Conjugated antisense compounds and their uses

Abstract

The present invention provides oligomeric compounds having a conjugated group. [Solution] A conjugated oligonucleotide comprising an oligonucleotide and a specific conjugated linker, branching group, tether, and ligand structure is provided, wherein the oligonucleotide comprises at least one modified nucleoside, the oligonucleotide is double-stranded, or has a nucleic acid base sequence comprising at least eight nucleic acid base portions complementary to an isolength portion of the target nucleic acid that activates the RISC pathway, and the target nucleic acid encodes a protein selected from androgen receptor, apolipoprotein (a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, protein tyrosine phosphatase 1B, STAT3, SRB-1, and transthyretin.

Description

[Technical Field]

[0001] Sequence List This application has been filed electronically along with its sequence listing. This sequence listing is provided as a file named CORE0115WOSEQ_ST25.txt, 692KB in size, created on May 1, 2014. The electronic information of this sequence listing is incorporated herein by reference in its entirety. [Background technology]

[0002] The principle behind antisense technology is that antisense compounds hybridize to target nucleic acids, thereby regulating the quantity, activity, and / or function of the target nucleic acid. For example, in certain cases, antisense compounds result in changes in the transcription or translation of the target. Such regulation of expression can be achieved, for example, by inhibition based on the degradation or occupation of the target mRNA. One example of regulation of RNA target function by degradation is the RNase H-based degradation of target RNA during hybridization with a DNA-like antisense compound. Another example of regulation of gene expression by targeted degradation is RNA interference (RNAi). RNAi refers to antisense-mediated gene silencing via a mechanism utilizing the RNA-induced silencing complex (RISC). Further examples of regulation of RNA target function are by occupation-based mechanisms, such as those naturally used by microRNAs. MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. Binding of an antisense compound to a microRNA prevents that microRNA from binding to its messenger RNA target, and therefore interferes with the function of the microRNA. MicroRNA mimetics can enhance the innate function of microRNAs. Certain antisense compounds alter premRNA splicing. Regardless of the specific mechanism, sequence specificity makes antisense compounds attractive as a means of target validation and gene functionalization, as well as therapeutic agents that selectively modulate the expression of genes involved in disease development.

[0003] Antisense technology is an effective means of regulating the expression of one or more specific gene products and therefore may prove uniquely useful for many therapeutic, diagnostic, and research applications. Chemically modified nucleosides can be incorporated into antisense compounds to enhance one or more properties of the target nucleic acid, such as nuclease resistance, pharmacokinetics, or affinity. In 1998, Vitravene® (homivirsen, developed by Isis Pharmaceuticals Inc. (Carlsbad, CA)), an antisense compound, became the first antisense drug to receive marketing authorization from the U.S. Food and Drug Administration (FDA) and is currently used to treat cytomegalovirus (CMV)-induced retinitis in AIDS patients. As another example, KYNAMRO™, an antisense oligonucleotide targeting ApoB, has been approved by the U.S. Food and Drug Administration (FDA) as a lipid-lowering and dietary adjunct therapy to reduce low-density lipoprotein cholesterol (LDL-C), ApoB, total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

[0004] Novel chemical modifications improve the strength and efficacy of antisense compounds, opening up possibilities for oral delivery, enhancing subcutaneous administration, reducing the potential for side effects, and improving patient convenience. Chemical modifications that increase the strength of antisense compounds enable lower dose administration, reduce the potential for toxicity, and lower overall treatment costs. Modifications that increase resistance to degradation lead to slower elimination from the body, allowing for reduced dosing frequency. Combining different types of chemical modifications within a single compound further optimizes the efficacy of the compound. It is possible. [Overview of the project]

[0005] In certain embodiments, the Disclosure provides a conjugated antisense compound. In certain embodiments, the Disclosure provides a conjugated antisense compound comprising an antisense oligonucleotide complementary to a nucleic acid transcript. In certain embodiments, the Disclosure provides a method comprising contacting cells with a conjugated antisense compound comprising an antisense oligonucleotide complementary to a nucleic acid transcript. In certain embodiments, the Disclosure provides a method comprising contacting cells with a conjugated antisense compound comprising an antisense oligonucleotide and reducing the amount or activity of nucleic acid transcript within the cells.

[0006] The asialoglycoprotein receptor (ASGP-R) has been previously described. See, for example, Park et al., PNAS vol.102, No.47, pp17125-17129 (2005). Such receptors are expressed on hepatocytes, specifically on hepatocytes. Furthermore, compounds containing a cluster of three N-acetylgalactosamine (GalNAc) ligands have been shown to bind to ASGP-R, resulting in the uptake of the compound into the cell. See, for example, Khorev et al., Bioorganic and Medicinal Chemistry, 16, 9, pp5216-5231 (May 2008). Thus, conjugates containing such GalNAc clusters are used to promote the uptake of certain compounds into hepatocytes, specifically hepatocytes. For example, certain GalNAc-containing conjugates have been shown to increase the activity of double-stranded siRNA compounds in hepatocytes in vivo. In such cases, the GalNAc-containing conjugate typically binds to the sense strand of the siRNA double-stranded compound. Because the sense strand is disposed of before the antisense strand ultimately hybridizes with the target nucleic acid, there is little concern that the conjugate will interfere with activity. Typically, the conjugate is attached to the 3' end of the sense strand of the siRNA. See, for example, U.S. Patent No. 8,106,022. Certain conjugated groups described herein are more active and / or easier to synthesize than those previously described.

