Carbohydrate-oligonucleotide conjugates, pharmaceutical compositions and therapeutic applications

Abstract

The invention provides a carbohydrate-oligonucleotide conjugate, a compound as shown in a formula (I) and a pharmaceutical composition of the carbohydrate-oligonucleotide conjugate. The invention also provides methods of therapeutic use thereof for treating, preventing or ameliorating one or more symptoms of a disorder, disease or condition. # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Pursuant to Section 119(a) of Title 35 of the United States Patent Act, this application claims priority to International Application No. PCT / CN2022 / 119522, filed on September 19, 2022, and International Application No. PCT / CN2023 / 095768, filed on May 23, 2023; the disclosure of each of the above applications is incorporated herein by reference in its entirety. field

[0002] The present invention provides a carbohydrate-oligonucleotide conjugate and a pharmaceutical composition thereof, and also provides a method for using the conjugate in treating, preventing or ameliorating one or more symptoms of disorders, diseases or conditions. References to sequence listings

[0003] This specification is submitted together with a sequence listing named "413A003WO01_SEQLIST_ST26.XML", which is 23144 bytes in size and was created on September 16, 2023; its contents are incorporated herein by reference in their entirety. Background Art

[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 Reviews: Drug Discovery, 2020, Vol. 19, pp. 673-694 (Roberts et al., Nat. Rev. Drug Dis. 2020, 19, 673-94). ASO is a single-stranded oligonucleotide that specifically binds to the target mRNA through Watson-Crick base pairing, thereby regulating the production of pathogenic proteins. Dhuri et al., Journal of Clinical Medicine, 2020, Vol. 9, p. 2004 (Dhuri et al., J. Clin. Med. 2020, 9, 2004). siRNA is a double-stranded RNA molecule that induces gene silencing by targeting and degrading complementary mRNA. 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., Chem Med Chem. 2010, 5, 328-349. When silencing the target gene, siRNA first binds to the RNA-induced silencing complex (RISC). Hammond et al., Nature, 2000, 404, 293-296. In RISC, the two strands of siRNA are separated, and the antisense strand forms an activated RISC with RISC, which binds to the target mRNA molecule for cutting. Nykanen et al., Cell, 2001, Vol. 107, pp. 309-321; Martinez et al., Cell, 2002, Vol. 110, pp. 563-574 (Nykanen et al., Cell 2001, 107, 309-21; Martinez et al., Cell 2002, 110, 563-74). This gene silencing process is carried out by sequence-specific hybridization of the guide RNA to the mRNA target site, and brings RISC close to its target mRNA molecule, which is then cut by the RISC nuclease Argonaute 2 (Ago 2).Liu et al., Science, 2004, Vol. 305, pp. 1437-1441; Rand et al., Proceedings of the National Academy of Sciences of the United States of America, 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, 305, 1437-41; Rand et al., Proc. Natl. Acad. Sci. USA 2004, 101, 14385-9; Rivas et al., Nat. Struct. Mol. Biol. 2005, 12, 340-9). Since RISC can be restored in subsequent cycles, this forms a catalytic process that leads to a selective reduction in specific mRNA molecules, thereby reducing the expression of the target gene.

[0005] In general, therapeutic oligonucleotides are specific and highly effective in regulating disease-related genes. Hu et al., Signal Transduction and Targeted Therapy, 2020, Vol. 5, p. 101; Alshaer et al., European Journal of Pharmacology, 2021, Vol. 905, p. 174178 (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 their poor cellular uptake and susceptibility to nuclease-mediated degradation. Roberts et al., Nature Reviews: Drug Discovery, 2020, Vol. 19, pp. 673-694; Gagliardi and Ashizawa, Biomedicines, 2021, Vol. 9, p. 433; Friedrich and Aigner, Biodrugs, 2022, pp. 1-23 (Roberts et al., Nat. Rev. Drug Dis. 2020, 19, 673-94; Gagliardi and Ashizawa, Biomedicines 2021, 9, 433; Friedrich and Aigner, BioDrugs 2022, 1-23). ​​Therefore, therapeutic oligonucleotides with drug properties suitable for therapeutic applications are needed. Summary of the invention

[0006] The invention provides a carbohydrate-oligonucleotide conjugate, which comprises an asialoglycoprotein receptor (ASGPR) binding group and two oligonucleotides.

[0007] The present invention also provides a carbohydrate-oligonucleotide conjugate, which comprises an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a trivalent linker or a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence and the end of the second sense or antisense sequence through the trivalent linker; or wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence through the first divalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to the end of the second sense or antisense sequence through the second divalent linker.

[0008] In addition, the present invention also provides a carbohydrate-oligonucleotide conjugate, which includes an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence and the end of the second sense or antisense sequence through the trivalent linker.

[0009] In addition, the present invention also provides a carbohydrate-oligonucleotide conjugate, which includes an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence through the first divalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to the end of the second sense or antisense sequence through the second divalent linker.

[0010] The present invention provides a carbohydrate-oligonucleotide conjugate, which comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a trivalent linker or a first and a second divalent linker; 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 through the trivalent linker; or wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide through the first divalent linker, and the other end of the first single-stranded oligonucleotide is connected to one end of the second single-stranded oligonucleotide through the second divalent linker.

[0011] The present invention provides a carbohydrate-oligonucleotide conjugate, comprising an ASGPR binding group, a first and a second single-stranded oligonucleotide, 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 through the trivalent linker.

[0012] The carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a first and a second divalent linker; wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide through the first divalent linker, and the other end of the first single-stranded oligonucleotide is connected to one end of the second single-stranded oligonucleotide through the second divalent linker.

[0013] The present invention provides a pharmaceutical composition, comprising the carbohydrate-oligonucleotide conjugate provided by the present invention and a pharmaceutically acceptable excipient.

[0014] 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 DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The effects of GalNAc-siRNA conjugates on hPCSK9 and mANGPTL3 protein levels in hPCSK9-UTR mice are shown.

[0016] Figure 2 The effects of GalNAc-siRNA conjugates on LDL-C and TG levels in hPCSK9-UTR mice are shown.

[0017] Figure 3 The effects of GalNAc-siRNA conjugates on C3, C5, and CFB protein levels in mice are shown.

[0018] Figure 4 The effect of GalNAc-siRNA conjugate A18f on the HBsAg level in the plasma of HBV-infected mice was demonstrated.

[0019] Figure 5 The effect of GalNAc-siRNA conjugate A18f on the number of HBV-infected mice with plasma HBsAb levels greater than 10 mIV / mL is shown.

[0020] Figure 6 The effect of GalNAc-siRNA conjugate A18f on the HBV DNA level in the plasma of HBV-infected mice was demonstrated. Illustrative Embodiments

[0021] Embodiment 1. A carbohydrate-oligonucleotide conjugate comprises an ASGPR binding group and two oligonucleotides.

[0022] Embodiment 2. The carbohydrate-oligonucleotide conjugate of embodiment 1, comprising an ASGPR binding group, two oligonucleotides and a trivalent linker.

[0023] Embodiment 3. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 2, comprising an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is linked to the end of the first sense or antisense sequence and the end of the second sense or antisense sequence via the trivalent linker.

[0024] Embodiment 4. The carbohydrate-oligonucleotide conjugate of embodiment 2 or 3, wherein the ASGPR binding group is linked 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.

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

[0026] Embodiment 6. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is linked to the 3'-end of the first sense sequence and the 5'-end of the second sense sequence via a trivalent linker.

[0027] Embodiment 7. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is linked to the 3'-end of the first sense sequence and the 3'-end of the second sense sequence via a trivalent linker.

[0028] Embodiment 8. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is linked to the 5'-end of the first antisense sequence and the 5'-end of the second antisense sequence via a trivalent linker.

[0029] Embodiment 9. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is linked to the 3'-end of the first antisense sequence and the 5'-end of the second antisense sequence via a trivalent linker.

[0030] Embodiment 10. The carbohydrate-oligonucleotide conjugate of any one of embodiments 2 to 4, wherein the ASGPR binding group is linked to the 3'-end of the first antisense sequence and the 3'-end of the second antisense sequence via a trivalent linker.

[0031] Embodiment 11. The carbohydrate-oligonucleotide conjugate of embodiment 1, comprising an ASGPR binding group, two oligonucleotides and two divalent linkers.

[0032] Embodiment 12. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 11, comprising an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is linked to an end of the first sense or antisense sequence via the first divalent linker, and one of the remaining ends of the first sense or antisense sequence is linked to an end of the second sense or antisense sequence via the second divalent linker.

[0033] Embodiment 13. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3 to 10 and 12, wherein the first oligonucleotide duplex is a double-stranded siRNA.

[0034] Embodiment 14. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3 to 10, 12 and 13, wherein each strand of the first oligonucleotide duplex independently comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0035] Embodiment 15. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3 to 10 and 12 to 14, wherein the second oligonucleotide duplex is a double-stranded siRNA.

[0036] Embodiment 16. The carbohydrate-oligonucleotide conjugate of any one of embodiments 3 to 10 and 12 to 15, wherein each strand of the second oligonucleotide duplex independently comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0037] Embodiment 17. The carbohydrate-oligonucleotide conjugate of embodiment 14 or 16, wherein each nucleotide is independently a natural nucleotide or a modified nucleotide.

[0038] 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.

[0039] Embodiment 19. The carbohydrate-oligonucleotide conjugate of any one of embodiments 14 and 16 to 18, wherein each chain has one or more phosphate attachment groups, each group being independently substituted with phosphorothioate or phosphorodithioate.

[0040] Embodiment 20. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 2, comprising an ASGPR binding group, a first and a second single-stranded oligonucleotide, 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.

[0041] Embodiment 21. The carbohydrate-oligonucleotide conjugate of embodiment 20, wherein the ASGPR binding group is linked to the 5'-end of the first single-stranded oligonucleotide and the 5'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0042] Embodiment 22. The carbohydrate-oligonucleotide conjugate of embodiment 20, wherein the ASGPR binding group is linked to the 3'-end of the first single-stranded oligonucleotide and the 5'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0043] Embodiment 23. The carbohydrate-oligonucleotide conjugate of embodiment 20, wherein the ASGPR binding group is linked to the 3'-end of the first single-stranded oligonucleotide and the 3'-end of the second single-stranded oligonucleotide via a trivalent linker.

[0044] Embodiment 24. The carbohydrate-oligonucleotide conjugate of embodiment 1 or 11, comprising an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a first and a second divalent linker; wherein the ASGPR binding group is connected to one end of the first single-stranded oligonucleotide via the first divalent 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 divalent linker.

[0045] Embodiment 25. The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 24, wherein the first single-stranded oligonucleotide is single-stranded RNA.

[0046] Embodiment 26. The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 25, wherein the first single-stranded oligonucleotide comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0047] Embodiment 27. The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 26, wherein the second single-stranded oligonucleotide is single-stranded RNA.

[0048] Specific embodiment 28. The carbohydrate-oligonucleotide conjugate of any one of embodiments 20 to 27, wherein the second single-stranded oligonucleotide comprises from about 10 to about 50, from about 10 to about 30, or from about 15 to about 25 nucleotides.

[0049] Embodiment 29. The carbohydrate-oligonucleotide conjugate of embodiment 26 or 28, wherein each nucleotide is independently a natural nucleotide or a modified nucleotide.

[0050] 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.

[0051] Embodiment 31. The carbohydrate-oligonucleotide conjugate of any one of embodiments 26 and 28 to 30, wherein each single-stranded oligonucleotide has one or more phosphate linking groups independently substituted with phosphorothioate or phosphorodithioate.

[0052] 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 a siRNA.

[0053] Embodiment 33. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 32, wherein the ASGPR binding group comprises from about 1 to about 10 N-acetylgalactosamines.

[0054] 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.

[0055] Embodiment 32. 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.

[0056] Embodiment 36. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 35, wherein the ASGPR binding group has a structure of formula (AI): 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 a and b are (iv) b is an integer 1; and E a is a bond, CH2 or NH; (v) b is the integer 2; and E a is a trivalent linker; or (vi) b is the integer 3; and E a is a tetravalent linker; and Each L a They are all independent connectors.

[0057] Embodiment 37. The carbohydrate-oligonucleotide conjugate of embodiment 36, wherein b is an integer of 2; E a It is a trivalent linker.

[0058] Embodiment 38. The carbohydrate-oligonucleotide conjugate of embodiment 37, wherein E a It is CH.

[0059] Embodiment 39. The carbohydrate-oligonucleotide conjugate of embodiment 37, wherein E a It is N.

[0060] Embodiment 40. The carbohydrate-oligonucleotide conjugate of embodiment 36, wherein b is an integer of 3, E a It is a tetravalent linker.

[0061] Embodiment 41. The carbohydrate-oligonucleotide conjugate of embodiment 40, wherein E a It is C.

[0062] Embodiment 42. The carbohydrate-oligonucleotide conjugate of any one of embodiments 36 to 41, wherein each L a Independently is with -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 an arylene group, a heteroarylene group or a heterocyclylene group; Each Z nare independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)2NR 1b -; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, 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; and z is an integer 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, wherein each Q is independently 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, each of which is further substituted by one or more (in one embodiment one, two, three or four) substituents Q a Optionally substituted; (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 b R c 、-NR aC(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 and -S(O)2NR b R c , where 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 optionally substituted by 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, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a replace; Each Q a are independently selected from the group consisting of: (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 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 、-NRe 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 g and -S(O)2NR f R g ; where 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

[0063] Embodiment 43. The carbohydrate-oligonucleotide conjugate of embodiment 42, wherein each R n Independently for C 1-10 Alkylene, C 6-14 Arylene, heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

[0064] Embodiment 44. The carbohydrate-oligonucleotide conjugate of embodiment 42 or 43, wherein each R nis independently methanediyl, ethanediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl or 1,2,3-triazolediyl, pyrrolidinediyl or piperidinediyl, each optionally substituted with one, two or three substituents Q.

[0065] Embodiment 45. The carbohydrate-oligonucleotide conjugate of any one of embodiments 42 to 44, wherein each R n is independently methane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-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.

[0066] 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-.

[0067] 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-.

[0068] Embodiment 48. The carbohydrate-coordinating nucleotide 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.

[0069] Embodiment 49. The carbohydrate-coordination nucleotide conjugate of any one of embodiments 42 to 48, wherein z is an integer of 0, 1, 2, 3, 4 or 5.

[0070] Embodiment 50. The carbohydrate-oligonucleotide conjugate of any one of embodiments 36 to 42, wherein each L a Independent as:

[0071] Embodiment 51. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 35, wherein the ASGPR binding group has a structure of formula (AV): 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 c are (iv) c is an integer 1; and E b is the key; (v) c is the integer 2; and E b is a trivalent linker; or (vi) c is the integer 3; and E b is a tetravalent linker; E c and d are (iv) d is an integer 1; and E c is the key; (v) d is the integer 2; and E c is a trivalent linker; or (vi) d is the integer 3; and E c is a tetravalent linker; G is a trivalent linker; and Each L b and L c They are all independent divalent linkers.

[0072] Embodiment 52. The carbohydrate-oligonucleotide conjugate of embodiment 51, wherein c is an integer of 1; E b is the key.

[0073] Embodiment 53. The carbohydrate-oligonucleotide conjugate of embodiment 51, wherein c is an integer of 2; E b It is a trivalent linker.

[0074] Embodiment 54. The carbohydrate-oligonucleotide conjugate of embodiment 53, wherein E b yes

[0075] Embodiment 55. The carbohydrate-oligonucleotide conjugate of any one of embodiments 51 to 53, wherein d is an integer of 2; E c It is a trivalent linker.

[0076] Embodiment 56. The carbohydrate-oligonucleotide conjugate of embodiment 55, wherein E c yes

[0077] Embodiment 57. The carbohydrate-oligonucleotide conjugate of any one of embodiments 51 to 56, wherein each L b and L cIndependently, it has the structure -Z n -(R n -Z n ) z - a linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 an arylene group, a heteroarylene group or a heterocyclylene group; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)2NR 1b -; Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl; and z is an integer 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, wherein each Q is independently 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, each of which is further substituted by one or more (in one embodiment one, two, three or four) substituents Q a Optionally substituted; (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)Ra 、-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 and -S(O)2NR b R c , where 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 7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by 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, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a replace; Each Q a are independently selected from the group consisting of: (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 Rg 、-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 g and -S(O)2NR f R g ; where 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

[0078] Embodiment 58. The carbohydrate-oligonucleotide conjugate of embodiment 57, wherein each R n Independently for C 1-10 Alkylene, C6-14 Aryl, heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

[0079] Embodiment 59. The carbohydrate-oligonucleotide conjugate of embodiment 57 or 58, wherein each R n is independently methanediyl, ethanediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3-triazolediyl, pyrrolidinediyl or piperidinediyl, each optionally substituted with one, two or three Q substituents.

