417] GalNAc-siRNA complex A25a is prepared as shown in Scheme 25, where R s and R tare as described in Example 2. 5'-ssRNA-a has the nucleotide sequence of SEQ ID NO: 23, and its 5'-end is linked to a trivalent linker. 5'-ssDNA has the nucleotide sequence of SEQ ID NO: 25, and its 5'-end is linked to a trivalent linker. 5'-siRNA-a comprises a sense strand having the nucleotide sequence of SEQ ID NO: 23, and its 5'-end is linked to a trivalent linker, and further comprises an antisense strand having the nucleotide sequence of SEQ ID NO: 24.

[0418] In Scheme 25, oligonucleotides of compounds 25.1 (SEQ ID NO: 23), 25.2 (SEQ ID NO: 25), and 25.4 (SEQ ID NO: 24) were prepared by solid phase oligonucleotide synthesis.

[0419] Preparation of Compound 25.3. A solution of Compound 25.1 (60 mg, 9 μmol) and Compound 25.2 (81 mg, 11 μmol) in water (3 mL) was supplemented with copper(I) bromide dimethyl sulfide (4 mg, 19 μmol). After stirring at 60°C for 2 hours, NaOAc (246 mg, 3 mmol) was added. The reaction mixture was then centrifuged, and the precipitate was collected and dried to give Compound 25.3 (68 mg). Mass spectrum mass-to-charge ratio: [M+H] + C 512 H 682 F4N 163 O 281 P 41 S 25 The calculated value is 15763.37; the observed value is 15763.01.

[0420] Preparation of Compound B29a. To a solution (1 mL) of Compound 25.3 (68 mg) in water was added 30% aqueous NaOH (0.12 mL). After shaking at 35°C for 30 minutes, the reaction mixture was neutralized with HOAc. The precipitate was collected and dried to give the crude product (41 mg). This was purified by C18 reverse-phase preparative HPLC and concentrated to approximately 1 mL to give Compound B29a (13.9 mg) in 12% yield. Mass spectrum mass-to-charge ratio: [M+H] + C 494 H 664 F4N 163 O272 P 41 S 25 The calculated value of is 15385.03; the observed value is 15385.45. [ka] Note: Oligonucleotide, Annealing

[0421] Preparation of Compound A29a: An aqueous solution of Compound B29a (1 equivalent) and Oligonucleotide 25.4 (1 equivalent) was heated at 70-95°C for about 1-5 minutes, and then cooled to room temperature to obtain Compound A29a.

[0422] The methods for preparing GalNAc-siRNA complexes A4, A12, A14 to A16, A18 to A33, B4, B12, B14 to B16, and B18 to B33 are similar to the procedures described in the present invention. Example B1 Inhibition of ANGPTL3 and PCSK9 mRNA expression

[0423] Resuscitated primary human hepatocytes (PPH) were cultured at 6 × 10 5 Cells were seeded in a 96-well plate at a concentration of 10, 100, or 500 nM of GalNAc-siRNA complex A18a for 48 hours at 37°C under 5% CO2. After harvesting the cells by centrifugation, RNA was extracted from the cells and reverse-transcribed into cDNA. The mRNA expression levels of ANGPTL3 and PCSK9 were analyzed by qPCR. The results are summarized in Table 1. [Table 3] (Example B2) Inhibition of HAO1 and LDHA mRNA expression

[0424] Resuscitated primary human hepatocytes (PPH) were cultured at 6 × 10 5Cells were seeded into 96-well plates at 1000 cells / mL. Cells were treated with 10 nM, 100 nM, and 500 nM GalNAc-siRNA complex A18b at 37°C under 5% CO2 for 48 hours. After harvesting the cells by centrifugation, RNA was extracted from the cells and reverse transcribed into cDNA. The mRNA expression levels of HAO1 and LDHA were analyzed by qPCR. The results are summarized in Table 2. [Table 4] (Example B3) Inhibition of C3 and CFB mRNA expression