[0007] In certain embodiments of the present invention, the conjugate is bound to single-stranded antisense compounds, including but not limited to RNase H-based antisense compounds and antisense compounds that alter the splicing of premRNA target nucleic acids. In such embodiments, the conjugate should remain bound to the antisense compound for a sufficient period to provide the benefit (improved uptake into cells), but should either be cleaved or not interfere with subsequent steps necessary for activity, such as hybridization to the target nucleic acid related to splicing or splicing regulation and interaction with RNase H or enzymes. This balance of properties is more important in the context of single-stranded antisense compounds than in siRNA compounds, and the conjugate may simply be bound to the sense strand. Conjugated single-stranded antisense compounds that exhibit improved strength in hepatocytes in vivo compared to the same antisense compound without a conjugate are disclosed herein. Given the required balance of properties of these compounds, such improvement in strength is remarkable.

[0008] In certain embodiments, the conjugated group as described herein includes a cleavable moiety. As described above, the conjugate should remain in the compound for a sufficiently long period to provide enhanced uptake without being bound by a mechanism, but it is logical thereafter desirable that part of the conjugate, or ideally all of it, be cleaved to release the parent compound (e.g., an antisense compound) in its most active form. In certain embodiments, the cleavable moiety is a cleavable nucleoside. The application method utilizes endogenous nucleases within the cell by attaching the remainder of the conjugate (cluster) to an antisense oligonucleotide via a nucleoside through one or more cleavable bonds, such as phosphodiester bonds. In certain embodiments, the cluster is attached to a cleavable nucleoside by a phosphodiester bond. In certain embodiments, the cleavable nucleoside is attached to an antisense oligonucleotide (antisense compound) by a phosphodiester bond. In certain embodiments, the conjugate group may contain two or three cleavable nucleosides. In such embodiments, such cleavable nucleosides are attached to each other, to the antisense compound, and / or to the cluster by cleavable bonds (such as phosphodiester bonds). Certain conjugates described herein do not contain cleavable nucleosides, but instead contain cleavable bonds. It is shown that sufficient cleavage of the conjugate from the oligonucleotide is provided by at least one bond (cleavable bond) that is vulnerable to cleavage in the cell.

[0009] In certain embodiments, a conjugated antisense compound is a prodrug. Such a prodrug is administered to an animal and ultimately metabolized to a more active form. For example, a conjugated antisense compound may be cleaved to remove all or part of the conjugate, resulting in an active (or more active) form of the antisense compound lacking all or part of the conjugate.

[0010] In certain embodiments, the conjugate is linked at the 5' end of the oligonucleotide. Certain such 5' conjugates are cleaved more efficiently than counterparts having a similar conjugated group linked at the 3' end. In certain embodiments, improved activity may correlate with improved cleavage. In certain embodiments, the effectiveness of oligonucleotides containing a conjugate at the 5' end is higher than that of oligonucleotides containing a conjugate at the 3' end (see, e.g., Examples 56, 81, 83, and 84). Furthermore, the 5' linkage allows for simpler oligonucleotide synthesis. Typically, oligonucleotides are synthesized on a solid support in the 3'-to-5' direction. To produce 3'-conjugated oligonucleotides, a pre-conjugated 3' nucleoside is typically linked to a solid support, and then the oligonucleotide is constructed as usual. However, linking the conjugated nucleoside to the solid support complicates the synthesis. Furthermore, by using this means, the conjugate may then be present throughout the synthesis of the oligonucleotide and may be degraded in subsequent steps, or it may limit the types of reactants and reagents that can be used. By using the 5'-conjugated oligonucleotide structures and techniques described herein, oligonucleotides can be synthesized using standard automated techniques to introduce a conjugate with the final (most 5') nucleoside, or oligonucleotides can be synthesized after they have been cleaved from a solid support.

[0011] In light of the art and this disclosure, a person skilled in the art can readily produce any of the conjugates and conjugated oligonucleotides described herein. Furthermore, the synthesis of certain such conjugates and conjugated oligonucleotides disclosed herein is easier and / or requires fewer steps than the synthesis of previously disclosed conjugates, and is therefore less expensive, offering advantages in production. For example, the synthesis of certain conjugated groups consists of fewer synthesis steps compared to previously described conjugated groups, resulting in increased yield. Conjugated groups such as GalNAc3-10 in Example 46 and GalNAc3-7 in Example 48 are much simpler than previously described conjugates such as those described in U.S. Patent No. 8,106,022 or U.S. Patent No. 7,262,177, which require the construction of more chemical intermediates. Therefore, these and other conjugates described herein, when used in conjunction with any oligonucleotide containing either single-stranded or double-stranded oligonucleotides (e.g., siRNA), are simpler than previously described. It is more advantageous than the compound that was previously used.

[0012] Similarly, conjugated groups having only one or two GalNAc ligands are disclosed herein. As shown, such conjugated groups enhance the activity of antisense compounds. Such compounds are easier to prepare than conjugates containing three GalNAc ligands. Conjugated groups containing one or two GalNAc ligands can be conjugated to any antisense compound containing either a single-stranded oligonucleotide or a double-stranded oligonucleotide (e.g., siRNA).

[0013] In certain embodiments, the conjugates described herein do not substantially alter tolerability to a certain extent. For example, it is shown herein that the immunogenicity of a conjugated antisense compound is lower than that of an unconjugated parent compound. Embodiments in which tolerability remains the same (or remains the same even if tolerability decreases only slightly compared to the increase in strength) have improved therapeutic properties.