[0080] Embodiment 60. The carbohydrate-oligonucleotide conjugate of any one of embodiments 57 to 59, wherein each R n is independently methylene, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-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.

[0081] 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-.

[0082] 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-.

[0083] 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.

[0084] 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.

[0085] Embodiment 65. The carbohydrate-oligonucleotide conjugate of embodiment 51 or 57, wherein L b and L c Each is independent of:

[0086] Embodiment 66. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 35, wherein the ASGPR binding group has the following structure:

[0087] 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 A connector of a structure, wherein: 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 an aryl group, a trivalent heteroaryl group or a trivalent heterocyclic group; Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 an arylene group, a heteroarylene group or a heterocyclylene group; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)2NR 1b - ； Each R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, 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; and z is an integer 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, wherein each Q is independently 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, each of which is further substituted by one or more (in one embodiment one, two, three or four) substituents Q aOptionally substituted; 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 、-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 Rc 、-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 and -S(O)2NR b R c , where 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 optionally substituted by 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, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a replace; Each Q a independently selected from the group consisting of (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 Rg 、-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 eS(O)2NR f R g 、-SR e 、-S(O)R e 、-S(O)2R e 、-S(O)NR f R g and -S(O)2NR f R g ; where 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

[0088] Embodiment 68. The carbohydrate-oligonucleotide conjugate of embodiment 67, wherein M is N.

[0089] Embodiment 69. The carbohydrate-oligonucleotide conjugate of embodiment 67, wherein M is CH or C(CH3).

[0090] Embodiment 70. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 69, wherein each R n Independently for C 1-10 Alkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

[0091] Embodiment 71. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 70, wherein each R n is independently methylenediyl, ethylenediyl, propylenediyl, butylenediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, phenylenediyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothiophenediyl or tetrahydropyrandiyl, each optionally substituted with one, two or three substituents Q.

[0092] Embodiment 72. The carbohydrate-oligonucleotide conjugate of any one of embodiments 67 to 71, wherein each R nThe following are independently selected from methane-1,2-diyl, 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, benzene- 1,4-diyl, 1,2,3-triazole-1,4-diyl or 2,5-dioxopyrrolidine-1,3-diyl.

[0093] 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-.

[0094] Specific 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-.

[0095] 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.

[0096] 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.

[0097] 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 has the structure:

[0098] Embodiment 78. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 11 to 19 and 24 to 66, wherein each divalent linker is independently a -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 an arylene group, a heteroarylene group or a heterocyclylene group; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)2NR 1b -; Each R 1a , R 1b , R 1cand R 1d are independently hydrogen, deuterium, 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; and z is an integer 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, wherein each Q is independently 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, each of which is further substituted by one or more (in one embodiment one, two, three or four) substituents Q a optionally substituted; 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)2NR b R c 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NR b R c , where 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 3-10Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by 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, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a replace; Each Q a are independently selected from the group consisting of: (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 Rg 、-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 g and -S(O)2NR f R g ; where 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocycloalkyl group.

[0099] Embodiment 79. The carbohydrate-oligonucleotide conjugate of embodiment 78, wherein each R nIndependently for C 1-10 Alkylene, C 6-14 Arylene, heteroarylene or heterocyclylene, each of which is optionally substituted by one or more substituents Q.

[0100] Embodiment 80. The carbohydrate-oligonucleotide conjugate of embodiment 78 or 79, wherein each R n is independently methanediyl, ethanediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3-triazolediyl or pyrrolidinediyl, each optionally substituted with one, two or three Q substituents.

[0101] Embodiment 81. The carbohydrate-oligonucleotide conjugate of any one of embodiments 78 to 80, wherein each R n are independently methane-1,2-diyl, 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, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl or 2,5-dioxopyrrolidine-1,3-diyl.

[0102] 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-.

[0103] 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-.

[0104] 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.

[0105] 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.

[0106] Embodiment 86. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 11 to 19, 24 to 66 and 78, wherein each divalent linker is independently a linker having the structure:

[0107] Embodiment 87. The carbohydrate-oligonucleotide conjugate of embodiment 1, having the structure: Each 3'-siRNA independently represents an siRNA with one of its 3'-ends linked to a trivalent linker; each 5'-siRNA represents an siRNA with one of its 5'-ends linked to a trivalent linker; and 5'-ssDNA represents a single-stranded DNA with its 5' end linked to a trivalent linker.

[0108] Embodiment 88. The carbohydrate-oligonucleotide conjugate of embodiment 1, having the structure: Among them, 3'-siRNA represents siRNA, one of whose 3'-ends is connected to the first divalent linker and one of whose 5'-ends is connected to the second divalent linker; 5'-siRNA represents siRNA, one of whose 5'-ends is connected to the second divalent linker.

[0109] Embodiment 89. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 19 and 33 to 88, wherein one oligonucleotide is an oligonucleotide duplex comprising 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.

[0110] Embodiment 90. The carbohydrate-oligonucleotide conjugate of embodiment 1, having the structure: Each 3'-ssRNA independently represents a single-stranded RNA, whose 3'-end is connected to a trivalent linker; each 5'-ssRNA independently represents a single-stranded RNA, whose 5'-end is connected to a trivalent linker; and each 5'-ssDNA represents a single-stranded RNA, whose 5'-end is connected to a trivalent linker.

[0111] Embodiment 91. The carbohydrate-oligonucleotide conjugate of embodiment 1, having the following structure: Among them, 3'-ssRNA refers to single-stranded RNA, whose 3'-end is connected to the first divalent linker and whose 5'-end is connected to the second divalent linker; 5'-ssRNA refers to single-stranded RNA, whose 5'-end is connected to the second divalent linker.

[0112] Embodiment 92. The carbohydrate-oligonucleotide conjugate of any one of embodiments 1, 2, 20 to 86, 90 and 91, wherein each oligonucleotide independently comprises a nucleotide sequence as shown in any one of SEQ ID NO: 1 to SEQ ID NO: 25.

[0113] Embodiment 93. A pharmaceutical composition comprising the carbohydrate-oligonucleotide conjugate of any one of embodiments 1 to 92 and a pharmaceutically acceptable excipient.

[0114] Embodiment 94. The pharmaceutical composition of embodiment 93, wherein the composition is in a single dosage form.

[0115] Embodiment 95. The pharmaceutical composition of embodiment 93 or 94, wherein the composition is in a parenteral or intravenous dosage form.

[0116] Embodiment 96. The pharmaceutical composition of embodiment 95, wherein the composition is formulated for intravenous injection. The present invention provides a carbohydrate-oligonucleotide conjugate, the conjugate comprising an asialoglycoprotein receptor (ASGPR) binding group and two oligonucleotides. Detailed description

[0117] To facilitate understanding of the present disclosure, some terms are defined below.

[0118] Generally speaking, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacology described herein are all 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 the present disclosure belongs.

[0119] The term "subject" refers to an animal, including but not limited to primates (such as humans), cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" can be used interchangeably in the present invention, such as mammalian subjects, such as human subjects. In one embodiment, the subject is a human.

[0120] The terms "treat," "treating," and "therapeutic method" are meant to include reducing or eliminating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or reducing or eliminating the cause of the disorder, disease, or condition itself.

[0121] The terms "prevent," "prophylaxis," and "preventative measure" are meant to include methods of delaying and / or eliminating the onset of a disorder, disease or condition and / or its attendant symptoms; preventing a subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition.

[0122] The terms "alleviate" and "alleviating" refer to relieving or alleviating one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms may also refer to reducing an adverse effect associated with an active ingredient. Sometimes, the beneficial effects a subject receives from a preventive or therapeutic regimen do not cure the disorder, disease, or condition.

[0123] The term "contacting" or "contacting" refers to contact of a therapeutic agent with a biomolecule (such as a protein, enzyme, RNA or DNA), a cell or a tissue, thereby producing a physiological and / or chemical effect. Contacting can be performed in vitro, ex vivo or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In another embodiment, contacting a therapeutic agent with a biomolecule, cell or tissue comprises administering a therapeutic agent to a subject having the biomolecule, cell or tissue to be contacted.

[0124] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound that, when administered, is sufficient to prevent the development 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" also refers to an amount of a compound that is sufficient to elicit a biological or medical response in a biomolecule (such as a protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is desired by a researcher, veterinarian, physician or clinician.

[0125] The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. In one embodiment, each ingredient is "pharmaceutically acceptable", i.e., compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of a subject (such as a human) without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, 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 Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015 (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 Preformulation and Formulation, 1st ed.; Gibson Ed.; CRC Press, 2015). Ed.; CRC Press, 2015).

[0126] The term "about" or "approximately" refers to the acceptable error of a particular value determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 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.

[0127] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents Q described herein. 1-6Alkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkyl group is a saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a saturated monovalent hydrocarbon group having 3 to 20 (C 3- 20 ), 3 to 15 (C 3-15 ), 3 to 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 isomeric forms, such as n-propyl and isopropyl), butyl (including all isomeric forms, such as n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including all isomers, such as n-pentyl, isopentyl, sec-pentyl, neopentyl and tert-pentyl) and hexyl (including all isomers, such as n-hexyl, isohexyl and sec-hexyl).

[0128] The terms "alkylene" and "alkanediyl" are used interchangeably herein and refer to a straight or branched saturated divalent hydrocarbon group, wherein the alkanediyl group is optionally substituted with one or more substituents Q described herein. 1-6 Alkanediyl refers to a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl group is a straight chain saturated divalent hydrocarbon group having 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6Alkanediyl is also called "lower alkanediyl". Examples of alkanediyl groups include, but are not limited to, methylenediyl, 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 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 groups include, but are not limited to, -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-, -C(O)(CH2) 10 -, -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.

[0129] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon group containing one or more heteroatoms in its main chain, each heteroatom being independently selected from O, S and N. The heteroalkyl group may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, heteroalkyl is a straight chain saturated monovalent hydrocarbon group having 1 to 20 carbon atoms (C 1-20 ), 1 to 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 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. 1-6 and branched chain C 3-6Heteroalkyl is also referred to as "lower heteroalkyl". Examples of heteroalkyl include, but are not limited to -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.

[0130] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably in the present invention and refer to a straight or branched saturated divalent hydrocarbon group containing one or more heteroatoms in its main chain, each heteroatom being independently selected from O, S and N. The heteroalkylene group may be optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a straight chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, heteroalkylene is a saturated divalent hydrocarbon group having 1 to 20 carbon atoms. 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a straight-chain saturated divalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 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, but are not limited to -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10 O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, or -CH2CH2S-. Examples of substituted heteroalkylene groups include, but are not limited to, -C(O)CH2O-, -C(O)(CH2)2O-, -C(O)(CH2)3O-, -C(O)(CH2)4O-, -C(O)(CH2)5O-, -C(O)(CH2)6O-, -C(O)(CH2)7O-, -C(O)(CH2)8O-, -C(O)(CH2)9O-, -C(O)(CH2)10 O-, -C(O)CH2OCH2CH2O-, -C(O)CH2O(CH2CH2O)2-, -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2- or -CH2CH2C(O)NH-.

[0131] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more carbon-carbon double bonds; in one embodiment, containing one, two, three or four carbon-carbon double bonds; in another embodiment, containing one carbon-carbon double bond. As described herein, the alkenyl group may be optionally substituted with one or more substituents Q. As will be understood by one of ordinary skill in the art, the term "alkenyl" includes groups having a "cis" or "trans" configuration or a mixture thereof, or a group having a "Z" or "E" configuration or a mixture thereof. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkenyl is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms such as propen-1-yl, propen-2-yl and allyl) and butenyl (including all isomeric forms such as buten-1-yl, buten-2-yl, buten-3-yl and 2-buten-1-yl).

[0132] The terms "alkenylene" and "alkenediyl" are used interchangeably in the present invention and refer to a straight or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds, in one embodiment, one, two, three or four carbon-carbon double bonds; in another embodiment, one carbon-carbon double bond. The alkenediyl group may be optionally substituted with one or more substituents Q as described herein. As will be understood by those of ordinary skill in the art, the term "alkenediyl" includes groups having "cis" or "trans" configurations or mixtures thereof, or groups having "Z" or "E" configurations or mixtures thereof. For example, C 2-6 Alkenyl refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkene diyl group is 2 to 30 (C2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of olefinediyl include, but are not limited to, ethylenediyl (including all isomeric forms, such as ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomeric forms, such as 1-propylene-1,1-diyl, 1-propylene-1,2-diyl and 1-propylene-1,3-diyl), butenediyl (including all isomeric forms, such as 1-butene-1,1-diyl, 1-butene-1,2-diyl and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, such as 1-pentene-1,1-diyl, 1-butene-1,2-diyl and 1-butene-1,4-diyl), and 1-pentene-1,2-diyl. isomers such as 1-pentene-1,1-diyl, 1-pentene-1,2-diyl and 1-pentene-1,5-diyl) and hexene-1,1-diyl (including all isomers such as 1-hexene-1,1-diyl, 1-hexene-1,2-diyl and 1-hexene-1,5-diyl), 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl and 1-hexene-1,6-diyl).

[0133] The terms "heteroalkenylene" and "heteroalkenediyl" are used interchangeably in the present invention and refer to a straight or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds, in one embodiment, one, two, three or four carbon-carbon double bonds; in another embodiment, one carbon-carbon double bond; and one or more heteroatoms independently selected from O, S and N in the hydrocarbon chain. The heteroalkene may be optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "heteroalkenylene" includes free radicals having "cis" or "trans" configurations or mixtures thereof, or free radicals having "Z" or "E" configurations or mixtures thereof. For example, C 2-6 Heteroalkenylene refers to a straight chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain divalent hydrocarbon group having 3 to 20 (C 3-20), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of heteroolefin groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCH2O-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0134] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more carbon-carbon triple bonds, in one embodiment, one, two, three or four carbon-carbon triple bonds; in another embodiment, one carbon-carbon triple bond. Alkynyl groups do not contain carbon-carbon double bonds. Alkynyl groups may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a straight chain unsaturated monovalent hydrocarbon group having 2-6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 4-6 carbon atoms. In certain embodiments, alkynyl is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain monovalent hydrocarbon group having 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms, such as 1-propynyl (—C≡CCH3) and propargyl (—CH2C≡CH), butynyl (including all isomeric forms, such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, such as 1-hexyn-1-yl and 2-hexyn-1-yl).

[0135] The terms "alkynylene" and "alkynediyl" are used interchangeably herein and refer to a straight or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds, in one embodiment, one, two, three or four carbon-carbon triple bonds; in another embodiment, one carbon-carbon triple bond. Alkynediyl does not contain a carbon-carbon double bond. Alkynediyl may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In certain embodiments, the alkynediyl group is a group having 2 to 30 (C2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain divalent hydrocarbon group having 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) carbon atoms. Examples of alkynediyl include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, such as 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynediyl (including all isomeric forms, such as 1-butyn-1,3-diyl, 1-butyn-1,4-diyl and 2-butyn-1,1-diyl), pentynediyl (including all isomeric forms, such as 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl and 2-pentyn-1,1-diyl) and hexynediyl (including all isomeric forms, such as 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).

[0136] The terms "heteroalkynylene" and "heteroalkynyldiyl" are used interchangeably herein and refer to a straight or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds, in one embodiment, one, two, three or four carbon-carbon triple bonds; in another embodiment, one carbon-carbon triple bond, and one or more heteroatoms in its backbone, each heteroatom independently selected from O, S and N. Heteroalkynylene does not contain a carbon-carbon double bond. The heteroalkynylene may be optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a straight chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In certain embodiments, a heteroalkynylene group is a group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight-chain divalent hydrocarbon group having 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 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-.

[0137] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl radical is saturated or unsaturated but non-aromatic, and / or is a bridged or unbridged ring, and / or is a fused bicyclic radical. In certain embodiments, the cycloalkyl radical has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl 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.

[0138] In the present invention, the terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably and refer to a cyclic divalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkanediyl group may be saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or a fused bicyclic group. In certain embodiments, the cycloalkanediyl group has 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7) carbon atoms. Examples of cycloalkanediyl include, but are not limited to, cyclopropanediyl (including all isomeric forms, such as cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, such as cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, such as cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, such as cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl), cycloheptane-1,1-diyl (including all isomeric forms, such as cycloheptane-1,2-diyl, cycloheptane-1,3-diyl and cycloheptane-1,4-diyl), decalin (including all isomeric forms, such as decalin-1,1-diyl, decalin-1,2-diyl and decalin-1,8-diyl) and adamantane (including all isomeric forms, such as adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).