[0425] Resuscitated primary human hepatocytes (PPH) were cultured at 6 × 10 5 Cells were seeded in a 96-well plate at a concentration of 10, 100, or 500 nM of GalNAc-siRNA complex A18c for 48 hours at 37°C under 5% CO2. After harvesting the cells by centrifugation, RNA was extracted from the cells and reverse-transcribed into cDNA. The mRNA expression levels of C3 and CFB were analyzed by qPCR. The results are summarized in Table 3. [Table 5] (Example B4) Inhibition of mRNA expression in Hep3 B cells

[0426] Hep3 B cells were plated in OPTI-MEM medium at 2 x 10 cells per well in a 96-well plate. 5 Cells were seeded at a concentration of 0.1 nM / mL. Cells were treated with 0.1 nM and 1 nM GalNAc-siRNA complexes at 37°C under 5% CO2 for 24 hours. Cells were harvested by centrifugation, and RNA was extracted and reverse-transcribed into cDNA. The mRNA expression levels of ANGPTL3, C3, C5, CFB, and PCSK9 were analyzed by qPCR. The results are summarized in Tables 4–7. A indicates an inhibition rate of 80% or more, B indicates an inhibition rate of less than 80% and 60% or more, and C indicates an inhibition rate of less than 60% and 40% or more. [Table 6] [Table 7] [Table 8] [Table 9] (Example B5) Inhibition of mRNA expression in NCI-H1944 cells

[0427] NCI-H1944 cells were plated in OPTI-MEM medium at 2 × 10 cells per well in a 96-well plate. 5 Cells were seeded at a concentration of 0.1 nM / mL. Cells were treated with 0.1 nM and 1 nM GalNAc-siRNA complexes at 37°C under 5% CO2 for 24 hours. Cells were harvested by centrifugation, and RNA was extracted and reverse-transcribed into cDNA. HAO1 and LDHA mRNA expression levels were analyzed by qPCR. The results are summarized in Table 8. A indicates 80% or greater inhibition, B indicates less than 80% and more than 60% inhibition, and C indicates less than 60% and more than 40% inhibition. [Table 10] (Example B6) Effects of GalNAc-siRNA complexes on ANGPTL3, hPCSK9, LDL-C, and TG in hPCSK9-UTR mice

[0428] The inhibitory effects of GalNAc-siRNA complexes on ANGPTL3, hPCSK9, LDL-C, and TG were evaluated in hPCSK9-UTR mice. GalNAc-siRNA complexes (6 mg / kg) were subcutaneously administered to hPCSK9-UTR mice (6–8 weeks old) on day 0. Blood samples were collected from each mouse on days 0, 7, 14, 21, and 28. LDL-C and TG concentrations in each blood sample were analyzed by blood biochemistry. hPCSK9 and mANGPTL3 protein concentrations were analyzed by ELISA. The results are shown in Figures 1 and 2. (Example B7) Effects of GalNAc-siRNA complexes on C3, C5, and CFB

[0429] The inhibitory effects of GalNAc-siRNA complexes on C3, C5, and CFB were evaluated in mice. GalNAc-siRNA complexes (6 mg / kg) were subcutaneously administered to mice (6–8 weeks old) on day 0. Blood samples were collected from each mouse on days 0, 7, 14, 21, and 28. C3, C5, and CFB protein levels were analyzed by ELISA. The results are shown in Figure 3. (Example B8) Antiviral effect of GalNAc-siRNA complexes in HBV-infected mice

[0430] Fifteen specific pathogen-free (SPF) C57BL / 6 male mice were housed in a controlled environment for 7 days. Daily observations confirmed that the mice were healthy and normal. Each mouse was injected with rAAV8-1.3 HBV ayw virus (1 × 10 11The mice were intravenously injected with a dose of 1000 mg / 150 μL (vg / 150 μL). Four weeks after the intravenous injection, blood samples were collected from the orbital plexus of each mouse, and the plasma HBsAg concentration was measured. Based on the HBsAg detection level, 10 mice were randomly divided into two groups, with five mice in each group. Blood samples were collected on day 0, and HBV DNA and HBsAg were detected in the mouse serum. GalNAc-siRNA complexes were administered by subcutaneous injection on day 0. Blood samples were collected from each mouse on days 7, 14, 21, 28, 35, 42, 49, 56, and 63. The levels of HBV DNA, HBsAg, and HBsAb in the serum of each mouse were analyzed. The results are shown in Figures 4–6.