[0014] In certain embodiments, conjugation allows for the modification of antisense compounds in a manner that would have less attractive results in the absence of conjugation. For example, in certain embodiments, substituting one or more phosphorothioate bonds in a complete phosphorothioate antisense compound with phosphodiester bonds results in some degree of improved tolerability. For instance, in certain cases, the immunogenicity of such an antisense compound having one or more phosphodiester bonds is lower than that of the same compound where each bond is a phosphorothioate bond. However, in certain cases, as shown in Example 26, a similar substitution of one or more phosphorothioate bonds with phosphodiester bonds also results in decreased cellular uptake and / or loss of strength. In certain embodiments, the conjugated antisense compounds described herein tolerate such bond changes with little or no loss of uptake and strength compared to their complete phosphorothioate-conjugated counterparts. In fact, in certain embodiments, for example in Examples 44, 57, 59, and 86, oligonucleotides containing a conjugate and at least one phosphodiester nucleoside linkage actually exhibit increased in vivo strength even when compared to complete phosphorothioate counterparts containing the same conjugate. Furthermore, since conjugation results in a substantial increase in uptake / strength, a slight loss of that substantial increase may be acceptable to achieve improved tolerability. Therefore, in certain embodiments, the conjugated antisense compound contains at least one phosphodiester linkage.

[0015] In certain embodiments, the conjugation of antisense compounds as described herein results in increased delivery, uptake, and activity in hepatocytes. Thus, more compounds are delivered to liver tissue. However, in certain embodiments, such increased delivery alone does not manifest an overall increase in activity. In certain embodiments, more compounds enter the hepatocytes. In certain embodiments, even such increased hepatocyte uptake does not manifest an overall increase in activity. In such embodiments, the productive uptake of the conjugated compound is increased. For example, as shown in Example 102, certain embodiments of the GalNAc-containing conjugate increase the enrichment of antisense oligonucleotides in hepatocytes compared to non-parenchymal cells. This enrichment is beneficial for oligonucleotides that target genes expressed in hepatocytes.

[0016] In certain embodiments, the conjugated antisense compounds described herein result in reduced renal exposure. For example, as shown in Example 20, the concentration of an antisense oligonucleotide containing a certain embodiment of the GalNAc-containing conjugate is lower in the kidney than the concentration of an antisense oligonucleotide lacking the GalNAc-containing conjugate. This is because, It has several beneficial therapeutic implications. For therapeutic targets where renal activity is not required, renal exposure carries the risk of nephrotoxicity and does not yield commensurate benefits. Furthermore, high concentrations in the kidneys typically lead to the loss of the compound into the urine, resulting in more rapid clearance. Therefore, in the case of non-renal targets, accumulation in the kidneys is undesirable.

[0017] In a particular embodiment, the present disclosure provides a conjugated antisense compound represented by the following formula: [ka] During the ceremony, A is an antisense oligonucleotide, B is a part that can be cut, C is a conjugate linker, D is a branching group, each E is a tether, each F is a ligand, q is an integer from 1 to 5.

[0018] In the above-mentioned figures in this specification and similar figures, the branching group "D" repeats branching as many times as necessary to accommodate the number of (E~F) groups indicated by "q". Therefore, when q = 1, the formula is as follows,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0019] In certain embodiments, a conjugated antisense compound having the following structure is provided.

Chemical formula

[0020] In certain embodiments, a conjugated antisense compound having the following structure is provided.

Chemical formula

[0021] In certain embodiments, a conjugated antisense compound having the following structure is provided.

Chemical formula

[0022] In certain embodiments, a conjugated antisense compound having the following structure is provided.

Chemical formula

[0023] The present disclosure provides the following non-limiting numbered embodiments.

[0024] Embodiment 1. A conjugated antisense compound comprising an antisense oligonucleotide comprising 12 to 30 linked nucleosides and a conjugation group, wherein the conjugation group comprises a cleavable moiety, a conjugation linker, and a cell targeting moiety.

[0025] Embodiment 2. The conjugated antisense compound of Embodiment 1, wherein the cleavable moiety is covalently attached to the antisense oligonucleotide, the conjugation linker is covalently attached to the cleavable moiety, and the cell targeting moiety is covalently attached to the conjugation linker.

[0026] Embodiment 3. The conjugated antisense compound of Embodiment 1 or 2, wherein the cell targeting moiety comprises a branching group.

[0027] Embodiment 4. The conjugated antisense compound of Embodiment 3, wherein the branching group is covalently attached to the conjugation linker.

[0028] Embodiment 5. The conjugated antisense compound according to any one of Embodiments 1 to 4, wherein the cell targeting moiety comprises at least one tether. [[ID=4;6]]

[0029] Embodiment 6. The conjugated antisense compound of Embodiment 5, wherein the at least one tether is covalently bonded to the branching group.

[0030] Embodiment 7. The conjugated antisense compound according to any one of Embodiments 1 to 6, wherein the cell target moiety comprises at least one ligand.

[0031] Embodiment 8. The conjugated antisense compound of Embodiment 7, wherein each of the at least one ligand is covalently bonded to a tether.

[0032] Embodiment 9. The compound has a structure represented by the following formula I,

Chemical formula

[0033] Embodiment 10. The conjugated antisense compound according to any one of Embodiments 1 to 9, wherein the cleavable moiety comprises 1 to 4 linked nucleosides of cleavable moieties, and the bond between the antisense oligonucleotide and the nucleoside of the first cleavable moiety is a phosphodiester internucleoside bond.

[0034] Embodiment 11. The conjugated antisense compound of Embodiment 10, wherein each internucleoside bond between each of the linked nucleosides of cleavable moieties is a phosphodiester internucleoside bond.