[0139] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbon ring. In certain embodiments, an aryl group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl and terphenyl. Aryl also refers to a bicyclic or tricyclic carbocyclic ring, in which one ring is an aromatic ring and the other rings can be saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, indanyl or tetrahydronaphthyl (tetrahydronaphthyl). In one embodiment, aryl is monocyclic. In another embodiment, aryl is bicyclic. In yet another embodiment, aryl is tricyclic. In yet another embodiment, aryl is polycyclic. In certain embodiments, aryl can be optionally substituted by one or more substituents Q as described herein.

[0140] In the present invention, the terms "arylene" and "arylene diyl" are used interchangeably and refer to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, the arylene group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10) ring atoms. Examples of aryl groups include, but are not limited to, phenylene (including all isomeric forms, such as benzene-1,2-diyl, benzene-1,3-diyl, and benzene-1,4-diyl), naphthylene (including all isomeric forms, such as naphthalene-1,2-diyl, naphthalene-1,3-diyl, and naphthalene-1,8-diyl), fluorenylene (including all isomeric forms, such as fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulenylene (including all isomeric forms, such as azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), anthracene (including all isomeric forms, such as anthracene-1,2-diyl , anthracene-1,3-diyl and anthracene-1,8-diyl), phenanthrenyl (including all isomeric forms, such as phenanthracene-1,2-diyl, phenanthracene-1,3-diyl and phenanthracene-1,8-diyl), pyrenyl (including all isomeric forms, such as pyrene-1,2-diyl, pyrene-1,3-diyl and pyrene-1,8-diyl), biphenylene (including all isomeric forms, such as biphenyl-2,3-diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl) and terphenylene (including all isomeric forms, such as terphenyl-2,3-diyl, terphenyl-3,4'-diyl and terphenyl-4,4'-diyl). Arylene also refers to a bicyclic or tricyclic carbon ring, one of which is aromatic and the other rings may be saturated, partially unsaturated or aromatic. For example, dihydronaphthylene (including all isomeric forms, such as dihydronaphthalene-1,2-diyl and dihydronaphthalene-1,8-diyl), indenylene (including all isomeric forms, such as indene-1,2-diyl, indene-1,5-diyl and indene-1,7-diyl), indanylene (including all isomeric forms, such as indane-1,2-diyl, indane-1,5-diyl and indane-1,7-diyl) or tetrahydronaphthylene (tetrahydronaphthalene) (including all isomeric forms, such as tetrahydronaphthalene-1,2-diyl, tetrahydronaphthalene-1,5-diyl and tetrahydronaphthalene-1,8-diyl). In certain embodiments, arylene can be optionally substituted with one or more substituents Q as described herein.

[0141] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atom. Examples of aralkyl include, but are not limited to, benzyl, phenethyl (including all isomeric forms, such as 1-phenethyl and 2-phenethyl) and phenylpropyl (including all isomeric forms, such as 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl). In certain embodiments, aralkyl may be optionally substituted with one or more substituents Q described herein.

[0142] The term "aralkylene" or "arylalkylene" refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atoms. Examples of aromatic hydrocarbon groups include, but are not limited to, benzylidene (including all isomeric forms, such as benzylmethanediyl), phenylethylene (including all isomeric forms, such as 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl) and phenylpropylene (including all isomeric forms, 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.

[0143] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each heteroatom being independently selected from O, S and N. For heteroaryl groups containing heteroaromatic rings and non-aromatic heterocyclic rings, the heteroaryl group is not connected to the rest of the molecule through its non-aromatic heterocyclic ring. Each ring of the heteroaryl 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 does not exceed four and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl group is a monocyclic ring. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl (including all isomeric forms such as 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 such as imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[1,2-a]pyridinyl [4,5-c]pyridinyl), imidazothiazolyl (including all isomers such as imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomers such as 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl and 1,8-naphthyridinyl), oxazolopyridinyl (including all 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, pyrrolopyridinyl (including all isomeric forms, such as pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl and pyrrolo[3,2-c]pyridinyl), quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, such as [1,2,5]thia [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl, as well as 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, the heteroaryl group is tricyclic.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl (including all isomeric forms, such as 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl and 2,10-phenanthrolinyl), phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q described herein.

[0144] In the present invention, the terms "heteroaryl" and "heteroaryldiyl" are used interchangeably and refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each heteroatom being independently selected from O, S and N. For heteroaryl containing heteroaromatic rings and non-aromatic heterocycles, the heteroaryl is not connected to the rest of the molecule through its non-aromatic heterocycle. Each ring of the heteroaryl can 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 heteroaryl 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, pyrazoldiyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazoldiyl, thiophenediyl, tetrazolediyl, triazinediyl, and triazolediyl.Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazolediyl, benzisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothiazoldiyl, benzothiophenediyl, benzotriazolediyl, benzooxazolediyl, furopyridinediyl (including all isomeric forms such as furano[2,3-b]pyridinediyl, furano[2,3-c]pyridinediyl, furano[3,2-b]pyridinediyl, furano[3,2-c]pyridinediyl, furano[3,4-b]pyridinediyl, and furano[3,4-c]pyridinediyl) ), imidazopyridinediyl (including all isomeric forms, such as imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl and imidazo[4,5-c]pyridinediyl), imidazothiazoldiyl (including all isomeric forms, such as imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazoldiyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothiophenediyl (i.e., benzo[c]thiophenediyl), isoindolediyl, isoquinolindiyl, naphthyridinediyl (including all isomeric forms, such as 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7-naphthyridindiyl and 1,8-naphthyridindiyl), oxazolopyridinediyl (including all isomeric forms, such as oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purinediyl, pyrrolopyridinediyl (including all isomeric forms, such as pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2 [1,2,5]thiadiazolo[3,4-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl) and thienopyridinediyl (including all isomeric forms, such as 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, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms such as 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,10-phenanthrolinediyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenothiazindiyl, and xanthendiyl. In certain embodiments, the heteroarylene group may be optionally substituted with one or more substituents Q as described herein.

[0145] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more non-aromatic ring atoms are heteroatoms, each heteroatom independently selected from O, S and N; the remaining ring atoms are carbon atoms. For heterocyclyl groups containing heteroaromatic rings and non-aromatic heterocyclic rings, the heterocyclyl group is not connected to the rest of the molecule through a heteroaromatic ring. In certain embodiments, the 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, the 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, the heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be fused or bridged, wherein the nitrogen or sulfur atoms can be optionally oxidized, the nitrogen atom can be optionally quaternized, and some rings can be partially or fully saturated, or aromatic. The heterocyclic group can be attached to any heteroatom or carbon atom of the main structure to form a stable compound. Examples of heterocyclic and heterocyclic groups include, but are not limited to, azepine, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms such as 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydro Pyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiacyclohexane, furanonyl, imidazolidinyl, imidazolinyl, dihydroindole, isochromanyl, isoindole, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindole, octahydroisoindolyl, oxazolidinone, oxazolidinyl, oxirane, piperazinyl, piperidinyl, 4-piperidone, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, thiochromonyl, tetrahydroquinolyl and 1,3,5-trithiacyclohexane. In certain embodiments, heterocyclic radical can be optionally substituted by one or more substituents Q as described herein.

[0146] 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, wherein one or more non-aromatic ring atoms are heteroatoms, which are independently selected from the heteroatoms of O, S and N, and the remaining ring atoms are carbon atoms. For heterocyclylene containing heteroaromatic rings and non-aromatic heterocycles, the heterocyclylene is connected to the rest of the molecule at least through a bond on its non-aromatic heterocycle. In certain embodiments, the heterocyclylene 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, the heterocyclylene is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can be fused or bridged, wherein the nitrogen or sulfur atom can be optionally oxidized, the nitrogen atom can be optionally quaternized, and some rings can be partially or completely saturated, or aromatic. The heterocyclylene can be connected to the main structure at any heteroatom or carbon atom to form a stable compound. Examples of such heterocyclic groups include, but are not limited to, azepanediyl, benzodioxanediyl, benzodioxolediyl, benzofuranediyl, chromonediyl, decahydroisoquinolinediyl, dihydrobenzofuranediyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomeric forms such as 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothiophenediyl, dihydroisobenzofuranediyl, dihydrobenzo[c]thiophenediyl, dihydrofuranediyl, dihydroisoindolediyl, dihydropyranediyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidined ... 1,4-dithiacyclohexanediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolindiyl, isochromonediyl, isoindolindiyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydroindolindiyl, octahydroisoindolindiyl, oxazolidinonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolinediyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofurandiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiophenediyl, thiomorpholindiyl, thiazolidinediyl, thiochromandiyl, tetrahydroquinolindiyl and 1,3,5-trithiacyclohexanediyl. In certain embodiments, the heterocyclylene group may be optionally substituted with one or more substituents Q as described herein.

[0147] "Halo," "halide," or "halo" refers to fluorine, chlorine, bromine, and / or iodine.

[0148] The term "optionally substituted" means that a group or substituent, such as, for example, alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl or heterocyclylene, may be substituted with one or more (in one embodiment, one, two, three or four) substituents Q, each of which is independently selected from, for example: (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2) 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 is further optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a optionally substituted; 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)2NRb 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 、-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)2NR b R c , where each R a , R b , R c and R d 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 optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q aor (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a Substitution. As used herein, all groups that may be substituted are "optionally substituted."

[0149] In one embodiment, each Q a independently selected from the following: (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 )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 Rg 、-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 、-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)2NR f R g ; where each R e , R f , R g and R h 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

[0150] In certain embodiments, "optically active" and "enantiomeric activity" refer to a collection of molecules having an enantiomeric excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture in question. 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 enantiomeric mixture in question.

[0151] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center. The prefixes (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which the plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound has levorotatory properties, that is, the compound rotates the plane of polarized light to the left, or counterclockwise. The prefix (+) indicates that the compound has dextrorotatory properties, that is, the compound rotates the plane of polarized light to the right, or clockwise. However, the signs of the optical rotation (+) and (-) have nothing to do with the absolute configuration (R and S) of the compound.

[0152] The terms "substantially pure" and "substantially homogeneous" when referring to a substance, mean that the homogeneity is sufficient to be free of easily 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 the purity is high enough that further purification will not cause detectable changes in the physical, chemical, biological and / or pharmacological properties (such as enzymatic activity and biological activity) of the substance. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection of molecules, 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 single compounds, including single enantiomers, racemic mixtures, or mixtures of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a specific position in an isotopically enriched molecule is designated as a specific isotope in lower concentration, a molecule containing a non-designated isotope at the designated position is an impurity relative to the isotopically enriched compound. Thus, for a deuterated compound in which an atom at a specific position is designated as deuterium, a compound containing protium at the same position is an impurity.

[0153] For the divalent groups described in the present invention, the arrangement direction of the divalent groups does not mean 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

[0154] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group and two oligonucleotides

[0155] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, two oligonucleotides and a trivalent linker.

[0156] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group, two oligonucleotides and two divalent linkers.

[0157] In certain embodiments, the two oligonucleotides are identical.In certain embodiments, the two oligonucleotides are different.

[0158] In certain embodiments, the two oligonucleotides are each a single-stranded oligonucleotide.In certain embodiments, the two oligonucleotides are each a double-stranded oligonucleotide.

[0159] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate, which includes an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, a trivalent linker, or a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence and the end of the second sense or antisense sequence through the trivalent linker; or wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence through the first divalent linker, and the first sense One of the remaining ends of the sense or antisense sequence is linked to a terminus of the second sense or antisense sequence via a second bivalent linker.

[0160] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence and the end of the second sense or antisense sequence through the trivalent linker.

[0161] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex having a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first sense sequence and the end of the second sense sequence through the trivalent linker.

[0162] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first antisense sequence and the end of the second sense sequence via the trivalent linker.

[0163] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first sense sequence and the end of the second antisense sequence through the trivalent linker.

[0164] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a trivalent linker; wherein the ASGPR binding group is connected to the end of the first antisense sequence and the end of the second antisense sequence through the trivalent linker.

[0165] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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.

[0166] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0167] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sense sequence via the trivalent linker.

[0168] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0169] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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.

[0170] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group. 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 through the trivalent linker.

[0171] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 5'-end of the second sense sequence via the trivalent linker.

[0172] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sense sequence via the trivalent linker.

[0173] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 5'-end of the second antisense sequence via the trivalent linker.

[0174] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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.

[0175] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate comprising an ASGPR binding group. ASGPR binding group is provided, comprising a first oligonucleotide duplex containing first sense and antisense sequences, a second oligonucleotide duplex containing second sense and antisense sequences, 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 through the trivalent linker.

[0176] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 3'-end of the second sense sequence via the trivalent linker.

[0177] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 3'-end of the second sense sequence via the trivalent linker.

[0178] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 sequence and the 3'-end of the second antisense sequence via the trivalent linker.

[0179] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex 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 3'-end of the second antisense sequence via the trivalent linker.

[0180] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense or antisense sequence through the first divalent linker, and one of the remaining ends of the first sense or antisense sequence is connected to the end of the second sense or antisense sequence through the second divalent linker.

[0181] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense sequence through the first divalent linker, and one of the remaining ends of the first sense sequence is connected to the end of the second sense sequence through the second divalent linker.

[0182] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is linked to the end of the first antisense sequence via the first divalent linker, and one of the remaining ends of the first antisense sequence is linked to the end of the second sense sequence via the second divalent linker.

[0183] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first sense sequence through the first divalent linker, and one of the remaining ends of the first sense sequence is connected to the end of the second antisense sequence through the second divalent linker.

[0184] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the end of the first antisense sequence through the first divalent linker, and one of the remaining ends of the first antisense sequence is connected to the end of the second antisense sequence through the second divalent linker.

[0185] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex containing a first sense and antisense sequence, a second oligonucleotide duplex containing a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first sense or antisense sequence through the first divalent 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 through the second divalent linker.

[0186] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first sense sequence through the first divalent linker, and the 3'-end of the first sense sequence is connected to the 5'-end of the second sense sequence through the second divalent linker.

[0187] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first antisense sequence through the first divalent linker, and the 3'-end of the first antisense sequence is connected to the 5'-end of the second sense sequence through the second divalent linker.

[0188] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first sense sequence through the first divalent linker, and the 3'-end of the first sense sequence is connected to the 5'-end of the second antisense sequence through the second divalent linker.

[0189] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first oligonucleotide duplex comprising a first sense and antisense sequence, a second oligonucleotide duplex comprising a second sense and antisense sequence, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first antisense sequence through the first divalent linker, and the 3'-end of the first antisense sequence is connected to the 5'-end of the second antisense sequence through the second divalent linker.

[0190] In certain embodiments, each oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein is independently a double-stranded oligodeoxynucleotide or oligoribonucleotide. In certain embodiments, each oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein is independently a double-stranded oligodeoxynucleotide. In certain embodiments, each oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein is independently a double-stranded oligoribonucleotide. In certain embodiments, each oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein is independently a siRNA.

[0191] In certain embodiments, each strand of the first oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein 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 oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 10 to about 50 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 10 to about 30 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 15 to about 25 nucleotides. In certain embodiments, each strand of the first oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein 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.

[0192] In certain embodiments, each strand of the second oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein 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 oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 10 to about 50 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 10 to about 30 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein independently comprises about 15 to about 25 nucleotides. In certain embodiments, each strand of the second oligonucleotide duplex in the carbohydrate-oligonucleotide conjugate provided herein 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.