[0431] The sequences according to the present invention are shown in the sequence listing below. [Table 11] JPEG2025531341000183.jpg218169 * * * * *

[0432] The above examples are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to those of ordinary skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A carbohydrate-oligonucleotide conjugate comprising one ASGPR-binding group and two oligonucleotides.

2. 2. The carbohydrate-oligonucleotide conjugate of claim 1, comprising one ASGPR-binding group, two oligonucleotides, and one trivalent linker.

3. having the structure of formula (I): 【Chemical 1】 where: R １ is an ASGPR binding group; R ２ and R ３ are each independently an oligonucleotide; L １ , L ２ , L ３ａ and L ３ｃ are each an independent linker; L ３ｂ is (i) heteroarylene or heterocyclylene; or (ii) a bond; M is (i) N or CH; or (ii) trivalent C １－６ Alkyl, trivalent C １－６ Heteroalkyl, trivalent C １－６ Alkenyl, trivalent C ３－１０ Cycloalkyl, trivalent C ６－１４ aryl, trivalent heteroaryl, or trivalent heterocyclyl; wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene is optionally substituted with one or more substituents Q, in one embodiment 1, 2, 3, or 4 substituents Q, wherein each Q is independently selected from the following items (a) through (c): (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; and (c)-C(O)R ａ 、-C(O)OR ａ 、-C(O)NR ｂ R ｃ 、-C(O)SR ａ 、-C(NR ａ )NR ｂ R ｃ 、-C(S)R ａ 、-C(S)OR ａ 、-C(S)NR ｂ R ｃ 、-OR ａ 、-OC(O)R ａ 、-OC(O)OR ａ 、-OC(O)NR ｂ R ｃ 、-OC(O)SR ａ 、-OC(NR ａ )NR ｂ R ｃ 、-OC(S)R ａ 、-OC(S)OR ａ 、-OC(S)NR ｂ R ｃ 、-OP(O)(OR ｂ )OR ｃ 、-OS(O)R ａ 、-OS(O) ２ R ａ 、-OS(O)NR ｂ R ｃ 、-OS(O) ２ NR ｂ R ｃ 、-NR ｂ R ｃ 、-NR ａ C(O)R ｄ 、-NR ａ C(O)OR ｄ 、-NR ａ C(O)NR ｂ R ｃ 、-NR ａ C(O)SR ｄ 、-NR ａ C(NR ｄ )NR ｂ R ｃ 、-NR ａ C(S)R ｄ 、-NR ａ C(S)OR ｄ 、-NR ａ C(S)NR ｂ R ｃ , -NR ａ S(O)R ｄ , -NR ａ S (O) ２ R ｄ , -NR ａ S(O)NR ｂ R ｃ , -NR ａ S (O) ２ NR ｂ R ｃ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ｂ R ｃ , and -S(O) ２ NR ｂ R ｃ , In the case of (b), each group may further comprise one or more (in one embodiment, one, two, three, or four) substituents Q ａ optionally replaced by In the case of (c), each R ａ , R ｂ , R ｃ and R ｄ are independently (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl, each of which is substituted with one or more (in one embodiment, one, two, three, or four) substituents Q ａ or (iii) R ｂ and R ｃ together with the N atom to which they are attached form a heterocyclyl, and one or more (in one embodiment, one, two, three, or four) substituents Q ａ optionally substituted with; Here, each Q ａ are (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; (c) —C(O)R ｅ , -C(O)OR ｅ , —C(O)NR ｆ R ｇ , -C(O)SR ｅ , -C(NR ｅ ) NR ｆ R ｇ , -C(S)R ｅ , -C(S)OR ｅ , -C(S)NR ｆ R ｇ , -OR ｅ , -OC(O)R ｅ , -OC(O)OR ｅ , -OC(O)NR ｆ R ｇ , -OC(O)SR ｅ , -OC(NR ｅ ) NR ｆ R ｇ , -OC(S)R ｅ , -OC(S)OR ｅ , -OC(S)NR ｆ R ｇ , -OP(O)(OR ｆ ) OR ｇ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｆ R ｇ , -OS(O) ２ NR ｆ R ｇ , -NR ｆ R ｇ , -NR ｅ C(O)R ｈ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｆ R ｇ , -NR ｅ C(O)SR ｆ , -NR ｅ C (NR ｈ ) NR ｆ R ｇ , -NR ｅ C(S)R ｈ , -NR ｅ C(S)OR ｆ , -NR ｅ C(S)NR ｆ R ｇ , -NR ｅ S(O)R ｈ , -NR ｅ S (O) ２ R ｈ , -NR ｅ S(O)NR ｆ R ｇ , -NR ｅ S (O) ２ NR ｆ R ｇ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｆ R ｇ and -S(O) ２ NR ｆ R ｇ and each R in (c) is independently selected from ｅ , R ｆ , R ｇ and R ｈ are independently (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ｆ and R ｇ The carbohydrate-oligonucleotide conjugate of claim 1 or 2, wherein together with the N atom to which they are attached form a heterocyclyl.