[0035] Embodiment 12. The conjugated antisense compound of Embodiment 10 or 11, wherein the cleavable portion comprises 1 to 3 linked cleavable portion nucleosides.

[0036] Embodiment 13. The conjugated antisense compound of Embodiment 10 or 11, wherein the cleavable portion comprises one or two linked cleavable portion nucleosides.

[0037] Embodiment 14. The conjugated antisense compound of Embodiment 10, wherein the cleavable portion comprises a nucleoside of one cleavable portion.

[0038] Embodiment 15. A conjugated antisense compound of any of Embodiments 1 to 14, wherein the cleavable portion is a nucleoside of a cleavable portion selected from the group consisting of purines, substituted purines, pyrimidines, or substituted pyrimidines.

[0039] Embodiment 16. A conjugated antisense compound of any of Embodiments 1 to 14, wherein the cleavable portion is a nucleoside of a cleavable portion selected from cytidine, uridine, adenosine, thymidine, and guanosine.

[0040] Embodiment 17. The cleavable portion is selected from deoxyadenosine, deoxyguanosine, deoxyinosine, thymidine, deoxyuridine, and deoxycytidine. A conjugated antisense compound of any of Embodiments 1 to 14, which is a deoxynucleoside of the cleavable portion.

[0041] Embodiment 18. A conjugated antisense compound of any of Embodiments 1 to 17, wherein the cleavable portion contains deoxyadenosine.

[0042] Embodiment 19. A conjugated antisense compound of any of Embodiments 1 to 18, wherein the cleavable portion is deoxyadenosine.

[0043] Embodiment 20. The severable portion has a structure selected from the following: [ka] In the formula, Bx, Bx1, Bx2, and Bx3 are each independently heterocyclic base parts. A conjugated antisense compound according to any of Embodiments 1 to 19.

[0044] Embodiment 21. The conjugated antisense compound of Embodiment 20, wherein the heterocyclic base moiety is selected from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0045] Embodiment 22. A conjugated antisense compound of any of Embodiments 1 to 19, wherein the cleavable portion has the following structure. [ka]

[0046] Embodiment 23. A conjugated antisense compound of any of Embodiments 1 to 22, wherein the conjugated linker contains pyrrolidine.

[0047] Embodiment 24. A conjugated antisense compound according to any of Embodiments 1 to 23, wherein the conjugated linker contains PEG.

[0048] Embodiment 25. A conjugated antisense compound of any of Embodiments 1 to 24, wherein the conjugated linker comprises an amide.

[0049] Embodiment 26. A conjugated antisense compound according to any one of Embodiments 1 to 25, wherein the conjugated linker comprises a polyamide.

[0050] Embodiment 27. A conjugated antisense compound of any of Embodiments 1 to 26, wherein the conjugated linker contains an amine.

[0051] Embodiment 28. A conjugated antisense compound according to any of Embodiments 1 to 27, wherein the conjugated linker contains one or more disulfide bonds.

[0052] Embodiment 29. A conjugated antisense compound according to any of Embodiments 1 to 28, wherein the conjugated linker includes a protein-binding moiety.

[0053] Embodiment 30. The conjugated antisense compound of Embodiment 29, wherein the protein-binding portion contains a lipid.

[0054] Embodiment 31. The protein binding portion is cholesterol, cholic acid, adamantane acetate, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethyltrityl, or phenoxazine), A conjugated antisense compound of Embodiment 30, selected from vitamins (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosome lysants, steroids (e.g., ubaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, sarsasapogenin, friederin, epifriederanol-derived lithocholic acid), or cationic lipids.

[0055] Embodiment 32. A conjugated antisense compound according to any of Embodiments 1 to 31, wherein the protein-binding portion is a C16-C22 long-chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0056] Embodiment 33. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20, and p is between 1 and 6. A conjugated antisense compound according to any of Embodiments 1 to 32. In such embodiments having two or more n, each n is independently selected.

[0057] Embodiment 34. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any of Embodiments 1 to 33.

[0058] Embodiment 35. The conjugate linker has a structure selected from the following: and [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any of Embodiments 1 to 33.

[0059] Embodiment 36. A conjugated antisense compound according to any of Embodiments 1 to 33, wherein the conjugated linker has a structure selected from the following. [ka]

[0060] Embodiment 37. A conjugated antisense compound according to any of Embodiments 1 to 33, wherein the conjugated linker has a structure selected from the following. [ka]

[0061] Embodiment 38. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any of Embodiments 1 to 33.

[0062] Embodiment 39. A conjugated antisense compound of any of Embodiments 1 to 33, wherein the conjugated linker has the following structure. [ka]

[0063] Embodiment 40. A conjugated antisense compound of any of Embodiments 1 to 39, wherein the cell targeting portion contains a carbohydrate.

[0064] Embodiment 41. A conjugated antisense compound of any of Embodiments 1 to 40, wherein the cell targeting portion includes a carbohydrate cluster.

[0065] Embodiment 42. A conjugated antisense compound according to any of Embodiments 1 to 41, wherein the cell targeting portion comprises a cell surface receptor ligand.

[0066] Embodiment 43. A conjugated antisense compound of any of Embodiments 1 to 42, wherein the target portion comprises at least one N-acetylgalactosamine (GalNAc).

[0067] Embodiment 44. A conjugated antisense compound of any of Embodiments 1 to 43, wherein the target portion includes a branched group.

[0068] Embodiment 45. The conjugated antisense compound of Embodiment 44, wherein the branched group contains an ether.