[0193] In certain embodiments, the first oligonucleotide duplex is a double-stranded siRNA. In certain embodiments, each strand of the first siRNA duplex in the carbohydrate-oligonucleotide conjugate provided by the present invention independently includes 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 in the carbohydrate-oligonucleotide conjugate provided by the present invention independently includes about 10 to about 50 nucleotides. In certain embodiments, each strand of the first siRNA duplex in the carbohydrate-oligonucleotide conjugate provided by the present invention independently includes about 10 to about 30 nucleotides. In certain embodiments, each strand of the first siRNA duplex in the carbohydrate-oligonucleotide conjugate provided by the present invention independently includes about 15 to about 25 nucleotides. In certain embodiments, each strand of the first siRNA duplex in the carbohydrate-oligonucleotide conjugate provided by the present invention independently includes about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0194] In certain embodiments, the second oligonucleotide duplex is a double-stranded siRNA. In certain embodiments, each strand of the second siRNA duplex in the carbohydrate-oligonucleotide conjugate provided herein independently includes 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 in the carbohydrate-oligonucleotide conjugate provided herein independently includes about 10 to about 50 nucleotides. In certain embodiments, each strand of the second siRNA duplex in the carbohydrate-oligonucleotide conjugate provided herein independently includes about 10 to about 30 nucleotides. In certain embodiments, each strand of the second siRNA duplex in the carbohydrate-oligonucleotide conjugate provided herein independently includes about 15 to about 25 nucleotides. In certain embodiments, each strand of the second siRNA duplex in the carbohydrate-oligonucleotide conjugate provided herein independently includes about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0195] In certain embodiments, each nucleotide in each strand of the first siRNA duplex can independently be a natural nucleotide or a modified nucleotide. In certain embodiments, natural nucleotides include adenylic acid (a), cytidylic acid (c), guanylic acid (g) and uridylic acid (u). In certain embodiments, modified nucleotides refer to nucleotides in which the nucleobase, sugar group and / or phosphate linker of the nucleotide are modified. 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 duplex 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 duplex has one or more phosphate linking groups substituted with phosphorothioate or phosphorodithioate.

[0196] In certain embodiments, each nucleotide in each strand of the second siRNA duplex is independently a natural nucleotide or a modified nucleotide. In certain embodiments, each nucleotide in each strand of the second siRNA duplex 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 duplex has one or more phosphate linking groups replaced by phosphorothioate or phosphorodithioate.

[0197] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate, which includes an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a trivalent linker or a first and a second divalent linker; wherein the ASGPR binding group is connected to one end of the first oligonucleotide and one end of the second oligonucleotide through a trivalent linker; or wherein the ASGPR binding group is connected to one end of the first oligonucleotide through a first divalent linker, and the other end of the first oligonucleotide is connected to one end of the second oligonucleotide through a second divalent linker.

[0198] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, 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.

[0199] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, 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.

[0200] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, 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.

[0201] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a first and a second divalent linker; wherein the ASGPR binding group is connected to one end of the first oligonucleotide via the first divalent linker, and the other end of the first oligonucleotide is connected to one end of the second oligonucleotide via the second divalent linker.

[0202] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 5'-end of the first oligonucleotide via the first divalent linker, and the 3'-end of the first oligonucleotide is connected to the 5'-end of the second oligonucleotide via the second divalent linker.

[0203] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an ASGPR binding group, a first and a second single-stranded oligonucleotide, and a first and a second divalent linker; wherein the ASGPR binding group is connected to the 3'-end of the first oligonucleotide via the first divalent linker, and the 5'-end of the first oligonucleotide is connected to the 3'-end of the second oligonucleotide via the second divalent linker.

[0204] In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention is an independent single-stranded oligodeoxynucleotide or oligoribonucleotide. In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention is an independent single-stranded oligodeoxynucleotide. In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention is an independent single-stranded oligoribonucleotide. In certain embodiments, each single-stranded oligonucleotide in the carbohydrate-oligonucleotide conjugate provided by the present invention can independently be an ASO, miRNA, mRNA or tRNA.

[0205] 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 includes 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 includes about 10 to about 50 nucleotides. In certain embodiments, the first single-stranded oligonucleotide includes about 10 to about 30 nucleotides. In certain embodiments, the first single-stranded oligonucleotide includes about 15 to about 25 nucleotides. In certain embodiments, the first single-stranded oligonucleotide includes about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0206] 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 includes 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 includes about 10 to about 50 nucleotides. In certain embodiments, the second single-stranded oligonucleotide includes about 10 to about 30 nucleotides. In certain embodiments, the second single-stranded oligonucleotide includes about 15 to about 25 nucleotides. In certain embodiments, the second single-stranded oligonucleotide includes about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 nucleotides.

[0207] In certain embodiments, each nucleotide in the first single-stranded oligonucleotide is independently a natural nucleotide or a 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 by phosphorothioate or phosphorodithioate.

[0208] In certain embodiments, each nucleotide in the second single-stranded oligonucleotide is independently a natural nucleotide or a 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 linking groups of the second single-stranded oligonucleotide are replaced by phosphorothioate or phosphorodithioate.

[0209] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group comprises one or more molecules, each of which independently has the following structure: 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.

[0210] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, The ASGPR binding group includes one or more N-acetylgalactosamine (GalNAc). In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group includes 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 includes about 1 to about 10 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group includes about 1 to about 6 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group includes 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 includes about 1 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, the ASGPR binding group includes about 2 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group comprises about 3 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group comprises about 4 GalNAc. In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group comprises about 5 GalNAc.

[0211] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group has the structure of formula (AI): 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 a and b are (i) b is an integer 1; and E a is the key; (ii) b is the integer 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 heterocyclic group, each optionally substituted with one or more substituents Q; (iii) b is the integer 3; and E a is (i) C; or (ii) tetravalent C1-6 Alkenyl, tetravalent C 3-10 Cycloalkyl, tetravalent C 6-14 aryl, tetravalent heteroaryl or tetravalent heterocyclic group, each optionally substituted with one or more substituents Q; and Each L a They are all independent connectors.

[0212] In one embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-II): 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 a Yes key; L a It is a connector.

[0213] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-III): 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; wherein 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 heterocyclic group, each optionally substituted with one or more substituents Q; and each L a Independent as a connector.

[0214] In certain embodiments, in Formula (A-III), E a is CH or N. In certain embodiments, in Formula (A-III), E a In certain embodiments, in Formula (A-III), E a is N.

[0215] In certain embodiments, in Formula (A-III), E a It is trivalent C 1-6 Alkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14aryl, trivalent heteroaryl or trivalent heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-III), E a For trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-III), E a Yes CR m , where R m It 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 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, in Formula (A-III), E a Yes CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, in Formula (A-III), E a It is trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-III), E a It is trivalent C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-III), E a It is trivalent C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (A-III ) In, E a is a trivalent heteroaryl group, optionally substituted by one or more Q substituents.

[0216] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-IV): 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; wherein 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 heterocyclic group, each optionally substituted with one or more substituents Q; and each L aIndependent as a connector.

[0217] In certain embodiments, in Formula (A-IV), E a is C. In certain embodiments, in Formula (A-IV), E a It is tetravalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-IV), E a It is tetravalent C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-IV), E a It is tetravalent C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-IV), E a is a tetravalent heteroaryl group, optionally substituted by one or more Q substituents.

[0218] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided by the present invention, The ASGPR binding groups are:

[0219] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group is:

[0220] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group is

[0221] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group has the structure of formula (AV): 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 c are (i) c is an integer 1; and E b is the key; (ii) c is the integer 2; and E b is (i) CH or N; or (ii) trivalent C1-6 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 heterocyclic group, each of which may be optionally substituted with one or more substituents Q; or (iii) c is the integer 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 heterocyclic group, each optionally substituted with one or more substituents Q; E c and d are (i) d is an integer 1; and E c is the key; (ii) d is the integer 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 heterocyclic group, each optionally substituted with one or more substituents Q; or (iii) d is the integer 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 heterocyclic group, each optionally 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 heterocyclic group, each optionally substituted with one or more substituents Q; and Each L b and L c All are independent connectors.

[0222] In one embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-VI): 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 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 heterocyclic group, each optionally substituted with one or more substituents Q; E c is the key; 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 heterocyclic group, each optionally substituted with one or more substituents Q; and Each L b and L c They are all independent connectors.

[0223] 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 It is N.

[0224] In certain embodiments, in Formula (A-VI), E b It 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 heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), E b is a trivalent C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in Formula (A-VI), E b Yes CR m , where R m It is C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, in Formula (A-VI), E b Yes CR m , where R m It is C 1-6 Alkyl, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (A-VI), E b is C(CH3). In certain embodiments, in Formula (A-VI), E b It is trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), E b It is trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), E b C 3-10 Cycloalkyl, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (A-VI), E b It is trivalent C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), E b is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), E b is a trivalent heterocyclic group, which may be optionally substituted by one or more substituents Q.

[0225] 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.

[0226] 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 aryl, trivalent heteroaryl or trivalent heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is a trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is CR m , where R m It 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 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, in Formula (A-VI), G is CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, in Formula (A-VI), G is C(CH3). In certain embodiments, in Formula (A-VI), G is a trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is a trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VI), G is a trivalent C 6-14 In some embodiments, in Formula (A-VI), G is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, in Formula (A-VI), G is a trivalent heterocyclyl group, optionally substituted with one or more substituents Q.

[0227] In certain embodiments, in Formula (A-VI), E b is CH or N; G is CH or N.

[0228] In another embodiment, in the carbohydrate-oligonucleotide conjugate provided by the present invention, the ASGPR binding group has the structure of formula (A-VII): 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 heterocyclic group, each optionally substituted with one or more substituents Q; G is (i) CH or N; or (ii) trivalent C 1-6 Alkyl, trivalent C1-6 Heteroalkyl, trivalent C 1-6 Alkenyl, trivalent C 3-10 Cycloalkyl, trivalent C 6-14 aryl, trivalent heteroaryl or trivalent heterocyclic group, each optionally substituted with one or more substituents Q; and Each L b and L c They are all independent connectors.

[0229] In certain embodiments, in Formula (A-VII), E b is CH or N. In certain embodiments, in Formula (A-VII), E b is CH. In certain embodiments, in Formula (A-VII), E b It is N.

[0230] In certain embodiments, in Formula (A-VII), E b It 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 heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b It is trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b Yes CR m , where R m It 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 heterocycloalkyl, each optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), E b Yes CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), E b is C(CH3). In certain embodiments, in Formula (A-VII), E b It is trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b It is trivalent C1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b It is trivalent C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b It is trivalent C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E b is a trivalent heterocyclic group, optionally substituted by one or more substituents Q.

[0231] In certain embodiments, in Formula (A-VII), E c is CH or N. In certain embodiments, in Formula (A-VII), E c is CH. In certain embodiments, in Formula (A-VII), E c It is N.

[0232] In certain embodiments, in Formula (A-VII), E c It 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 heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c It is trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c Yes CR m , where R m It 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 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), E c Yes CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), E cis C(CH3). In certain embodiments, in Formula (A-VII), E c It is trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c It is trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c It is trivalent C 3-10 Cycloalkyl is optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c It is trivalent C 6-14 Aryl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), E c is a trivalent heterocyclic group, optionally substituted by one or more substituents Q.

[0233] 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.

[0234] 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) aryl, trivalent heteroaryl or trivalent heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), G is a trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), G is CR m , where R m It 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 optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), G is CR m , where R m It is C 1-6alkyl, optionally substituted with one or more Q. In certain embodiments, in Formula (A-VII), G is C(CH3). In certain embodiments, in Formula (A-VII), G is a trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), G is a trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), G is a trivalent C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (A-VII), G is a trivalent C 6-14 In some embodiments, in Formula (A-VII), G is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, in Formula (A-VII), G is a trivalent heterocyclyl group, optionally substituted with one or more substituents Q.

[0235] In certain embodiments, in Formula (A-VII), E b is CH or N; E c is CH or N; G is CH or N.

[0236] In certain embodiments, in any one of Formulae (AV) to (A-VII), E b yes In certain embodiments, in any of Formulas (AV) to (A-VII), E b for

[0237] In certain embodiments, in any of Formulas (AV) to (A-VII), E c for In certain embodiments, in Formula (AV) or (A-VII), E c Yes N.

[0238] In certain embodiments, in the carbohydrate-oligonucleotide conjugates provided herein, the ASGPR binding group is:

[0239] In certain embodiments, in any one of Formulae (AI) to (A-IV), each L aIn certain embodiments, in any one of Formulas (AI) to (A-IV), each L a In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a Independently is a non-cleavable linker.

[0240] In certain embodiments, in any one of Formulae (AI) to (A-IV), each L a are all independently cleavable linkers that are sensitive to acidic pH. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L ( a ) are independently cleavable linkers comprising a reducible disulfide. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a is independently a linker cleavable by glutathione. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a In certain embodiments, in any one of Formulae (AI) to (A-IV), each L a In certain embodiments, in any one of Formulae (AI) to (A-IV), each L a In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a L is independently a linker cleavable by cathepsin B. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a In certain embodiments, in any one of Formulae (AI) to (A-IV), each L a In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a is independently a linker cleavable by β-galactosidase. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a is independently a linker cleavable by β-galactosidase. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a is independently a linker cleavable by glucuronidase. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L ais independently a linker cleavable by β-glucuronidase. In certain embodiments, in any one of Formulas (AI) to (A-IV), each L a Independently is a linker cleavable by a phosphatase.

[0241] In certain embodiments, in any one of Formulae (AV) to (A-VII), each L b and L c is independently a cleavable linker that is sensitive to acidic pH. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c is independently a cleavable linker comprising a reducible disulfide. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c is independently a linker cleavable by glutathione. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c is independently a linker that can be cleaved by a lysosomal protease. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c L is independently a linker cleavable by cathepsin B. In certain embodiments, in any of Formulas (AV) to (A-VII), each L b and L c In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c is independently a linker cleavable by β-glycosidase. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c L is independently a linker cleavable by β-galactosidase. b and L cis independently a linker cleavable by β-galactosidase. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c L is independently a linker cleavable by glucuronidase. b and L c is independently a linker cleavable by β-glucuronidase. In certain embodiments, in any one of Formulas (AV) to (A-VII), each L b and L c Independently is a linker cleavable by a phosphatase.

[0242] In certain embodiments, each L of any one of Formulae (AI) to (A-IV) a Independently is with -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, 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-, -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 1aC(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)2NR 1b -, -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b -or-S(O)2NR 1b -; Each R 1a , R 1b , R 1c and R 1d 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; and z is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0243] In certain embodiments, each L in any one of Formulas (AV) to (A-VII) b Independently is with -Z n -(R n -Z n ) z - a linker structure, where each R n , Z n and z are as defined in the present invention.

[0244] In certain embodiments, each L in any one of Formulas (AV) to (A-VII) c Independently is with -Z n -(R n -Z n ) z - a linker structure, where each R n , Z n and z are as defined in the present invention.

[0245] In certain embodiments, each R nIndependently for C 1-10 Alkylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q; each Z n are independently a bond, -C(O)-, -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 0, 1, 2, 3, 4, 5 or 6; wherein each R 1a , R 1b and R 1d As defined in the present invention.

[0246] In certain embodiments, each R n Independently for C 1-10 Alkylene, C 2-10 Alkynylidene, C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q; each Z n are independently a bond, -C(O)-, -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 -; and z is an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8; wherein each R 1a , R 1b and R 1d As defined in the present invention.

[0247] In certain embodiments, each R nR is independently methylenediyl, ethylenediyl, propylenediyl, butylenediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, propynediyl, pentynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, benzenediyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocyclooctanedi[d]pyridazinediyl, azetidinediyl, 1,3-dioxolanediyl, pyrrolidinediyl, piperazinediyl, piperidinediyl or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R n The 1,2-diyl, 1,3-diyl, 1,4-diyl, 1,5-diyl, 1,6-diyl, 1,7-diyl, 1,8-diyl, 1,9-diyl, 1,10-diyl, 1,11-diyl, 1,12-diyl, 1,3-diyl, 1,4-diyl, 1,5-diyl, 1,6-diyl, 1,7-diyl, 1,8-diyl, 1,9-diyl, 1,10-diyl, 1,11-diyl, 1,3 ... 1,13-diyl, acetylene-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 Q is optionally substituted with one or more substituents Q.

[0248] In certain embodiments, each R n R is independently methylenediyl, cyclopropylmethylenediyl, ethylenediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, ethynediyl, propynediyl, pentynediyl, azetidinediyl, pyrrolidinediyl, piperazinediyl or piperidinediyl. In certain embodiments, each R nis independently methanediyl, cyclopropylmethanediyl, ethane-1,2-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, acetylene-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.

[0249] In certain embodiments, each R n Independently for C 1-10 Alkylene, C 6-14 arylene or heteroarylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, each R n R is independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl or 1,2,3-triazolediyl, each of which is optionally substituted with one, two or three substituents Q. In certain embodiments, each R n independently methane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-1,4-diyl or 1,2,3-triazole-1,4-diyl, each optionally substituted by one or more substituents Q.

[0250] In certain embodiments, each Z n is 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-. 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-.

[0251] In certain embodiments, z is an integer of 0. In certain embodiments, z is an integer of 1. In certain embodiments, z is an integer of 2. In certain embodiments, z is an integer of 3. In certain embodiments, z is an integer of 4. In certain embodiments, z is an integer of 5. In certain embodiments, z is an integer of 6. In certain embodiments, z is an integer of 7. In certain embodiments, z is an integer of 8. In certain embodiments, z is an integer of 0, 1, 2, 3, 4, or 5.