4. L ３ｂ The carbohydrate-oligonucleotide conjugate of claim 3 , wherein is heteroarylene and is optionally substituted with one or more substituents Q.

5. L ３ｂ The carbohydrate-oligonucleotide conjugate of claim 3 or 4, wherein is a monocyclic heteroarylene, optionally substituted with one or more substituents Q.

6. L ３ｂ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 5, wherein is a five-membered heteroarylene, optionally substituted with one or more substituents Q.

7. L ３ｂ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 6, wherein is [1,2,3]triazolediyl, optionally substituted with one or more substituents Q.

8. having the structure of formula (II): 【Chemistry 2】 The carbohydrate-oligonucleotide conjugate according to any one of claims 3 to 7.

9. R １ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 8, wherein is an ASGPR binding group consisting of about 1 to about 10 N-acetylgalactosamines.

10. R １ 10. The carbohydrate-oligonucleotide conjugate of claim 3, wherein is an ASGPR binding group consisting of about 1, about 2, about 3, about 4, or about 5 N-acetylgalactosamines.

11. R １ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 10, wherein is an ASGPR binding group consisting of about 2, about 3, or about 4 N-acetylgalactosamines.

12. R １ is an ASGPR binding group having the structure of formula (AI), 【Chemistry 3】 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; Here, E ａ and b are respectively (i) b is an integer equal to 2; E ａ is a trivalent linker; (ii) b is an integer equal to 1; ａ is a bond, CH ２ or NH; or (iii) b is an integer of 3; E ａ is a tetravalent linker; Each L ａ The carbohydrate-oligonucleotide conjugate according to any one of claims 3 to 11, wherein is an independent linker.

13. b is an integer of 2; E ａ The carbohydrate-oligonucleotide conjugate of claim 12, wherein is a trivalent linker.

14. E ａ The carbohydrate-oligonucleotide conjugate of claim 12 or 13, wherein is CH or N.

15. b is an integer of 3, and E ａ The carbohydrate-oligonucleotide conjugate of claim 12, wherein is a tetravalent linker.