[0069] Embodiment 46. The branching base has the following structure: [ka] Each n is independently between 1 and 20. m is between 2 and 6. A conjugated antisense compound of Embodiment 44 or 45.

[0070] Embodiment 47. The conjugated antisense compound of Embodiment 44 or 45, wherein the branched group has the following structure. [ka]

[0071] Embodiment 48. The branching base has the following structure: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. A conjugated antisense compound of Embodiment 44 or 45.

[0072] Embodiment 49. The conjugated antisense compound of Embodiment 44 or 45, wherein the branched group has the following structure. [ka]

[0073] Embodiment 50. A conjugated antisense compound of any of Embodiments 1 to 49, wherein the cell targeting portion comprises one tether.

[0074] Embodiment 51. A conjugated antisense compound of any of Embodiments 1 to 49, wherein the cell targeting portion comprises two tethers.

[0075] Embodiment 52. A conjugated antisense compound of any of Embodiments 1 to 49, wherein the cell targeting portion comprises three tethers.

[0076] Embodiment 53. A conjugated antisense compound according to any of Embodiments 1 to 49, wherein the cell targeting moiety comprises four or more tethers.

[0077] Embodiment 54. A conjugated antisense compound of any of Embodiments 1 to 53, wherein at least one tether contains PEG.

[0078] Embodiment 55. A conjugated antisense compound of any of Embodiments 1 to 54, wherein at least one tether comprises an amide.

[0079] Embodiment 56. A conjugated antisense compound of any of Embodiments 1 to 55, wherein at least one tether comprises a polyamide.

[0080] Embodiment 57. A conjugated antisense compound of any of Embodiments 1 to 56, wherein at least one tether contains an amine.

[0081] Embodiment 58. Any of Embodiments 1 to 57, wherein at least two tethers are different from each other. A conjugated antisense compound of [the specified compound].

[0082] Embodiment 59. A conjugated antisense compound of any of Embodiments 1 to 57, wherein all of the tethers are identical to each other.

[0083] Embodiment 60. Each tether is selected from the following: [ka] Each n is independently between 1 and 20. Each p is between 1 and approximately 6. A conjugated antisense compound according to any of Embodiments 1 to 59.

[0084] Embodiment 61. A conjugated antisense compound from any of Embodiments 1 to 60, wherein each tether is selected from the following: [ka]

[0085] Embodiment 62. Each tether has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of Embodiments 1 to 61.

[0086] Embodiment 63. A conjugated antisense compound of any of Embodiments 1 to 61, wherein each tether has the following structure. [ka]

[0087] Embodiment 64. A conjugated antisense compound of any of Embodiments 1 to 63, wherein the cell targeting moiety comprises at least one ligand.

[0088] Embodiment 65. The conjugated antisense compound of Embodiment 64, wherein the cell targeting portion contains one ligand.

[0089] Embodiment 66. The conjugated antisense compound of Embodiment 64, wherein the target portion comprises two ligands.

[0090] Embodiment 67. The conjugated antisense compound of Embodiment 64, wherein the target portion comprises three ligands.

[0091] Embodiment 68. A conjugated antisense compound according to any of Embodiments 64-67, wherein one ligand is covalently bonded to each tether.

[0092] Embodiment 69. A conjugated antisense compound of any of Embodiments 1 to 68, wherein at least one ligand is N-acetylgalactosamine (GalNAc).

[0093] Embodiment 70. A conjugated antisense compound of any of Embodiments 1 to 69, wherein each ligand is N-acetylgalactosamine (GalNAc).

[0094] Embodiment 71. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose Lanose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[( R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl2,3,4-tri-O-acetyl-1-thio A conjugated antisense compound according to any of Embodiments 1 to 70, selected from 6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0095] Embodiment 72. A conjugated antisense compound according to any of Embodiments 1 to 71, wherein the ligand is galactose.

[0096] Embodiment 73. A conjugated antisense compound of any of Embodiments 1 to 71, wherein the ligand is mannose-6-phosphate.

[0097] Embodiment 74. Each ligand is selected from the following: [ka] In the formula, each R1 is selected from OH and NHCOOH. A conjugated antisense compound according to any of Embodiments 1 to 71.

[0098] Embodiment 75. A conjugated antisense compound of any of Embodiments 1 to 71, wherein each ligand is selected from the following. [ka]

[0099] Embodiment 76. A conjugated antisense compound of any of Embodiments 1 to 71, wherein each ligand has the following structure. [ka]

[0100] Embodiment 77. A conjugated antisense compound of any of Embodiments 1 to 71, wherein each ligand has the following structure. [ka]

[0101] Embodiment 78. The cell target group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of Embodiments 1 to 77.

[0102] Embodiment 79. A conjugated antisense compound of any of Embodiments 1 to 77, wherein the cell target group has the following structure. [ka]

[0103] Embodiment 80. The conjugate has the following structure: [ka] In the formula, each n is independently between 1 and 20. Z is H or a bonded solid support. Q is the antisense compound, X is either O or S, Bx is the heterocyclic base portion. A conjugated antisense compound according to any of Embodiments 1 to 79.

[0104] Embodiment 81. The conjugate has the following structure: [ka] In the formula, Z is H or a bonded solid support. Q is the antisense compound. A conjugated antisense compound according to any of Embodiments 1 to 79.

[0105] Embodiment 82. A conjugated antisense compound according to any of Embodiments 1 to 81, wherein the conjugated group is bonded to the 2' position of the nucleoside of the antisense oligonucleotide.

[0106] Embodiment 83. A conjugated antisense compound according to any one of Embodiments 1 to 81, wherein the conjugated group is bonded to the 3' position of the nucleoside of the antisense oligonucleotide.