[0252] In certain embodiments, each R nZ is independently methylenediyl, ethylenediyl, propylenediyl, butylenediyl, pentanediyl, hexanediyl, heptanediyl, octanediyl, nonanediyl, decanediyl, undecanediyl, dodecanediyl, tridecanediyl, ethynediyl, propynediyl, pentynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, bicyclo[2.2.2]octanediyl, benzenediyl, pyrazolediyl, imidazolediyl, tetrazolediyl, pyrimidinediyl, 5,6,7,8,9,10-hexahydrocyclooctanedi[d]pyridazinediyl, azetidinediyl, 1,3-dioxolanediyl, pyrrolidinediyl, piperazinediyl, piperidinediyl or 3,9-diazaspiro[5.5]undecanediyl, each of which may be optionally substituted with one or more substituents Q. Each Z n are 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 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0253] In certain embodiments, each R n The 1,2-diyl, 1,3-diyl, 1,4-diyl, 1,5-diyl, 1,6-diyl, 1,7-diyl, 1,8-diyl, 1,9-diyl, 1,10-diyl, 1,11-diyl, 1,12-diyl, 1,3-diyl, 1,4-diyl, 1,5-diyl, 1,6-diyl, 1,7-diyl, 1,8-diyl, 1,9-diyl, 1,10-diyl, 1,1 ...3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,3-diyl, 1,13-diyl, acetylene-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 1,3-diyl, benzene-1,3-diyl, benzene-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-hexahydrocyclooctano[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 of which is optionally substituted with one or more substituents Q. Each Z nare 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 0, 1, 2, 3, 4 or 5.

[0254] In certain embodiments, each R n Each Z is independently methylenediyl, cyclopropylmethylenediyl, ethylenediyl, 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-; z is an integer of 0, 1, 2, 3, 4 or 5.

[0255] In certain embodiments, in certain embodiments, each R n is independently methanediyl, cyclopropylmethanediyl, ethane-1,2-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, acetylene-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. Each Z 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 0, 1, 2, 3, 4 or 5.

[0256] In certain embodiments, in any of Formulae (AI) to (A-IV), each L a All are independent:

[0257] In certain embodiments, in any of Formulae (AI) to (A-IV), each L a are independently:

[0258] In certain embodiments, in any of Formulae (AV) to (A-VII), each L b and L c are independently:

[0259] In certain embodiments, in any of Formulae (AV) to (A-VII), each L b and L c are independently:

[0260] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is independently a linker having the following structure: in: 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 heterocyclic group, each optionally substituted with one or more substituents Q; and Each R n , Z n and z are as defined in the present invention.

[0261] In certain embodiments, M is N or CH. In certain embodiments, M is N. In certain embodiments, M is CH.

[0262] In certain embodiments, M 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 optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, M is CR m , where R m It 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, C7-15 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, M is CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, M is C(CH3). In certain embodiments, M is a trivalent C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, M is a trivalent C 6-14 In some embodiments, M is a trivalent heteroaryl group, which may be optionally substituted with one or more substituents Q. In some embodiments, M is a trivalent heterocyclyl group, which may be optionally substituted with one or more substituents Q.

[0263] In certain embodiments, each R n Independently for C 1-10 Alkylene, C 6-14 arylene, heteroarylene or heterocyclyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, each R n R is independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothiophenediyl or tetrahydropyrandiyl, each optionally substituted with one, two or three substituents Q. In certain embodiments, each R n R is independently methane-1,2-diyl, 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, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,2-diyl, 2,5-dioxopyrrolidine-1,3-diyl, tetrahydrothiophene-2,5-diyl, or tetrahydropyran-1,3-diyl. In certain embodiments, each R n The 1,2-diyl group 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, phenyl-1,4-diyl, 1,2,3-triazole-1,4-diyl or 2,5-dioxopyrrolidine- 1,3-Diyl.

[0264] In certain embodiments, each Zn is independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -C(CH3)=NO-, -O-, -OC(O)NH-, -NH-, -N(CH3)-, -OP(O2)-, -OP(O)(S)-, -P(O2)O-, -P(O)(S)O-, -S-, or -S(O)2-. In certain embodiments, each Z n are independently a bond, -C(O)-, -C(O)NH-, -C(CH3)=NO-, -O-, -NH-, -OP(O2)-, -P(O2)O-, -P(O)(S)O- or -S-.

[0265] 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.

[0266] In certain embodiments, each R n is independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3-triazolediyl, pyrrolidinediyl, tetrahydrothiophenediyl or tetrahydropyrandiyl, each optionally substituted with one, two or three substituents Q. 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)-, -OP(O2)-, -OP(O)(S)-, -P(O2)O-, -P(O)(S)O-, -S- or -S(O)2-; each z is independently an integer 0, 1, 2, 3, 4 or 5.

[0267] In certain embodiments, each R n is independently methane-1,2-diyl, 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, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, tetrahydrothiophene-2,5-diyl or tetrahydropyran-1,3-diyl; 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)-, -OP(O2)-, -OP(O)(S)-, -P(O2)O-, -P(O)(S)O-, -S- or -S(O)2-; each z is independently an integer 0, 1, 2, 3 or 4.

[0268] In certain embodiments, each R n are independently methane-1,2-diyl, 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, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl or 2,5-dioxopyrrolidine-1,3-diyl; each Z n is independently a bond, -C(O)-, -C(O)NH-, -C(CH3)=NO-, -O-, -NH-, -OP(O2)-, -P(O2)O-, -P(O)(S)O- or -S-; each Z is independently an integer 0, 1, 2 or 3.

[0269] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention has the following structure:

[0270] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention has the following structure:

[0271] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention has the following structure:

[0272] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is a cleavable or non-cleavable linker. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is a cleavable linker. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is a non-cleavable linker.

[0273] In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate 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 conjugate provided by the present invention is a cleavable linker that contains a reducible disulfide. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by glutathione. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by an enzyme. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by a protease. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by a lysosomal protease. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by cathepsin B. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by a glycosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by β-glycosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by β-galactosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by β-galactosidase. In certain embodiments, the trivalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a linker that can be cleaved by 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 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. Exemplary linkers suitable for use in the carbohydrate-oligonucleotide conjugates provided herein include, but are not limited to, those disclosed in: Beck et al., Nature Drug Discovery Review, 2017, Vol. 16, pp. 317-337; Bargh et al., Chemical Society Reviews, 2019, Vol. 48, pp. 4361-4374 (Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74); the disclosure of each of which is incorporated herein by reference in its entirety.

[0274] In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently -Zn -(R n -Z n ) z - a linker structure, where each R n , Z n and z are as defined in the present invention.

[0275] In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugates provided herein independently has the following structure:

[0276] In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is independently a cleavable or non-cleavable linker. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is independently a cleavable linker. In certain embodiments, each bivalent linker in the carbohydrate-oligonucleotide conjugate provided herein is independently a non-cleavable linker.

[0277] In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is a cleavable linker that is sensitive to acidic pH. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a cleavable linker containing a reducible disulfide. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by glutathione. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by an enzyme. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by a protease. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by a lysosomal protease. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by cathepsin B alone. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by glycosidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by β-glycosidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by β-galactosidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by β-galactosidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by glucuronidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by β-glucuronidase. In certain embodiments, each divalent linker in the carbohydrate-oligonucleotide conjugate provided by the present invention is independently a linker that can be cleaved by phosphatase.Exemplary linkers suitable for use with the carbohydrate-oligonucleotide conjugates provided herein include, but are not limited to, those disclosed in: Beck et al., Nature Reviews: Drug Discovery, 2017, Vol. 16, pp. 317-337; Bargh et al., Chemical Society Reviews, 2019, Vol. 48, pp. 4361-4374 (Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74); the disclosures of each of which are incorporated herein by reference in their entirety.

[0278] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate having the structure of formula (I): in: R 1 is the ASGPR binding group; R 2 and R 3 each independently an oligonucleotide; L 1 , L 2 , L 3a and L 3c They are independent connectors; L 3b is (i) a bond; or (ii) heteroarylene or heterocyclylene, each optionally 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 6-14 The aryl group, the trivalent heteroaryl group or the trivalent heterocyclic group are each optionally substituted by one or more substituents Q.

[0279] In certain embodiments, in Formula (I), L 3b In certain embodiments, in Formula (I), L 3b is heteroarylene or heterocyclylene, each optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is heteroarylene, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a monocyclic heteroarylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3bis a 5- or 6-membered heteroarylene group, 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 group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is [1,2,3]triazolediyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), L 3b is [1,2,3]triazole-1,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a 6-membered heteroarylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a bicyclic heteroarylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a tricyclic heteroaryl group, optionally substituted by one or more Q substituents.

[0280] In certain embodiments, in Formula (I), L 3b is a heterocyclylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a monocyclic heterocyclylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is a bicyclic heterocyclylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is 4,5,6,7,8,9-hexahydrocyclooctan[d][1,2,3]triazolediyl or 5,6,7,8,9,10-hexahydrocyclooctan[d]pyridazinediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), L 3b It is 4,5,6,7,8,9-hexahydrocyclooctano[d][1,2,3]triazole-1,6-diyl, 4,5,6,7,8,9-hexahydrocyclooctano[d]-[1,2,3]triazole-1,7-diyl, or 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazine-1,7-diyl, each of which is optionally substituted by one or more substituents Q.

[0281] In certain embodiments, in Formula (I), L 3b is a tricyclic heterocyclylene group, optionally substituted by one or more substituents Q. In certain embodiments, in Formula (I), L 3b is 1,5a,6,6a-tetrahydrocyclopropane[5,6]cyclooctane[1,2-d][1,2,3]triazolediyl, optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I), L 3bis 1,5a,6,6a-tetrahydro-cyclopropane[5,6]cyclooctane[1,2-d][1,2,3]triazole-1,6-diyl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (I), L 3b is a tetracyclic heterocyclylene group, optionally substituted by 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]azocindiyl, 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]azocin-1,8-diyl or 8,9-dihydrodibenzo[b,f]-[1,2,3]triazolo[4,5-d]azocin-3,8-diyl, each of which is optionally substituted by one or more substituents Q.

[0282] In certain embodiments, in Formula (I), L 3b yes

[0283] In certain embodiments, in Formula (I), L 3b yes

[0284] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate having the structure of formula (II): Where R 1 , R 2 , R 3 , L 1 , L 2 , L 3a , L 3c and M are each as defined in the present invention.

[0285] In certain embodiments, in Formula (I) or (II), R 1 is the ASGPR binding group of the present invention. In certain embodiments, in formula (I) or (II), R1 is an ASGPR binding group represented by formula (AI). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group represented by formula (A-II). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group represented by formula (A-III). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group represented by formula (A-IV). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group represented by formula (AV). In certain embodiments, in formula (I) or (II), R 1 is an ASGPR binding group represented by formula (A-VI). In certain embodiments, in formula (I) or (II), R 1 It is an ASGPR binding molecule represented by formula (A-VII).

[0286] In certain embodiments, in Formula (I) or (II), R 1 yes

[0287] 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 oligodeoxynucleotide or oligoribonucleotide. In certain embodiments, in formula (I) or (II), R 2 is a single-stranded oligodeoxynucleotide (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 It is ASO, miRNA, mRNA or tRNA.

[0288] 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 2It is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:5 or SEQ ID NO:9.

[0289] In certain embodiments, in Formula (I) or (II), R 2 is a single-stranded oligonucleotide comprising a nucleotide sequence of any one of 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 It 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.

[0290] 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 It is a double-stranded oligoribonucleotide.

[0291] In certain embodiments, in Formula (I) or (II), R2 In certain embodiments, in formula (I) or (II), R 2 is a siRNA comprising 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 The siRNA comprises 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.

[0292] In certain embodiments, in Formula (I) or (II), R 2 In certain embodiments, in formula (I) or (II), R 2 is a siRNA comprising 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 2It is a siRNA comprising 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: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.

[0293] 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 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 It is a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:3, SEQ ID NO:7 or SEQ ID NO:11.

[0294] In certain embodiments, in Formula (I) or (II), R 3 is a single-stranded oligonucleotide comprising a nucleotide sequence of any one of SEQ ID NO: 1 to 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, SEQ ID NO: 23 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: 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 It 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.

[0295] 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 It is a double-stranded oligoribonucleotide.

[0296] In certain embodiments, in Formula (I) or (II), R 3 In certain embodiments, in formula (I) or (II), R 3is a double-stranded oligonucleotide comprising a pair of nucleotide sequences of SEQ ID NO:s 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 It is a double-stranded oligonucleotide comprising a pair of 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.

[0297] In certain embodiments, in Formula (I) or (II), R 3 In certain embodiments, in formula (I) or (II), R 3 is a double-stranded oligonucleotide comprising 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 3 It is a double-stranded oligonucleotide comprising 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.

[0298] In certain embodiments, in Formula (I) or (II), L 1is a linker as defined herein. In certain embodiments, in formula (I) or (II), L 1 Is with -Z n -(R n -Z n ) z - a linker of a structure, wherein each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 1 Yes -NHC(O)(CH2) e C(O)NH-, wherein 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 Yes -NHC(O)(CH2) e C(O)NH-, wherein e is an integer of 3, 6 or 10. In certain embodiments, in Formula (I) or (II), L 1 is -NHC(O)(CH2)3C(O)NH-. In certain embodiments, in formula (I) or (II), L 1 is -NHC(O)(CH2)6C(O)NH-. In certain embodiments, in formula (I) or (II), L 1 Yes -NHC(O)(CH2) 10 C(O)NH-. In certain embodiments, in Formula (I) or (II), L 1 yes

[0299] 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 Is with -Z n -(R n -Z n ) z - a linker of a structure, wherein each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 2 Yes - (CH2) f C(O)NH(CH2) g OP(O2)-, wherein 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. In certain embodiments, in Formula (I) or (II), L 2is -(CH2)NHC(O)(CH2)6OP(O2)- or -NHC(O)(CH2)6OP(O2)-. In certain embodiments, in formula (I) or (II), L 2 is -(CH2)NHC(O)(CH2)6OP(O2)-. In certain embodiments, in formula (I) or (II), L 2 It is -NHC(O)(CH2)6OP(O2)-.

[0300] In certain embodiments, in Formula (I) or (II), L 2 is a linker comprising -O-, -S- or -N(H)-. In certain embodiments, in formula (I) or (II ) In, L 2 It contains C 6-14 A linker of an arylene or heterocyclylene group, each optionally substituted by one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene or monocyclic heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene, 5- or 6-membered heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 2 is a linker comprising phenylene, pyrrolidinediyl, tetrahydrothiophenediyl, tetrahydropyrandiyl or piperidinediyl, each optionally substituted with one or more substituents Q.

[0301] In certain embodiments, in Formula (I) or (II), L 2 Yes -X(CH2) h X-, wherein 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 Yes -X(CH2) i CH(OH)(CH2) j X-, wherein 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 yes In certain embodiments, in Formula (I) or (II), L 2 yes Where L 2Attached to the 5'-end of the oligonucleotide. In certain embodiments, in formula (I) or (II), L 2 yes In certain embodiments, in Formula (I) or (II), L 2 yes Where L 2 Ligate to the 3'-end of the oligonucleotide.

[0302] In certain embodiments, in Formula (I) or (II), L 2 yes

[0303] 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 Is with -Z n -(R n -Z n ) z - a linker of a structure, wherein each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 3a It is C 1-10 Alkylene or C 7-15 arylalkylene, each optionally substituted by one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3a is methylene or benzene, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3a is -(CH2)- or -(CH2)-benzene-1,4-diyl, each optionally substituted by one or more substituents Q.

[0304] In certain embodiments, in Formula (I) or (II), L 3a It is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0305] 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 a Z n -(R n-Z n ) z - a linker of a structure, wherein each R n , Z n and z are as defined herein. In certain embodiments, in formula (I) or (II), L 3c Yes - (CH2) m C(O)NH(CH2) n OP(O2)-, wherein 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 It is -(CH2)5C(O)NH(CH2)6OP(O2)-.