16. E ａ The carbohydrate-oligonucleotide conjugate of claim 15, wherein

17. Each L ａ is independently -Z ｎ -(R ｎ -Z ｎ ) ｚ - is a linker having the structure Here, each R ｎ is independently C １－１０ Alkylene, C ２－１０ Alkenylene, C ２－１０ Alkynylene, C ３－１０ Cycloalkylene, C ６－１４ arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q; Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, or —C(O)NR １ｂ -, -C(O)S-, -C(NR １ａ ) NR １ｂ -, -C(S)-, -C(S)O-, -C(S)NR １ｂ -, -C(R １ａ )=NO-, -O-, -OC(O)O-, -OC(O)NR １ｂ -, -OC(O)S-, -OC(NR １ａ ) NR １ｂ -, -OC(S)O-, -OC(S)NR １ｂ -, -OS(O)-, -OS(O) ２ -, -OS(O)NR １ｂ -, -OS(O) ２ NR １ｂ -, -NR １ｂ -, -NR １ａ C(O)NR １ｂ -, -NR １ａ C(O)S-, -NR １ａ C (NR １ｄ ) NR １ｂ -, -NR １ａ C(S)NR １ｂ -, -NR １ａ S(O)NR １ｂ -, -NR １ａ S (O) ２ NR １ｂ -, -P(O ２ )O-, -P(O)(S)O-, -S-, -S(O)-, -S(O) ２ -, -S(O)NR １ｂ -, or -S(O) ２ NR １ｂ - and; Each R １ａ , R １ｂ , R １ｃ and R １ｄ are independently (i) hydrogen or deuterium; or (ii) C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; 17. The carbohydrate-oligonucleotide conjugate of any one of claims 12 to 16, wherein z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

18. Each R ｎ is independently C １－１０ Alkylene, C ６－１４ 18. The carbohydrate-oligonucleotide conjugate of claim 17, wherein the carbohydrate-oligonucleotide conjugate is arylene or heteroarylene, each of which is optionally substituted with one or more substituents Q.

19. Each R ｎ is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazolediyl, pyrrolidinediyl, or piperidinediyl, each optionally substituted with one, two, or three substituents Q.

20. Each R ｎ is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,3-diyl, or piperidine-1,4-diyl, each optionally substituted with one or more substituents Q.

21. Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH ３ ) = NO-, -O-, -OP(O ２ ) O-, -OP(O ２ )S-, -NH-, -N(CH ３ )-, -S-, or -S(O) ２ The carbohydrate-oligonucleotide conjugate according to any one of claims 17 to 20, wherein

22. Each Z ｎ are independently a bond, —C(O)NH—, —O—, —OP(O ２ ) O-, -OP(O ２ 22. The carbohydrate-oligonucleotide conjugate of claim 17, wherein the carbohydrate-oligonucleotide conjugate is -S-, or -NH-.

23. 23. The carbohydrate-oligonucleotide conjugate of any one of claims 17 to 22, wherein z is an integer of 0, 1, 2, 3, 4, or 5.

24. Each L ａ is, independently, 【Chemistry 4】 The carbohydrate-oligonucleotide conjugate according to any one of claims 17 to 23, wherein

25. The ASGPR binding group has the structure of formula (AV): 【Chemistry 5】 or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; Here, E ｂ and c are respectively (iv) c is an integer of 2, and E ｂ is a trivalent linker; (v) c is an integer equal to 1; ｂ is a bond; or (vi) c is an integer of 3; E ｂ is a tetravalent linker; E ｃ and d are respectively (iv) d is an integer equal to 1; E ｃ is a bond; (v) d is an integer of 2, and E ｃ is a trivalent linker; or (vi) d is an integer of 3; E ｃ is a tetravalent linker; G is a trivalent linker; and Each L ｂ and L ｃ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 11, wherein are independently bivalent linkers.

26. c is an integer of 2, and E ｂ The carbohydrate-oligonucleotide conjugate of claim 25, wherein is a trivalent linker.

27. E ｂ teeth, 【Chemistry 6】 26. The carbohydrate-oligonucleotide conjugate of claim 25, wherein

28. c is an integer equal to 1, and E ｂ The carbohydrate-oligonucleotide conjugate of claim 25, wherein is a bond.

29. d is an integer of 2, and E ｃ The carbohydrate-oligonucleotide conjugate of any one of claims 25 to 28, wherein is a trivalent linker.