[0107] Embodiment 84. A conjugated antisense compound according to any of Embodiments 1 to 81, wherein the conjugated group is bonded to the 5' position of the nucleoside of the antisense oligonucleotide.

[0108] Embodiment 85. A conjugated antisense compound according to any of Embodiments 1 to 82, wherein the conjugated group is bonded to the 5' terminal nucleoside of the antisense oligonucleotide.

[0109] Embodiment 86. A conjugated antisense compound according to any of Embodiments 1 to 84, wherein the conjugated group is bonded to the 3' terminal nucleoside of the antisense oligonucleotide.

[0110] Embodiment 87. A conjugated antisense compound according to any of Embodiments 1 to 84, wherein the conjugated group is bonded to the internal nucleoside of the antisense oligonucleotide.

[0111] Embodiment 88. A conjugated antisense compound according to any of Embodiments 1 to 87, wherein the conjugated group increases the uptake of the conjugated antisense compound into hepatocytes compared to a non-conjugated antisense compound.

[0112] Embodiment 89. A conjugated antisense compound according to any of Embodiments 1 to 88, wherein the conjugated group increases the uptake of the conjugated antisense compound into liver cells compared to a non-conjugated antisense compound.

[0113] Embodiment 90. A conjugated antisense compound of any of Embodiments 1 to 89, wherein the conjugated group increases the accumulation of the conjugated antisense compound in the liver compared to a non-conjugated antisense compound.

[0114] Embodiment 91. The conjugated group, compared to the unconjugated antisense compound, exhibits pre-inflammatory effects in the kidney. A conjugated antisense compound according to any of Embodiments 1 to 90 that reduces the accumulation of the conjugated antisense compound.

[0115] Embodiment 92. A conjugated antisense compound according to any of Embodiments 1 to 91, wherein the antisense oligonucleotide is an RNase H-based antisense compound.

[0116] Embodiment 93. A conjugated antisense compound according to any one of Embodiments 1 to 92, wherein the antisense oligonucleotide comprises at least one modified nucleoside.

[0117] Embodiment 94. A conjugated antisense compound according to any of Embodiments 1 to 93, wherein each nucleoside of the antisense oligonucleotide is a modified nucleoside.

[0118] Embodiment 95. A conjugated antisense compound according to any of Embodiments 1 to 94, wherein the antisense oligonucleotide is single-stranded.

[0119] Embodiment 96. A conjugated antisense compound of Embodiments 93-95, wherein at least one modified nucleoside contains a modified sugar moiety.

[0120] Embodiment 97. The antisense oligonucleotide is A 5' region consisting of 2 to 8 linked 5' region nucleosides, wherein at least 2 5' region nucleosides are modified nucleosides, and the 5' region nucleoside closest to the 3' side is a modified nucleoside, and A 3' region consisting of 2 to 8 linked 3' region nucleosides, wherein at least 2 of the 3' region nucleosides are modified nucleosides, and the 3' region nucleoside closest to the 5' side is a modified nucleoside, and A central region between the 5' region and the 3' region, each consisting of 5 to 10 linked central region nucleosides, wherein each is independently selected from modified nucleosides and unmodified deoxynucleosides, the central region nucleoside furthest to the 5' side is an unmodified deoxynucleoside, and the central region nucleoside furthest to the 3' side is an unmodified deoxynucleoside. A conjugated antisense compound of embodiment 96 having a sugar motif including the sugar motif.

[0121] Embodiment 98. The conjugated antisense compound of Embodiment 97, wherein the 5' region consists of two linked 5' region nucleosides.

[0122] Embodiment 99. The conjugated antisense compound of Embodiment 97, wherein the 5' region consists of three linked 5' region nucleosides.

[0123] Embodiment 100. The conjugated antisense compound of Embodiment 97, wherein the 5' region consists of four linked 5' region nucleosides.

[0124] Embodiment 101. The conjugated antisense compound of Embodiment 97, wherein the 5' region consists of five linked 5' region nucleosides.

[0125] Embodiment 102. A conjugated antisense compound according to any of Embodiments 97 to 101, wherein the 3' region consists of two linked 3' region nucleosides.

[0126] Embodiment 103. A conjugated antisense compound according to any of Embodiments 97 to 101, wherein the 3' region consists of three linked 3' region nucleosides.

[0127] Embodiment 104. A conjugated antisense compound according to any of Embodiments 97 to 91, wherein the 3' region consists of four linked 3' region nucleosides.

[0128] Embodiment 105. A conjugated antisense compound according to any of Embodiments 97 to 101, wherein the 3' region consists of five linked 3' region nucleosides.

[0129] Embodiment 106. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of five linked central region nucleosides.

[0130] Embodiment 107. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of six linked central region nucleosides.

[0131] Embodiment 108. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of seven linked central region nucleosides.

[0132] Embodiment 109. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of eight linked central region nucleosides.

[0133] Embodiment 110. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of nine linked central region nucleosides.

[0134] Embodiment 111. A conjugated antisense compound according to any of Embodiments 97 to 105, wherein the central region consists of 10 linked central region nucleosides.

[0135] Embodiment 112. A conjugated antisense compound according to any of Embodiments 1 to 111, wherein the antisense oligonucleotide consists of 14 to 26 linked nucleosides.

[0136] Embodiment 113. A conjugated antisense compound according to any of Embodiments 1 to 111, wherein the antisense oligonucleotide consists of 15 to 25 linked nucleosides.