[0306] 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 It contains C 6-14 A linker of an arylene or heterocyclylene group, each optionally substituted by one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene or monocyclic heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene, 5- or 6-membered heterocyclylene, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), L 3c is a linker comprising phenylene, pyrrolidinediyl, tetrahydrothiophenediyl, tetrahydropyrandiyl or piperidinediyl, each optionally substituted by one or more substituents Q

[0307] In certain embodiments, in Formula (I) or (II), L 3c is X(CH2) p X-, wherein 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 Yes -X(CH2) q CH(OH)(CH2) r X-, wherein each X is as defined herein; and 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 yes In certain embodiments, in Formula (I) or (II), L 3c yes Where L 3c Attached to the 5'-end of the oligonucleotide. In certain embodiments, in formula (I) or (II), L 3c yes In certain embodiments, in Formula (I) or (II), L 3c yes Where L 3c Ligate to the 3'-end of the oligonucleotide.

[0308] In certain embodiments, in Formula (I) or (II), L 3c yes

[0309] 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.

[0310] 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 aryl, trivalent heteroaryl or trivalent heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is CR m , where R m It 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 arylalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q. In certain embodiments, in formula (I) or (II), M is CR m , where R m It is C 1-6 alkyl, optionally substituted with one or more Q. In certain embodiments, in formula (I) or (II), M is C(CH3). In certain embodiments, in formula (I) or (II), M is a trivalent C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 1-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in formula (I) or (II), M is a trivalent C 6-14 In some embodiments, in formula (I) or (II), M is a trivalent heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, in formula (I) or (II), M is a trivalent heterocyclyl group, optionally substituted with one or more substituents Q.

[0311] In certain embodiments, in Formula (I) or (II), L 1 Yes -NHC(O)(CH2) e C(O)NH- wherein e is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; L 2 yes -(CH2) f C(O)NH(CH2) g OP(O2)-, wherein 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 methylene or benzene, each of which is optionally substituted by one or more substituents Q; L 3c Yes - (CH2) m C(O)NH(CH2) n OP(O2)-, wherein m and n are each independently an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and M is a trivalent C 1-6 alkyl.

[0312] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 3'-siRNA independently represents an siRNA whose 3'-ends are connected to a trivalent linker; each 5'-siRNA independently represents an siRNA whose 5'-ends are connected to a trivalent linker.

[0313] In another embodiment, the present invention provides a carbohydrate-oligonucleotide: Herein, 3'-siRNA refers to siRNA whose 3'-ends are connected to the first divalent linker and whose 5'-ends are connected to the second divalent linker; 5'-siRNA refers to siRNA whose 5'-ends are connected to the second divalent linker.

[0314] In another embodiment, the present invention provides a carbohydrate-oligonucleotide: Each 5'-siRNA independently represents a siRNA having one 5'-end connected to a trivalent linker.

[0315] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 5'-siRNA independently represents a siRNA having one 5'-end connected to a trivalent linker.

[0316] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Herein, 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.

[0317] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 5'-siRNA independently represents a siRNA having one 5'-end connected to a trivalent linker.

[0318] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 3'-siRNA independently represents a siRNA with one of its 3'-ends connected to a trivalent linker.

[0319] In one embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 3'-ssRNA independently represents a single-stranded RNA, and its 3'-end is connected to a trivalent linker; each 5'-ssRNA independently represents a single-stranded RNA, and its 5'-end is connected to a trivalent linker.

[0320] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Among them, 3'-ssRNA refers to a single-stranded RNA, whose 3'-end is connected to the first divalent linker and whose 5'-end is connected to the second divalent linker; 5'-ssRNA refers to a single-stranded RNA, whose 5'-end is connected to the second divalent linker.

[0321] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0322] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0323] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Among them, 5'-siRNA refers to single-stranded RNA, 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.

[0324] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 5'-ssRNA independently represents a single-stranded RNA, the 5'-end of which is connected to a trivalent linker.

[0325] In another embodiment, the present invention provides a carbohydrate-oligonucleotide conjugate: Each 3'-ssRNA independently represents a single-stranded RNA, the 3'-end of which is connected to a trivalent linker.

[0326] In one embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention is any one of carbohydrate-oligonucleotide conjugates A18a to A18c.

[0327] In another embodiment, the carbohydrate-oligonucleotide conjugate provided by the present invention is any one of carbohydrate-oligonucleotide conjugates A4a, A18a to A18h, and A19a to A29a.

[0328] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:3 and SEQ ID NO:4.

[0329] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:5 and SEQ ID NO:6; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:7 and SEQ ID NO:8.

[0330] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:9 and SEQ ID NO:10; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:11 and SEQ ID NO:12.

[0331] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 13 and SEQ ID NO: 14; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 7 and SEQ ID NO: 8.

[0332] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 15 and SEQ ID NO: 16; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 17 and SEQ ID NO: 18.

[0333] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:9 and SEQ ID NO:10; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:19 and SEQ ID NO:20.

[0334] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 19 and SEQ ID NO: 20; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO: 21 and SEQ ID NO: 22.

[0335] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises a first and a second oligonucleotide duplex, wherein the first oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:3 and SEQ ID NO:4; and the second oligonucleotide duplex comprises the nucleotide sequences of SEQ ID NO:1 and SEQ ID NO:2.

[0336] In certain embodiments, the carbohydrate-oligonucleotide conjugate provided by the present invention comprises an oligonucleotide duplex and a single-stranded oligonucleotide, wherein the oligonucleotide duplex comprises the nucleotide sequence of SEQ ID NO:23 and SEQ ID NO:24; and the single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:25.

[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:1; and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:3.

[0338] 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:5; and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:7.

[0339] 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.

[0340] 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.

[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:15; and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:17.

[0342] 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:19.

[0343] 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: 19; and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO: 21.

[0344] 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:3; and the second single-stranded oligonucleotide comprises the nucleotide sequence of SEQ ID NO:1.

[0345] 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. Drug ingredients

[0346] In one embodiment, the present invention provides a pharmaceutical composition comprising the carbohydrate-oligonucleotide conjugate provided by the present invention and a pharmaceutically acceptable excipient.

[0347] In one embodiment, the present invention The pharmaceutical composition provided is formulated into a dosage form for parenteral administration. In another embodiment, the pharmaceutical composition provided by the invention is formulated into a dosage form for intravenous administration. In another embodiment, the pharmaceutical composition provided by the invention is formulated into a dosage form for intramuscular administration. In another embodiment, the pharmaceutical composition provided by the invention is formulated into a dosage form for subcutaneous administration.

[0348] The pharmaceutical composition provided by the present invention can be provided in single-dose dosage form or multi-dose dosage form. The single-dose dosage form mentioned here refers to physically discrete units suitable for being taken by a subject, and is packaged separately in a manner known in the art. Each unit dose contains a predetermined amount of active ingredients (e.g., carbohydrate-oligonucleotide conjugates provided by the present invention), which is sufficient to produce the expected therapeutic effect together with the required pharmaceutical excipients. Examples of single-dose dosage forms include, but are not limited to, ampoules and syringes. Single-dose forms can be administered in fractions or multiples. Multi-dose dosage forms are multiple identical single-dose dosage forms packaged in a container and administered in an independent single-dose form. Examples of multi-dose dosage forms include, but are not limited to, pint- or gallon-loaded vials or bottles.

[0349] The pharmaceutical composition provided by the present invention can be administered once or multiple times at intervals. It should be understood that the exact dosage and duration of treatment may vary depending on the age, weight, and condition of the subject being treated, and can be determined empirically using known test protocols, or inferred by in vivo or in vitro tests or diagnostic data. It should also be understood that for any particular individual, the specific dosage regimen should be adjusted over time based on the needs of the subject and the professional judgment of the person responsible for administering or supervising the administration of the pharmaceutical composition.

[0350] The present invention can be further understood through the following non-limiting examples. Example

[0351] In the processes, schemes and examples used in the present invention, whether or not specific abbreviations are specifically defined, the symbols and conventions are consistent with those used in contemporary scientific literature (such as the Journal of the American Chemical Society, the Journal of Medicinal Chemistry or the Journal of Biological Chemistry). Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromole); mmol (millimole); min (minute or number of minutes); h (hour or number of hours); AcOH (acetic acid); DEA (diethylamine); DIPEA (N,N-diisopropylethylamine); DMSO (dimethyl sulfoxide); DMTr (4,4-dimethoxytrityl); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); ETT (5-nitropropene); -(ethylthio)tetrazole); HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HOSu (N-hydroxy-succinimide); NaOAc (sodium acetate); iPr (isopropyl); Pfp (pentafluorophenyl); SDPD (succinimidyl 3-(2-pyridyldisulfide)-propionate); TBAF (tetrabutylammonium fluoride); TBDPS (tert-butyldiphenylsilane); TCEP (tris(2-carboxyethyl)phosphine); TFAPFP (pentafluorophenyl trifluoroacetate); THF (tetrahydrofuran); MS (mass spectrometry); prep-HPLC (preparative high performance liquid chromatography).

[0352] For all of the following examples, standard processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methods described here are intended to illustrate applicable chemical methods by using specific examples and do not represent the scope of the present disclosure. Example 1 Preparation of GalNAc-siRNA conjugate A1

[0353] GalNAc-siRNA conjugate A1 was prepared as shown in Scheme 1, wherein R p Is has Structural group; R q Is has ASGPR binding group of 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 connected to a trivalent linker; and each 5'-siRNA independently represents an siRNA whose 5'-end is connected to a trivalent linker. In Scheme 1, the preparation of compound 1.2 is similar to the description in WO 2020 / 259497 A1, the entire disclosure of which is incorporated herein by reference. Note: Complementary ssRNA is complementary ssRNA Example 2 Preparation of GalNAc-siRNA conjugate A2

[0354] GalNAc-siRNA conjugate A2 was prepared as shown in Scheme 2, where R s Is has Structural group; R t Is has ASGPR binding group of 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 connected to a trivalent linker; and each 5'-siRNA independently represents an siRNA whose 5'-end is connected to a trivalent linker. In Scheme 2, the preparation of compound 2.2 is similar to the description in WO 2020 / 259497 A1, the disclosure of which is incorporated herein by reference in its entirety. Note: Complementary ssRNA is complementary ssRNA Example 3 Preparation of GalNAc-siRNA conjugate A3

[0355] GalNAc-siRNA conjugate A3 was prepared as shown in Scheme 3, where R s and R t As described in Embodiment 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; each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. Note: Solid Phase Synthesis refers to solid phase synthesis, and Complementary ssRNA refers to complementary ssRNA Example 4 Preparation of GalNAc-siRNA conjugate A4a

[0356] The preparation of GalNAc-siRNA conjugate A4a is shown in Schemes 4A and 4B, wherein R s and R t As described in Example 2; wherein 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and has an antisense strand of a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and has an antisense strand of a nucleotide sequence of SEQ ID NO: 4.

[0357] 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. Note: Oligonucleotid means oligonucleotide, Annealing means annealing

[0358] Preparation of compound 4.3. Compound 4.2 (210 mg, 29 μmol) was dissolved in 0.1M Na2B4O7 aqueous solution (1 ml), and compound 4.1 (37 mg, 147 μmol) dissolved in dimethyl sulfoxide (1 ml) solution was added. After the reaction mixture was sonicated for 2 hours, NaOAc (164 mg, 2 mmol) was added. The reaction mixture was then centrifuged, the precipitate was collected and dried to obtain compound 4.3 (150 mg) with a yield of 70%. Mass spectrometry mass-to-charge ratio: [M+H] + C 229 H 302 F3N 80 O 142 P 21The calculated value of S4 is 7283.04; the found value is 7283.21 (MS m / z: [M+H] + Calcd for C 229 H 302 F3N 80 O 142 P 21 S4 7283.04; Found 7283.21).

[0359] Preparation of compound 4.6. Compound 4.5 (280 mg, 38 μmol) was dissolved in 0.1M Na2B4O7 aqueous solution (2.6 mL), and DIPEA (0.5 mL) and compound 4.4 (88 mg, 159 μmol) dissolved in DMSO (2.6 mL) were added. After the reaction mixture was sonicated for 2 hours, DEA solution (2 mL) was added. The reaction mixture was sonicated for another 2 hours. NaOAc (467 mg, 5.7 mmol) was then added. The reaction mixture was then centrifuged, the precipitate was collected and dried to give compound 4.6 (210 mg) with a yield of 73%. Mass spectrometry mass-to-charge ratio: [M+H] + C 229 H 305 F2N 66 O 151 P 21 The calculated value of S4 is 7214.96; the measured value is 7215.17.

[0360] Preparation of compound 4.7. Compound 4.6 (210 mg, 28 μmol) was dissolved in 0.1M Na2B4O7 aqueous solution (3.5 ml), and DIPEA (0.5 ml) and compound 2.2 (332 mg, 175 μmol) dissolved in DMSO (4 ml) were added. After the reaction mixture was sonicated for 2 hours, NaOAc (656 mg, 8 mmol) was added. The reaction mixture was then centrifuged, the precipitate was collected and dried to obtain compound 4.7 (160 mg) with a yield of 62%. Mass spectrometry: [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.

[0361] 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 cuprous 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 spectrometry: [M+H] + C 536 H 730 F5N 153 O 328 P 42 The calculated value of S8 is 16216.85; the measured value is 16217.16.

[0362] Preparation of compound B4a. To an aqueous solution (1 ml) of compound 4.8 (53 mg) was added a 30% aqueous solution of 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 a crude product (29 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B4a (13.7 mg) with a yield of 17%. Mass spectrometry: [M+H] + C 518 H 712 F5N 153 O 319 P 42 The calculated value of S8 is 15838.52; the measured value is 15838.75.

[0363] Preparation of Compound A4a. An aqueous solution of Compound B4a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to give Compound A4a. Example 5 Preparation of GalNAc-siRNA conjugate A5

[0364] GalNAc-siRNA conjugate A5 was prepared as shown in Scheme 5, where R s and R t 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; each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. Note: Succinic Anhydride is succinic anhydride, Resin is resin, Solid Phase Synthesis is solid phase synthesis, Cleavage is cleavage, Deprotection is deprotection, Complementary ssRNA is complementary ssRNA Example 6 Preparation of GalNAc-siRNA conjugate A6

[0365] GalNAc-siRNA conjugate A6 was prepared as shown in Scheme 6, where R s and R t As described in Example 2; 3'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 3'-end is connected to a trivalent linker; 5'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 5'-end is connected to a trivalent linker; 3'-siRNA represents siRNA, one of whose 3'-ends is connected to a trivalent linker; 5'-siRNA represents siRNA, one of whose 5'-ends is connected to a trivalent linker. Note: Succinic Anhydride is succinic anhydride, Resin is resin, Solid Phase Synthesis is solid phase synthesis, Cleavage is cleavage, Deprotection is deprotection, Complementary ssRNA is complementary ssRNA Example 7 Preparation of GalNAc-siRNA conjugate A7

[0366] GalNAc-siRNA conjugate A7 was prepared as shown in Scheme 7, where R s and R t As described in Example 2; 3'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 3'-end is connected to a trivalent linker; 5'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 5'-end is connected to a trivalent linker; 3'-siRNA represents siRNA, one of whose 3'-ends is connected to a trivalent linker; 5'-siRNA represents siRNA, one of whose 5'-ends is connected to a trivalent linker. Note: Piperidine is piperidine, Complementary ssRNA is complementary ssRNA Example 8 Preparation of GalNAc-siRNA conjugate A8

[0367] GalNAc-siRNA conjugate A8 was prepared as shown in Scheme 8, where R s and R t 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; each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. Note: Complementary ssRNA is complementary ssRNA Example 9 Preparation of GalNAc-siRNA conjugate A9

[0368] GalNAc-siRNA conjugate A9 was prepared as shown in Scheme 9, wherein R s and R t As described in Example 2; 3'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 3'-end is connected to a trivalent linker; 5'-ssRNA represents single-stranded RNA (e.g., the sense or antisense sequence of siRNA, or an ASO sequence), whose 5'-end is connected to a trivalent linker; 3'-siRNA represents siRNA, one of whose 3'-ends is connected to a trivalent linker; 5'-siRNA represents siRNA, one of whose 5'-ends is connected to a trivalent linker. Note: Complementary ssRNA is complementary to ss RNA Example 10 Preparation of GalNAc-siRNA conjugate A10

[0369] GalNAc-siRNA conjugate A10 was prepared as shown in Scheme 9, where R s and R tAs 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; each 3'-siRNA independently represents an siRNA whose one 3'-end is linked to a trivalent linker. Note: Complementary ssRNA is complementary ssRNA Example 11 Preparation of GalNAc-siRNA conjugate A11

[0370] GalNAc-siRNA conjugate A11 was prepared as shown in Scheme 11, wherein R s and R t 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; each 5'-siRNA independently represents an siRNA whose one 5'-end is linked to a trivalent linker. Note: Complementary ssRNA is complementary ssRNA Example 12 Preparation of GalNAc-siRNA conjugate A13

[0371] GalNAc-siRNA conjugate A13 is prepared as shown in Scheme 10, wherein each 5'-ssRNA independently represents a single-stranded RNA (e.g., a sense or antisense sequence of siRNA, or an ASO sequence) whose 5'-end is linked to a trivalent linker; each 5'-siRNA independently represents an siRNA whose one of the 5'-ends is linked to a trivalent linker. Note: Coupling Reagent is coupling reagent, Complementary ssRNA is complementary ssRNA Example 13 Preparation of GalNAc-siRNA conjugate A17

[0372] GalNAc-siRNA conjugate A17 was prepared as shown in Scheme 13, wherein R s and R tAs described in Embodiment 2; 3'-ssRNA represents single-stranded RNA (e.g., sense or antisense sequence of siRNA or ASO sequence), whose 3'-end is connected to the first divalent linker, and whose 5'-end is connected to the second divalent linker; 5'-ssRNA represents single-stranded RNA (e.g., sense or antisense sequence of siRNA or ASO sequence), whose 5'-end is connected to the second divalent linker; 3'-siRNA represents siRNA, whose 3'-end is connected to the first divalent linker, and whose 5'-end is connected to the second divalent linker; 5'-ssRNA represents single-stranded RNA (e.g., sense or antisense sequence of siRNA or ASO sequence), whose 5'-end is connected to the second divalent linker; 3'-siRNA represents siRNA, one of whose 3'-ends is connected to the first divalent linker, and one of whose 5'-ends is connected to the second divalent linker; 5'-siRNA represents siRNA, one of whose 5'-ends is connected to the second divalent linker. Note: Succinic Anhydride is succinic anhydride, Resin is resin, Solid Phase Synthesis is solid phase synthesis, Complementary ssRNA is complementary ssRNA Example 14 Preparation of GalNAc-siRNA conjugate A18a

[0373] GalNAc-siRNA conjugate A18a was prepared as shown in Scheme 14, where R s and R t As described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4 The antisense strand of the nucleotide sequence.