30. E ｃ teeth, 【Chemistry 7】 30. The carbohydrate-oligonucleotide conjugate of any one of claims 25 to 29, wherein

31. Each L ｂ and L ｃ is independently -Z ｎ -(R ｎ -Z ｎ ) ｚ - is a linker having the structure Each R ｎ is independently C １－１０ Alkylene, C ２－１０ Alkenylene, C ２－１０ Alkynylene, C ３－１０ Cycloalkylene, C ６－１４ arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents; Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, or —C(O)NR １ｂ -, -C(O)S-, -C(NR １ａ ) NR １ｂ -, -C(S)-, -C(S)O-, -C(S)NR １ｂ -, -C(R １ａ )=NO-, -O-, -OC(O)O-, -OC(O)NR １ｂ -, -OC(O)S-, -OC(NR １ａ ) NR １ｂ -, -OC(S)O-, -OC(S)NR １ｂ -, -OS(O)-, -OS(O) ２ -, -OS(O)NR １ｂ -, -OS(O) ２ NR １ｂ -, -NR １ｂ -, -NR １ａ C(O)NR １ｂ -, -NR １ａ C(O)S-, -NR １ａ C (NR １ｄ ) NR １ｂ -, -NR １ａ C(S)NR １ｂ -, -NR １ａ S(O)NR １ｂ -, -NR １ａ S (O) ２ NR １ｂ -, -P(O ２ )O-, -P(O)(S)O-, -S-, -S(O)-, -S(O) ２ -, -S(O)NR １ｂ -, or -S(O) ２ NR １ｂ - and; Each R １ａ , R １ｂ , R １ｃ and R １ｄ are independently (i) hydrogen or deuterium; or (ii) C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents; 31. The carbohydrate-oligonucleotide conjugate of any one of claims 25 to 30, wherein z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

32. Each R ｎ is independently C １－１０ Alkylene, C ６－１４ 32. The carbohydrate-oligonucleotide conjugate of claim 31, wherein the carbohydrate is arylene or heteroarylene, each of which is optionally substituted with one or more substituents Q.

33. Each R ｎ is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazolediyl, pyrrolidinediyl, or piperidinediyl, each optionally substituted with one, two, or three substituents Q.

34. Each R ｎ is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,3-diyl, or piperidine-1,4-diyl, each substituted with one or more substituents Q.

35. Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH ３ ) = NO-, -O-, -OP(O ２ ) O-, -OP(O ２ )S-, -NH-, -N(CH ３ ) -, -P(O ２ )O-, -P(O)(S)O-, -S-, or -S(O) ２ The carbohydrate-oligonucleotide conjugate according to any one of claims 31 to 34, wherein

36. Each Z ｎ are independently a bond, —C(O)NH—, —O—, —OP(O ２ ) O-, -OP(O ２ 36. The carbohydrate-oligonucleotide conjugate of any one of claims 31 to 35, wherein the carbohydrate-oligonucleotide conjugate is -S-, or -NH-.

37. 37. The carbohydrate-oligonucleotide conjugate of any one of claims 31 to 36, wherein z is an integer of 0, 1, 2, 3, 4, or 5.

38. L ｂ and L ｃ are each independently 【Chemistry 8】 38. The carbohydrate-oligonucleotide conjugate of claim 31, wherein

39. R １ is an ASGPR binding group having the structure: 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 、 A carbohydrate-oligonucleotide conjugate according to any one of claims 3 to 38.

40. R ２ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 39, wherein is a double-stranded siRNA.

41. 41. The carbohydrate-oligonucleotide conjugate of claim 40, wherein each strand of the double-stranded siRNA is independently about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

42. R ２ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 39, wherein is a single-stranded oligonucleotide.

43. R ２ The carbohydrate-oligonucleotide conjugate of claim 42, wherein is a single-stranded oligodeoxyribonucleotide.

44. 44. The carbohydrate-oligonucleotide conjugate of claim 42 or 43, wherein the single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

45. R ３ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 44, wherein is a double-stranded siRNA.

46. 46. ​​The carbohydrate-oligonucleotide conjugate of claim 45, wherein each strand of the double-stranded siRNA independently comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

47. R ３ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 44, wherein is a single-stranded oligonucleotide.

48. R ３ The carbohydrate-oligonucleotide conjugate of claim 47, wherein is a single-stranded oligodeoxyribonucleotide.

49. 49. The carbohydrate-oligonucleotide conjugate of claim 47 or 48, wherein the single-stranded oligonucleotide comprises about 10 to about 50, about 10 to about 30, or about 15 to about 25 nucleotides.

50. 50. The carbohydrate-oligonucleotide conjugate of any one of claims 41, 44, 46, and 49, wherein each nucleotide is independently a natural or modified nucleotide.