[0137] Embodiment 114. A conjugated antisense compound according to any of Embodiments 1 to 111, wherein the antisense oligonucleotide consists of 16 to 20 linked nucleosides.

[0138] Embodiment 115. A conjugated antisense compound of any of Embodiments 1 to 114, wherein each modified nucleoside independently comprises a 2'-substituted sugar moiety or a bicyclic sugar moiety.

[0139] Embodiment 116. The conjugated antisense compound of Embodiment 115, wherein the at least one modified nucleoside comprises a 2'-substituted sugar moiety.

[0140] Embodiment 117. Each modified nucleoside containing the 2'-substituted sugar moiety contains a 2' substituent independently selected from halogen, optionally substituted allyl, optionally substituted amino, azide, optionally substituted SH, CN, OCN, CF3, OCF3, O, S, or N(Rm)-alkyl; O, S, or N(Rm)-alkenyl; O, S, or N(Rm)-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted O-aralkyl, O(CH2)2SCH3, O-(CH2)2-ON(Rm)(Rn), or O-CH2-C(=O)-N(Rm)(Rn), wherein each Rm and Rn independently comprises H, an amino protecting group, or substituted or unsubstituted C1-C 10 It is alkyl, Each of the optionally substituted groups is hydroxyl, amino, alkoxy, carboxy, or benzyl. The conjugated antisense compound of Embodiment 116, optionally substituted with substituents independently selected from phenyl, nitro(NO2), thiol, thioalkoxy(S-alkyl), halogen, alkyl, aryl, alkenyl, and alkynyl.

[0141] Embodiment 118. Each 2' substituent is halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-SCH3, O(CH2)2-OCF3, O(CH2)3-N(R1)(R2), O(CH2)2-ON(R1)(R2), O(CH2)2-O(CH2)2- A conjugated antisense compound of Embodiment 116, independently selected from N(R1)(R2), OCH2C(=O)-N(R1)(R2), OCH2C(=O)-N(R3)-(CH2)2-N(R1)(R2), and O(CH2)2-N(R3)-C(=NR4)[N(R1)(R2)], wherein R1, R2, R3, and R4 are each independently H or C1-C6 alkyl.

[0142] Embodiment 119. A conjugated antisense compound of Embodiment 116, wherein each 2' substituent is independently selected from halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3(MOE), O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

[0143] Embodiment 120. The conjugated antisense compound of Embodiment 116, wherein the at least one 2'-modified nucleoside contains a 2'-MOE sugar moiety.

[0144] Embodiment 121. The conjugated antisense compound of Embodiment 116, wherein the at least one 2'-modified nucleoside contains a 2'-OMe sugar moiety.

[0145] Embodiment 122. The conjugated antisense compound of Embodiment 116, wherein the at least one 2'-modified nucleoside contains a 2'-F sugar moiety.

[0146] Embodiment 123. A conjugated antisense compound of any of Embodiments 1 to 122, wherein the antisense oligonucleotide comprises at least one modified nucleoside containing a sugar substitute.

[0147] Embodiment 124. The conjugated antisense compound of Embodiment 123, wherein the modified nucleoside contains an F-HNA sugar moiety.

[0148] Embodiment 125. The conjugated antisense compound of Embodiment 123, wherein the modified nucleoside contains an HNA sugar moiety.

[0149] Embodiment 126. A conjugated antisense compound of any of Embodiments 1 to 125, wherein the antisense oligonucleotide comprises at least one modified nucleoside containing a bicyclic sugar moiety.

[0150] Embodiment 127. The conjugated antisense compound of Embodiment 126, wherein the bicyclic sugar portion is a cEt sugar portion.

[0151] Embodiment 128. The conjugated antisense compound of Embodiment 126, wherein the bicyclic sugar portion is an LNA sugar portion.

[0152] Embodiment 129. A conjugated antisense compound of any of Embodiments 1 to 128, wherein the antisense oligonucleotide contains at least one modified internucleoside bond.

[0153] Embodiment 130. The conjugated antisense compound of Embodiment 129, wherein each nucleoside bond in the antisense oligonucleotide is a modified nucleoside bond.

[0154] Embodiment 131. The conjugated antisense compound of Embodiment 129, wherein the antisense oligonucleotide comprises at least one modified bond and at least one unmodified phosphodiester nucleoside bond.

[0155] Embodiment 132. A conjugated antisense compound of any of Embodiments 129 to 131, wherein at least one modified nucleoside bond is a phosphosphorothioate nucleoside bond.

[0156] Embodiment 133. A conjugated antisense compound according to any of Embodiments 129 to 122, wherein each modified nucleoside bond is a phosphorothioate nucleoside bond.

[0157] Embodiment 134. A conjugated antisense compound according to any of Embodiments 129 to 133, wherein the antisense oligonucleotide contains at least two phosphodiester nucleoside interbonding bonds.

[0158] Embodiment 135. A conjugated antisense compound according to any of Embodiments 129 to 133, wherein the antisense oligonucleotide contains at least three phosphodiester nucleoside interbonding groups.

[0159] Embodiment 136. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least four phosphodiester nucleoside interbonding groups.

[0160] Embodiment 137. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least five phosphodiester nucleoside interbondings.

[0161] Embodiment 138. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least six phosphodiester nucleoside interbondings.

[0162] Embodiment 139. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least seven phosphodiester nucleoside interbonding bonds.

[0163] Embodiment 140. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least eight phosphodiester nucleoside interbondings.

[0164] Embodiment 141. A conjugated antisense compound according to any of Embodiments 129 to 132, wherein the antisense oligonucleotide contains at least nine phosphodiester nucleoside interbondings.