[0374] Preparation of compound 14.3. Compound 14.2 (280 mg, 38 μmol) was dissolved in 0.1M Na2B4O7 aqueous solution (2.6 mL), and DIPEA (0.5 mL) and a solution of compound 14.1 (79 mg, 159 μmol) in DMSO (2.6 mL) were added. After the reaction mixture was sonicated for 2 hours, a DEA solution (2 mL) was added. The reaction mixture was sonicated for another 2 hours, and then NaOAc (467 mg, 5.7 mmol) was added. The reaction mixture was centrifuged, the precipitate was collected and dried to give compound 14.3 (250 mg) with a yield of 88%. Mass spectrometry: [M+H] + C 225 H 297 F2N 66 O 151 P 21 The calculated value of S4 is 7158.85; Found 7158.92.

[0375] Preparation of compound 14.4. Compound 14.3 (250 mg, 34 μmol) was dissolved in 0.1M Na2B4O7 aqueous solution (3.5 ml), and DIPEA (0.5 ml) and a solution of compound 2.2 (399 mg, 210 μmol) in DMSO (4 ml) were added. After the reaction mixture was sonicated for 2 hours, NaOAc (656 mg, 8 mmol) was added. The reaction mixture was then centrifuged, the particles were collected and dried to obtain compound 14.4 (270 mg) with a yield of 87%. Mass spectrometry: [M+H] + C 303 H 420 F2N 73 O 186 P 21 The calculated value of S4 is 8877.7; the measured value is 8877.78.

[0376] 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 cuprous 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; the measured value is 16161.09.

[0377] Preparation of compound B18a. To an aqueous solution (1 ml) of compound 14.5 (65 mg) was added a 30% aqueous solution of 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 a crude product (51 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B18a (20.5 mg) with a yield of 19%. Mass spectrometry: [M+H] + C 514 H 704 F5N 153 O 319 P 42 The calculated value of S8 is 15782.41; the measured value is 15782.53.

[0378] Preparation of Compound A18a. An aqueous solution of Compound B18a (1 equivalent) and oligonucleotide 4.9 (1 equivalent) and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to give Compound A18a. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0379] The preparation method of GalNAc-siRNA conjugates A18b to A18h was similar to that shown in Example 14. Conjugate siRNA-a sense siRNA-a antisense siRNA-b sense siRNA-b antisense A18b SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQ ID NO:8 A18c SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:11 SEQ ID NO:12 A18d SEQ ID NO:13 SEQ ID NO:14 SEQ ID NO:7 SEQ ID NO:8 A18e SEQ ID NO:15 SEQ ID NO:16 SEQ ID NO:17 SEQ ID NO:18 A18f SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:19 SEQ ID NO:20 A18g SEQ ID NO:19 SEQ ID NO:20 SEQ ID NO:21 SEQ ID NO:22 A18h SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:1 SEQ ID NO:2

[0380] The preparation method of GalNAc-siRNA conjugates B18b to B18g was similar to that shown in Example 14. Example 15 Preparation of GalNAc-siRNA conjugate A19a

[0381] GalNAc-siRNA conjugate A19a was prepared as shown in Scheme 15, where R s and R tAs described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0382] 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 cuprous 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 spectrometry mass-to-charge ratio: [M+H] + C 535 H 728 F5N 153 O 328 P 42 The calculated value of S8 is 16202.82; the measured value is 16202.93.

[0383] Preparation of compound B19a. To an aqueous solution (1 ml) of compound 15.2 (78 mg) was added a 30% aqueous solution of 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 a crude product (52 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B19a (26.3 mg) with a yield of 24%. Mass spectrometry: [M+H] + C 517 H 710 F5N 153 O 319 P 42 The calculated value of S8 is 15824.49; the measured value is 15824.72.

[0384] Preparation of Compound A19a. An aqueous solution of Compound B19a (1 equivalent) and oligonucleotide 4.9 (1 equivalent) and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to obtain Compound A19a. Example 16 Preparation of GalNAc-siRNA conjugate A20a

[0385] GalNAc-siRNA conjugate A20a was prepared as shown in Scheme 16, wherein R s and R t As described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0386] 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 cuprous 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 spectrometry: [M+H] + C 539 H 736 F5N 153 O 328 P 42 The calculated value of S8 is 16258.93; the measured value is 16258.94.

[0387] Preparation of compound B20a. To an aqueous solution (1 ml) of compound 16.2 (67 mg) was added a 30% aqueous solution of 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 a crude product (51 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B20a (23.9 mg) with a yield of 18%. Mass spectrometry: [M+H] + C 521 H 718 F5N 153 O 319 P 42 The calculated value of S8 is 15880.6; the measured value is 15880.86.

[0388] Preparation of Compound A20a. An aqueous solution of Compound B20a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A20a. Example 17 Preparation of GalNAc-siRNA conjugate A21a

[0389] GalNAc-siRNA conjugate A21a was prepared as shown in Scheme 17, wherein R s and R t As described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0390] Preparation of compound 17.2. To an aqueous solution (3 ml) of compound 17.1 (80 mg, 11 μmol) and compound 4.3 (98 mg, 14 μmol) was added cuprous bromide dimethyl sulfide (6 mg, 29 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 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 of S8 is 16174.77; the measured value is 16175.1. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0391] Preparation of compound B21a. To an aqueous solution (1 ml) of compound 17.2 (73 mg) was added a 30% aqueous solution of 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 a crude product (57 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B21a (25.7 mg) with a yield of 18%. Mass spectrometry: [M+H] + C 515 H 706 F5N 153 O 319 P 42 The calculated value of S8 is 15796.44; the measured value is 15797.07.

[0392] Preparation of Compound A21a. An aqueous solution of Compound B21a (1 equivalent) and oligonucleotide 4.9 (1 equivalent) and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to give Compound A21a. Example 18 Preparation of GalNAc-siRNA conjugate A22a

[0393] GalNAc-siRNA conjugate A22a was prepared as shown in Scheme 18, wherein R s and R tAs described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0394] 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 cuprous 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 of S8 is 16202.82; the measured value is 16202.95.

[0395] Preparation of compound B22a. To an aqueous solution (1 ml) of compound 18.2 (76 mg) was added a 30% aqueous solution of 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 a crude product (66 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B22a (19.8 mg) with a yield of 20%. Mass spectrometry: [M+H] + C 517 H 710 F5N 153 O 319 P 42 The calculated value of S8 is 15824.49; the measured value is 15824.67. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0396] Preparation of Compound A22a. An aqueous solution of Compound B22a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A22a. Example 19 Preparation of GalNAc-siRNA conjugate A23a

[0397] GalNAc-siRNA conjugate A23a was prepared as shown in Scheme 19, wherein R s and R t As described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0398] Preparation of compound 19.2. To an aqueous solution (3 ml) of compound 19.1 (60 mg, 8 μmol) and compound 4.3 (74 mg, 10 μmol) was added cuprous 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 19.2 (82 mg). Mass spectrometry: [M+H] + C 538 H 726 F5N 153 O 328 P 42 The calculated value of S8 is 16236.84; the measured value is 16236.98.

[0399] Preparation of compound B22a. To an aqueous solution (1 ml) of compound 18.2 (82 mg) was added a 30% aqueous solution of 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 a crude product (56 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B23a (21.7 mg) with a yield of 20%. Mass spectrometry: [M+H]+ C 520 H 708 F5N 153 O 319 P 42 The calculated value of S8 is 15858.51; the measured value is 15858.84. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0400] Preparation of Compound A23a. An aqueous solution of Compound B23a (1 equivalent) and oligonucleotide 4.9 (1 equivalent) and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to give Compound A23a. Example 20 Preparation of GalNAc-siRNA conjugate A24a

[0401] GalNAc-siRNA conjugate A24a was prepared as shown in Scheme 20, where R u Is has Structural group; R v Is has The invention relates to an ASGPR binding group of the structure; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0402] 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) was added cuprous 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 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.

[0403] Preparation of compound B24a. To an aqueous solution (1 ml) of compound 20.2 (61 mg) was added a 30% aqueous solution of 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 a crude product (38 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B24a (18.8 mg) with a yield of 15%. Mass spectrometry: [M+H] + C 520 H 713 F5N 156 O 322 P 42 The calculated value of S8 is 15953.56; the measured value is 15953.67.

[0404] Preparation of Compound A24a. An aqueous solution of Compound B24a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A24a. Example 21 Preparation of GalNAc-siRNA conjugate A25a

[0405] GalNAc-siRNA conjugate A25a was prepared as shown in Scheme 21, where R x Is has Structural group; R y Is has The invention relates to an ASGPR binding group of the structure; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0406] Preparation of compound 21.2. To an aqueous solution (3 ml) of compound 21.1 (72 mg, 10 μmol) and compound 4.3 (89 mg, 12 μmol) was added cuprous 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 spectrometry: [M+H] + C 523 H 703 F5N 154 O 329 P 42 The calculated value of S8 is 16063.5; the measured value is 16063.97.

[0407] Preparation of compound B25a. To an aqueous solution (1 ml) of compound 21.2 (68 mg) was added a 30% aqueous solution of 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 a crude product (46 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B25a (19.8 mg) with a yield of 15%. Mass spectrometry: [M+H] + C 505 H 685 F5N 154 O 320 P 42 The calculated value of S8 is 15685.16; the measured value is 15684.94.

[0408] Preparation of Compound A25a. An aqueous solution of Compound B25a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A25a. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing Preparation of GalNAc-siRNA conjugate A26a

[0409] GalNAc-siRNA A26a was prepared as shown in Scheme 22, where R p and R q As described in Example 1; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0410] 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 cuprous 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 spectrometry: [M+H] + C 508 H 684 F5N 151 O 317 P 42 The calculated value of S8 is 15630.17; the measured value is 15630.67.

[0411] Preparation of compound B26a. To an aqueous solution (1 ml) of compound 22.2 (68 mg) was added a 30% aqueous solution of 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 a crude product (49 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B26a (26.7 mg) with a yield of 20%. Mass spectrometry: [M+H] + C 496 H 672 F5N 151 O 311 P 42 The calculated value of S8 is 15377.95; the measured value is 15378.25.

[0412] Preparation of Compound A26a. An aqueous solution of Compound B26a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A26a. Example 23 Preparation of GalNAc-siRNA conjugate A27a

[0413] GalNAc-siRNA conjugate A27a was prepared as shown in Scheme 23, wherein R p and R q As described in Example 1; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0414] 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 cuprous 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 of S8 is 15672.25; the measured value is 15672.31. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0415] Preparation of compound B27a. To an aqueous solution (1 ml) of compound 23.2 (72 mg) was added a 30% aqueous solution of 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 a crude product (56 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B27a (25.4 mg) with a yield of 20%. Mass spectrometry: [M+H] + C 499 H 678 F5N 151 O 311 P 42 The calculated value of S8 is 15420.03; the measured value is 15420.46.

[0416] Preparation of Compound A27a. An aqueous solution of Compound B27a (1 equivalent) and oligonucleotide 4.9 (1 equivalent) and oligonucleotide 4.10 (1 equivalent) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to give Compound A27a. Example 24 Preparation of GalNAc-siRNA conjugate A28a

[0417] GalNAc-siRNA conjugate A28a was prepared as shown in Scheme 24, where R p and R qAs described in Example 1; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 1, and its 5'-end is connected to a trivalent linker; 5'-ssRNA-b has a nucleotide sequence of SEQ ID NO: 3, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a sense strand having a nucleotide sequence of SEQ ID NO: 1, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 2; 5'-siRNA-b includes a sense strand having a nucleotide sequence of SEQ ID NO: 3, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 4.

[0418] 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 cuprous 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 of S8 is 15728.36; the measured value is 15730.0.

[0419] Preparation of compound B28a. To an aqueous solution (1 ml) of compound 24.2 (81 mg) was added a 30% aqueous solution of 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 a crude product (64 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B28a (29.3 mg) with a yield of 21%. Mass spectrometry: [M+H] + C 503 H 686 F5N 151 O 311 P 42 The calculated value of S8 is 15476.14; the measured value is 15475.88. Note: Compound is compound, Oligonucleotide is oligonucleotide, Annealing is annealing

[0420] Preparation of Compound A28a. An aqueous solution of Compound B28a (1 eq.) and oligonucleotide 4.9 (1 eq.) and oligonucleotide 4.10 (1 eq.) was heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A28a. Example 25 Preparation of GalNAc-siRNA conjugate A29a

[0421] GalNAc-siRNA conjugate A25a was prepared as shown in Scheme 25, wherein R s and R t As described in Example 2; 5'-ssRNA-a has a nucleotide sequence of SEQ ID NO: 23, and its 5'-end is connected to a trivalent linker; 5'-ssDNA has a nucleotide sequence of SEQ ID NO: 25, and its 5'-end is connected to a trivalent linker; 5'-siRNA-a includes a positive strand having a nucleotide sequence of SEQ ID NO: 23, its 5'-end is connected to a trivalent linker, and an antisense strand having a nucleotide sequence of SEQ ID NO: 24.

[0422] 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.

[0423] Preparation of compound 25.3. To a solution of compound 25.1 (60 mg, 9 μmol) and compound 25.2 (81 mg, 11 μmol) in water (3 ml) was added cuprous 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 measured value is 15763.01.

[0424] Preparation of compound B29a. To an aqueous solution (1 ml) of compound 25.3 (68 mg) was added a 30% aqueous solution of 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 a crude product (41 mg), which was purified by C18 reverse phase preparative HPLC and concentrated to about 1 ml to give compound B29a (13.9 mg) with a yield of 12%. Mass spectrometry: [M+H] + C 494 H 664 F4N 163 O 272 P 41 S 25 The calculated value is 15385.03; the measured value is 15385.45. Note: Oligonucleotide is oligonucleotide, Annealing is annealing

[0425] Preparation of Compound A29a. An aqueous solution of Compound B29a (1 eq.) and oligonucleotide 25.4 (1 eq.) is heated at 70-95°C for about 1 to 5 minutes and then cooled to room temperature to provide Compound A29a.