51. 51. The carbohydrate-oligonucleotide conjugate of any one of claims 41, 44, 46, 49, and 50, wherein each nucleotide is independently adenylic acid, cytidylic acid, guanylic acid, uridylic acid, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxythymidine, 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine, or 2'-O-methyluridine.

52. 52. The carbohydrate-oligonucleotide conjugate of any one of claims 41 to 51, wherein each chain has one or more phosphate linking groups, each group being independently substituted by phosphorothioate or phosphorodithioate.

53. R ２ 53. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 41 and 45 to 52, which is a double-stranded siRNA and comprises the paired nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:

24.

54. R ２ 54. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 41 and 45 to 53, which is a double-stranded siRNA and comprises a pair of nucleotides of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:19 and SEQ ID NO:20, or SEQ ID NO:23 and SEQ ID NO:

24.

55. R ３ 55. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 46 and 50 to 54, which is a double-stranded siRNA and comprises a pair of nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:

24.

56. R ３ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 46 and 50 to 55, which is a double-stranded siRNA and comprises a pair of nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, or SEQ ID NO:21 and SEQ ID NO:

22.

57. R ３ is a single-stranded oligonucleotide having a nucleotide sequence comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:

25.

58. L １ , L ２ , L ３ａ and L ３ｃ are each independently -Z ｎ -(R ｎ -Z ｎ ) ｚ - a linker having the structure: Each R ｎ is independently C １－１０ Alkylene, C ２－１０ Alkenylene, C ２－１０ Alkynylene, C ３－１０ Cycloalkylene, C ６－１４ arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents; Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, or —C(O)NR １ｂ -, -C(O)S-, -C(NR １ａ ) NR １ｂ -, -C(S)-, -C(S)O-, -C(S)NR １ｂ -, -C(R １ａ )=NO-, -O-, -OC(O)O-, -OC(O)NR １ｂ -, -OC(O)S-, -OC(NR １ａ ) NR １ｂ -, -OC(S)O-, -OC(S)NR １ｂ -, -OS(O)-, -OS(O) ２ -, -OS(O)NR １ｂ -, -OS(O) ２ NR １ｂ -, -NR １ｂ -, -NR １ａ C(O)NR １ｂ -, -NR １ａ C(O)S-, -NR １ａ C (NR １ｄ ) NR １ｂ -, -NR １ａ C(S)NR １ｂ -, -NR １ａ S(O)NR １ｂ -, -NR １ａ S (O) ２ NR １ｂ -, -P(O ２ )O-, -P(O)(S)O-, -S-, -S(O)-, -S(O) ２ -, -S(O)NR １ｂ -, or -S(O) ２ NR １ｂ - and; Each R １ａ , R １ｂ , R １ｃ and R １ｄ are independently (i) hydrogen or deuterium; or (ii) C １－６ Alkyl, C １－６ Heteroalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents; and 58. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 57, wherein z is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

59. Each R ｎ is independently C １－１０ Alkylene, C ６－１４ 59. The carbohydrate-oligonucleotide conjugate of claim 58, wherein the carbohydrate-oligonucleotide conjugate is arylene or heteroarylene, each of which is optionally substituted with one or more substituents Q.

60. Each R ｎ is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, phendiyl, 1,2,3-triazolediyl, or pyrrolidinediyl, each optionally substituted by one, two, or three substituents Q.

61. Each R ｎ is independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or pyrrolidine-1,3-diyl, each substituted with one or more substituents Q.

62. Each Z ｎ are independently a bond, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)NH—, —C(CH ３ ) = NO-, -O-, -OP(O ２ ) O-, -OP(O ２ )S-, -NH-, -N(CH ３ ) -, -P(O ２ ) O-, -P(O ２ ) S-, -S-, or -S(O) ２ 62. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 61, wherein

63. Each Z ｎ are independently a bond, —C(O)NH—, —O—, —OP(O ２ ) O-, -OP(O ２ )S-, -NH-, -P(O ２ ) O-, or -P(O ２ 63. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 62, wherein:

64. 64. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 63, wherein z is an integer of 0, 1, 2, 3, 4, or 5.