[0426] The preparation methods of GalNAc-siRNA conjugates A4, A12, A14 to A16, A18 to A33, B4, B12, B14 to B16 and B18 to B33 are similar to the steps described in the present invention. Example B1 Inhibition of ANGPTL3 and PCSK9 mRNA expression

[0427] The revived primary human hepatocytes (PPH) were cultured at 6×10 5 Cells / ml were inoculated in 96-well plates containing INVITROGRO. Then, the cells were treated with 10 nanomolar, 100 nanomolar and 500 nanomolar GalNAc-siRNA conjugate A18a at 37 degrees Celsius and 5% carbon dioxide for 48 hours. After centrifugation, the cells were collected, and the RNA of the cells was extracted and reverse transcribed into cDNA. The mRNA expression levels of ANGPTL3 and PCSK9 were analyzed by qPCR. The results are shown in Table 1. Table 1. Inhibition of ANGPTL3 and PCSK9 mRNA expression levels Example B2 Inhibition of mRNA expression of HAO1 and LDHA

[0428] The revived primary human hepatocytes (PPH) were cultured at 6×10 5 Cells / ml were inoculated in 96-well plates containing INVITROGRO. Then, the cells were treated with 10 nanomolar, 100 nanomolar and 500 nanomolar GalNAc-siRNA conjugate A18b at 37 degrees Celsius and 5% carbon dioxide for 48 hours. After centrifugation to collect the cells, the RNA of the cells was extracted and reverse transcribed into cDNA. The mRNA expression levels of HAO1 and LDHA were analyzed by qPCR. The results are shown in Table 2. Table 2. Inhibition of the expression levels of HAO1 and LDHA Example B3 Inhibition of C3 and CFB mRNA expression

[0429] The revived primary human hepatocytes (PPH) were cultured at 6×10 5 Cells / ml were inoculated in 96-well plates containing INVITROGRO. Then, the cells were treated with 10 nanomolar, 100 nanomolar and 500 nanomolar GalNAc-siRNA conjugate A18c at 37 degrees Celsius and 5% carbon dioxide for 48 hours. After centrifugation, the cells were collected, and the RNA of the cells was extracted and reverse transcribed into cDNA. The mRNA expression levels of C3 and CFB were analyzed by qPCR. The results are shown in Table 3. Table 3. Inhibition of C3 and CFB expression levels Example B4 Inhibition of mRNA expression in Hep3 B cells

[0430] Hep3 B cells were cultured at 2 × 10 5 The number of cells per ml was cultured in a 96-well plate. The cells were then treated with 0.1 and 1 nanomolar GalNAc-siRNA conjugates at 37°C and 5% CO2 for 24 hours. After the cells were collected by centrifugation, the RNA of the cells 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 to 7, where A represents an inhibition rate of not less than 80%; B represents an inhibition rate of less than 80%, but not less than 60%; and C represents an inhibition rate of less than 60%, but not less than 40%. Table 4. Inhibition of ANGPTL3 and PCSK9 mRNA expression levels Table 5. Inhibition of C3 and C5 mRNA expression levels Table 6. Inhibition of C3 and CFB mRNA expression levels Table 7. Inhibition of C5 and CFB mRNA expression levels Example B5 Inhibition of mRNA expression in NCI-H1944 cells

[0431] NCI-H1944 cells were cultured at 2 × 10 5 The number of cells per ml was cultured in a 96-well plate. The cells were then treated with 0.1 and 1 nM GalNAc-siRNA conjugates at 37°C and 5% CO2 for 24 hours. After the cells were collected by centrifugation, the RNA of the cells was extracted and reverse transcribed into cDNA. The mRNA expression levels of HAO1 and LDHA were analyzed by qPCR. The results are shown in Table 8, where A represents an inhibition rate of not less than 80%; B represents an inhibition rate of less than 80% but not less than 60%; and C represents an inhibition rate of less than 60% but not less than 40%. Table 8. Inhibition of HAO1 and LDHA mRNA expression levels Example B6 Effects of GalNAc-siRNA conjugates on ANGPTL3, hPCSK9, LDL-C and TG in hPCSK9-UTR mice

[0432] The effects of GalNAc-siRNA conjugates on hPCSK9-UTR expression were evaluated in hPCSK9-UTR mice. Inhibitory effects of ANGPTL3, hPCSK9, LDL-C, and TG. On day 0, hPCSK9-UTR mice (6-8 weeks old) were subcutaneously injected with GalNAc-siRNA conjugate (6 mg / kg). Blood samples from each mouse were collected on days 0, 7, 14, 21, and 28. LDL-C and TG levels in each blood sample were analyzed by blood biochemistry. hPCSK9 and mANGPTL3 protein levels were analyzed by ELISA. The results are shown in Figure 1 and Figure 2 . Example B7 Effects of GalNAc-siRNA conjugates on C3, C5 and CFB

[0433] The inhibitory effects of GalNAc-siRNA conjugates on C3, C5, and CFB were evaluated in mice. Mice (6-8 weeks old) were injected subcutaneously with GalNAc-siRNA conjugates (6 mg / kg) 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 conjugates in HBV-infected mice

[0434] Fifteen specific pathogen-free (SPF) C57BL / 6 male mice were housed in a controlled environment for 7 days. Daily observation confirmed that the mice were healthy. Each mouse was intravenously injected with rAAV8-1.3HBV ayw Virus (1×10 11 vg / 150μL). At 4 weeks after intravenous injection, blood samples were collected from the orbital venous plexus of each mouse to detect the HBsAg content in plasma. Detection values ​​10 mice were randomly divided into two groups, 5 mice in each group. Blood samples were collected on day 0 to detect HBV DNA and HBsAg levels in mouse serum. GalNAc-siRNA conjugates were injected subcutaneously on day 0. Blood samples were collected from each mouse on days 7, 14, 21, 28, 35, 42, 49, 56, and 63. HBV DNA, HbsAg, and HBsAb levels in the serum of each mouse were analyzed. The results are shown in Figures 4 to 6 .

[0435] The sequence listing below provides the sequences described in the present invention. Sequence Listing fA, fC, fG and fU represent 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine and 2'-fluorouridine, respectively; A, C, G and U represent 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine and 2'-O- dA, dC, dG and dT represent 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine and 2'-deoxythymidine, respectively; s represents phosphorothioate. *****

[0436] The above examples are intended to provide those skilled in the art with a complete disclosure and description of how to make and use the claimed embodiments, but are not intended to limit the scope of the invention disclosed. Modifications that are obvious to those skilled in the art are within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference, as if each such publication, patent, or patent application was specifically and individually incorporated herein by reference.

Claims

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

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

3. The carbohydrate-oligonucleotide conjugate according to claim 1 or 2, having the structure of formula (I): in: R 1 is the ASGPR binding group; R 2 and R 3 each independently an oligonucleotide; L 1 , L 2 , L 3a and L 3c Each independently is a connector; L 3b is (i) a heteroarylene or heterocyclylene group; or (ii) a bond; 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 6-14 an aryl group, a trivalent heteroaryl group or a trivalent heterocyclic group; wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heteroarylene, heterocyclyl or heterocyclylene may be optionally substituted with one or more (in one embodiment, one, two, three or four) substituents Q, wherein each Q is independently 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, each of which is further substituted by one or more (in one embodiment one, two, three or four) substituents Q a optionally substituted; 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 、-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 and -S(O)2NR b R c , where each R a , R b , R c and R d 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 optionally substituted by 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, they form a heterocyclic group, which may be optionally substituted by one or more (in one embodiment one, two, three or four) substituents Q a replace; Each Q a independently selected from the group consisting of (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 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 g and -S(O)2NR f R g ; where 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 heterocyclic; or (iii) R f and R g Together with the N atom to which they are attached they form a heterocyclyl.

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

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

6. The carbohydrate-oligonucleotide coupling according to any one of claims 3 to 5 , among which L 3b is a 5-membered heteroarylene group, which is optionally substituted by one or more substituents Q.

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

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

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

10. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 9, wherein R 1 The ASGPR binding group is composed of about 1, about 2, about 3, about 4 or about 5 N-acetylgalactosamines.

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

12. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 11, wherein R 1 is an ASGPR binding group having the structure of formula (AI): or enantiomers, mixtures of enantiomers, diastereomers isomer, a mixture of two or more diastereomers, a tautomer or a mixture of two or more tautomers; wherein E a and b are (i) b is the integer 2; E a It is a trivalent linker; (ii) b is an integer 1; and E a is a bond, CH2 or NH; or (iii) b is the integer 3; and E a is a tetravalent linker; and Each L a They are all independent connectors.

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

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

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

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

17. The carbohydrate-oligonucleotide conjugate according to any one of claims 12 to 16. Thing, where each L a Independently is with -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3- 10 Cycloalkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -、 -P(O2)O-, -P(O)(S)O-, -S-, -S(O)-, -S(O)2-, -S(O)NR 1b - or -S(O)2NR 1b -; Each R 1a , R 1b , R 1c and R 1d 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 optionally substituted with one or more substituents Q; and z is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

18. The carbohydrate-oligonucleotide conjugate of claim 17, wherein each R n Independently for C 1-10 Alkylene, C 6-14 Arylene or heteroarylene, each optionally substituted with one or more substituents Q.

19. The carbohydrate-oligonucleotide conjugate of claim 17 or 18, wherein each R n is independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3-triazolediyl, pyrrolidinediyl or piperidinediyl, each optionally substituted with one, two or three Q substituents.

20. The carbohydrate-oligonucleotide conjugate of any one of claims 17 to 19, wherein each R n is independently methane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-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. The carbohydrate-oligonucleotide conjugate of any one of claims 17 to 20, 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-.

22. The carbohydrate-oligonucleotide conjugate of any one of claims 17 to 21 , where each Z n are independently a bond, -C(O)NH-, -O-, -OP(O2)O-, -OP(O2)S- or -NH-.

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. The carbohydrate-oligonucleotide conjugate of any one of claims 17 to 23, wherein each L a Are independent of:

25. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 11, wherein the ASGPR binding group has the structure of formula (AV): or enantiomers, mixtures of enantiomers, diastereomers isomer, a mixture of two or more diastereomers, a tautomer or a mixture of two or more tautomers; wherein E b and c are (i) c is the integer 2; and E b It is a trivalent linker; (ii) c is an integer 1; and E b is a key; or (iii) c is the integer 3; and E b is a tetravalent linker; E c and d are (i) d is an integer 1; and E c is the key; (ii) d is the integer 2; and E c is a trivalent linker; or (iii) d is the integer 3; and E c is a tetravalent linker; G is a trivalent linker; and Each L b and L c They are all independent divalent linkers.

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

27. The carbohydrate-oligonucleotide conjugate of claim 25, wherein E b yes 28. The carbohydrate-oligonucleotide conjugate of claim 25, wherein c is an integer of 1; E b is the key.

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

30. The carbohydrate-oligonucleotide conjugate of any one of claims 25 to 29, wherein E c yes 31. The carbohydrate-oligonucleotide conjugate according to any one of claims 25 to 30. Thing, where each L b and L c Independently is with -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3- 10 Cycloalkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each of which may be optionally substituted with one or more substituents; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -、-P(O2)O-、-P(O)(S)O-、-S-、-S(O)-、-S(O)2-、-S(O)NR 1b - or -S(O)2NR 1b -; Each R 1a , R 1b , R 1c and R 1d 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 optionally substituted with one or more substituents; and z is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

32. The carbohydrate-oligonucleotide conjugate of claim 31, wherein each R n Independently for C 1-10 Alkylene, C 6-14 Arylene or heteroarylene, each optionally substituted with one or more substituents Q.

33. The carbohydrate-coordination nucleotide conjugate of claim 31 or 32, wherein each R n are independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3- triazolediyl, pyrrolidinediyl or piperidinediyl, each optionally substituted with one, two or three substituents Q.

34. The carbohydrate-oligonucleotide conjugate of any one of claims 31 to 33, wherein each R n are independently methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4- diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl, pyrrolidine-1,3- diyl or piperidine-1,4-diyl, each optionally substituted by one or more substituents Q.

35. The carbohydrate-oligonucleotide conjugate of any one of claims 31 to 34, wherein each Z n independently 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-.

36. The carbohydrate-oligonucleotide conjugate of any one of claims 31 to 35, wherein each Z n are independently a bond, -C(O)NH-, -O-, -OP(O2)O-, -OP(O2)S- or -NH-.

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

38. The carbohydrate-oligonucleotide conjugate of any one of claims 31 or 37, wherein L b and L c Each is independent of:

39. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 38, wherein R 1 is an ASGPR binding group having the following structure:

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

41. The carbohydrate-oligonucleotide conjugate of claim 40, 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.

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

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

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

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

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

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

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

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

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

53. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 41 and 45 to 52, wherein R 2 It is a double-stranded siRNA, comprising 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.

54. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 41 and 45 to 53, wherein R 2 It is a double-stranded siRNA comprising 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: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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 46 and 50 to 54, wherein R 3 It is a double-stranded siRNA, comprising 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 46 and 50 to 55, wherein R 3 It is a double-stranded siRNA comprising 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 44 and 47 to 56, wherein R 3 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 58. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 57, wherein L 1 , L 2 , L 3a and L 3c Each independently has -Z n -(R n -Z n ) z - a structural linker, wherein: Each R n Independently for C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3- 10 Cycloalkylene, C 6-14 arylene, heteroarylene or heterocyclylene, each of which may be optionally substituted with one or more substituents; Each Z n are independently a bond, -C(O)-, -C(O)O-, -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)2NR 1b -、-P(O2)O-、-P(O)(S)O-、-S-、-S(O)-、-S(O)2-、-S(O)NR 1b - or -S(O)2NR 1b -; 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 optionally substituted with one or more substituents; and z is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

59. The carbohydrate-oligonucleotide conjugate of claim 58, wherein each R n Independently for C 1-10 Alkylene, C 6-14 Arylene or heteroarylene, each optionally substituted with one or more substituents Q.

60. The carbohydrate-oligonucleotide conjugate of claim 58 or 59, wherein each R n are independently methylenediyl, ethylenediyl, propylenediyl, butanediyl, pentanediyl, hexanediyl, phenylenediyl, 1,2,3- triazolediyl or pyrrolidinediyl, each optionally substituted with one, two or three Q substituents.

61. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 60, wherein each R n The 1,2-diyl group is independently methane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-1,4-diyl, 1,2,3-triazole-1,4-diyl or pyrrolidine-1,3- The diradicals are each optionally substituted with one or more substituents Q.

62. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 61, 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(O2)S-, -S- or -S(O)2-.

63. The carbohydrate-oligonucleotide conjugate of any one of claims 58 to 62, wherein each Z n are independently a bond, -C(O)NH-, -O-, -OP(O2)O-, -OP(O2)S-, -NH-, - P(O2)O- or -P(O2)S-.

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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 64, wherein L 1 Yes -NHC(O)(CH2) e C(O)NH-, where e is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

66. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 65, wherein L 1 yes 67. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein L 2 With the structure -X(CH2) h X-; 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein L 2 With the structure -X(CH2) i CH(OH)(CH2) j X-; 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein L 2 With structure And L 2 Attached to the 5'-end of the oligonucleotide.

70. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein L 2 With structure And L 2 Attached to the 3'-end of the oligonucleotide.

71. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 66, wherein L 2 for:

72. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 71, wherein L 3a It is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, 73. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein L 3c With the structure -X(CH2) p X-; 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein L 3c With the structure -X(CH2) q CH(OH)(CH2) r 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. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein L 3c With structure And L 3c Attached to the 5'-end of the oligonucleotide.

76. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein L 3c With structure And L 3c Attached to the 3'-end of the oligonucleotide.

77. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 72, wherein L 3c yes 78. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 77, wherein M is N, CH or C(CH3).

79. The carbohydrate-oligonucleotide conjugate of any one of claims 3 to 78, wherein the trivalent group Has the following structure:

80. The carbohydrate-oligonucleotide conjugate of any one of claims 1 to 3, having the following structure: Each 3'-siRNA independently represents an siRNA whose 3'-ends are connected to a trivalent linker; each 5'-siRNA represents an siRNA whose 5'-ends are connected to a trivalent linker; and 5'-ssDNA represents a single-stranded DNA whose 5'-end is connected to a trivalent linker.

81. The carbohydrate-oligonucleotide conjugate of claim 1, having the structure in, 3'-siRNA refers to siRNA, one of whose 3'-ends is linked to a first divalent linker and one of whose 5'-ends is linked to a second divalent linker; 5'-siRNA refers to siRNA, one of whose 5'-ends is linked to a second divalent linker.

82. The carbohydrate-oligonucleotide conjugate of claim 80 or 81. The invention relates to a compound wherein each double-stranded oligonucleotide independently 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.

83. The carbohydrate-oligonucleotide conjugate of claim 80 The composition comprises a single-stranded oligonucleotide comprising the nucleotide sequence of SEQ ID NO:

25.

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

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

86. A pharmaceutical composition as described in claim 84 or 85, wherein the composition is in parenteral or intravenous dosage form.

87. The pharmaceutical composition of claim 86, wherein the composition is formulated for intravenous administration.

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