65. L １ is -NHC(O)(CH ２ ) ｅ 65. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 64, wherein e is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

66. L １ teeth, 【Chemistry 10】 66. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 65, wherein

67. L ２ is -X(CH ２ ) ｈ 67. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, having the structure X-, where each X is independently -O-, -S-, or -N(H)-; and h is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

68. L ２ is -X(CH ２ ) ｉ CH(OH)(CH ２ ) ｊ 67. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, having the structure X-, wherein each X is independently -O-, -S-, or -N(H)-; and i and j are each independently an integer of 2, 3, 4, 5, 6, 7, 8, 9, or 10.

69. L ２ teeth, 【Chemistry 11】 and L ２ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein is linked to the 5'-end of the oligonucleotide.

70. L ２ teeth, 【Chemistry 12】 and L ２ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein is linked to the 3'-end of the oligonucleotide.

71. L ２ teeth, 【Chemistry 13】 having the structure 67. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66.

72. L ３ａ は、-CH ２ -、-CH ２ CH ２ -、-CH ２ CH ２ CH ２ -、-CH ２ CH ２ CH ２ CH ２ - 【Chemistry 14】 That is, A carbohydrate-oligonucleotide conjugate according to any one of claims 3 to 71.

73. L ３ｃ is -X(CH ２ ) ｐ 73. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, having the structure X-, where each X is independently -O-, -S-, or -N(H)-; and p is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

74. L ３ｃ is -X(CH ２ ) ｑ CH(OH)(CH ２ ) ｒ 73. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, having the structure X-; each X is independently -O-, -S-, or -N(H)-; and q and r are each independently an integer of 2, 3, 4, 5, 6, 7, 8, 9, or 10.

75. L ３ｃ teeth, 【Chemistry 15】 and L ３ｃ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein is linked to the 5'-end of the oligonucleotide.

76. L ３ｃ teeth, 【Chemistry 16】 and L ３ｃ The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein is linked to the 3'-end of the oligonucleotide.

77. L ３ｃ teeth, 【Chemistry 17】 73. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein

78. M is N, CH, or C(CH ３ 78. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 77, wherein

79. It is a trivalent group 【Chemistry 18】 has the following structure: 【Chemistry 19】 【change】 【change】 【change】 【change】 、 A carbohydrate-oligonucleotide conjugate according to any one of claims 3 to 78. 【Request 80】 【Chemical 20】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 It has a structure like Here, each 3'-siRNA independently represents an siRNA having one of its 3'-ends linked to a trivalent linker, each 5'-siRNA independently represents an siRNA having one of its 5'-ends linked to a trivalent linker; and 5'-ssDNA independently represents a single-stranded DNA having one of its 5'-ends linked to a trivalent linker. The carbohydrate-oligonucleotide conjugate according to any one of claims 1 to 3.

81. 【Catalog 21】 It has a structure like The carbohydrate-oligonucleotide conjugate of claim 1, wherein 3'-siRNA means that one of the 3'-ends of the siRNA is linked to a first bivalent linker and one of the 5'-ends is linked to a second bivalent linker; and 5'-siRNA means that one of the 5'-ends of the siRNA is linked to a second bivalent linker.

82. 82. The carbohydrate-oligonucleotide conjugate of claim 80 or 81, wherein each double-stranded oligonucleotide independently comprises a pair of nucleotide sequences: SEQ ID NO:1 and SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22, or SEQ ID NO:23 and SEQ ID NO:

24.

83. 81. The carbohydrate-oligonucleotide conjugate of claim 80, wherein each single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:

25.

84. A pharmaceutical composition comprising the carbohydrate-oligonucleotide conjugate of any one of claims 1 to 83 and a pharmaceutically acceptable excipient.

85. 85. The pharmaceutical composition of claim 84, wherein the composition is in a unit dosage form.

86. 86. The pharmaceutical composition of claim 84 or 85, wherein the composition is in a parenteral or intravenous dosage form.

87. 87. The pharmaceutical composition of claim 86, formulated in an intravenous dosage form.

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