[0165] Embodiment 142. The antisense oligonucleotide comprises at least 10 phosphodi A conjugated antisense compound according to any of embodiments 129 to 132, comprising an ester nucleoside bond.

[0166] Embodiment 143. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 16 phosphorothioate nucleoside bonds.

[0167] Embodiment 144. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 15 phosphorothioate nucleoside bonds.

[0168] Embodiment 145. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 14 phosphorothioate nucleoside bonds.

[0169] Embodiment 146. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 13 phosphorothioate nucleoside bonds.

[0170] Embodiment 147. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 12 phosphorothioate nucleoside bonds.

[0171] Embodiment 148. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 11 phosphorothioate nucleoside bonds.

[0172] Embodiment 149. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than 10 phosphorothioate nucleoside bonds.

[0173] Embodiment 150. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than nine phosphorothioate nucleoside bonds.

[0174] Embodiment 151. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than eight phosphorothioate nucleoside bonds.

[0175] Embodiment 152. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than seven phosphorothioate nucleoside bonds.

[0176] Embodiment 153. A conjugated antisense compound according to any of Embodiments 129 to 142, wherein the antisense oligonucleotide contains fewer than six phosphorothioate nucleoside bonds.

[0177] Embodiment 154. A conjugated antisense compound according to any of Embodiments 129 to 153, wherein the internucleoside bonds between each terminal nucleoside of the antisense oligonucleotide are phosphorothioate nucleoside bonds.

[0178] Embodiment 155. A conjugated antisense compound according to any of Embodiments 129 to 154, wherein the internucleoside bonds connecting the two deoxynucleosides of the antisense oligonucleotide are phosphorothioate internucleoside bonds.

[0179] Embodiment 156. A conjugated antisense compound according to any of Embodiments 129 to 155, wherein each non-terminal nucleoside bond connecting the two modified nucleosides of the antisense oligonucleotide is a phosphodiester nucleoside bond.

[0180] Embodiment 157. A conjugated antisense compound according to any of Embodiments 129 to 156, wherein each non-terminal nucleoside bond of the antisense oligonucleotide, which is the 3' of the modified nucleoside, is a phosphodiester nucleoside bond.

[0181] Embodiment 158. A conjugated antisense compound according to any of Embodiments 129 to 157, wherein each nucleoside bond of the antisense oligonucleotide that is the 3' of the deoxynucleoside is a phosphorothioate nucleoside bond.

[0182] Embodiment 159. The antisense oligonucleotide is MsMy(Ds) 0-1 (DsDs) (3-5) MsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMyMsM MsMyMyMyMy(Ds) 0-1 (DsDs)​​​​​​​​​​​​​​​​​​​It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each s is a phosphorothioate nucleoside bond, and each y is either a phosphodiester nucleoside bond or a phosphorothioate nucleoside bond, provided that at least one y is a phosphodiester nucleotide bond. A conjugated antisense compound according to any of Embodiments 1 to 158.

[0183] Embodiment 160. The antisense oligonucleotide is MsMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMo(Ds)0-1(DsDs)(3-5)MoMoMsM MsMo(Ds)0-1(DsDs)(3-5)MoMoMoMsM MsMoMo(Ds)0-1(DsDs)(3-5)MsM MsMoMo(Ds)0-1(DsDs)(3-5)MoMsM MsMoMo(Ds)0-1(DsDs)(3-5)MoMoMsM MsMoMo(Ds)0-1(DsDs)(3-5)MoMoMoMsM MsMoMoMo(Ds)0-1(DsDs)(3-5)MsM MsMoMoMo(Ds)0-1(DsDs)(3-5)MoMsM MsMoMoMo(Ds)0-1(DsDs)(3-5)MoMoMsM MsMoMoMo(Ds)0-1(DsDs)(3-5)MoMoMoMsM MsMoMoMoMo(Ds)0-1(DsDs)(3-5)MsM MsMoMoMoMo(Ds)0-1(DsDs)(3-5)MoMsM MsMoMoMoMo(Ds)0-1(DsDs)(3-5)MoMoMsM, and MsMoMoMoMo(Ds)0-1(DsDs)(3-5)MoMoMoMsM It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each o is a phosphodiester nucleoside bond, and each s is a phosphorothioate nucleoside bond. A conjugated antisense compound according to any of Embodiments 1 to 158.

[0184] Embodiment 161. A conjugated antisense compound of Embodiment 159 or 160, wherein each M is independently selected from 2'-MOE nucleosides and bicyclic nucleosides.

[0185] Embodiment 162. The conjugated antisense compound of Embodiment 161, wherein each M is independently selected from 2'-MOE nucleoside, cEt nucleoside, and LNA nucleoside.

[0186] Embodiment 163. A conjugated antisense compound of Embodiment 159 or 160, wherein each M is a 2'-MOE nucleoside.

[0187] Embodiment 164. A conjugated antisense compound of Embodiment 159 or 160, wherein each M is a cEt nucleoside.

[0188] Embodiment 165. A conjugated antisense compound of Embodiment 159 or 160, wherein each M is an LNA nucleoside.

[0189] Embodiment 166. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least eight nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0190] Embodiment 167. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 10 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0191] Embodiment 168. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 12 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0192] Embodiment 169. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 14 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0193] Embodiment 170. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 16 nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0194] Embodiment 171. A conjugated antisense compound according to any one of Embodiments 1 to 165, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 18 nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0195] Embodiment 172. A conjugated antisense compound according to any one of Embodiments 1 to 171, wherein the antisense oligonucleotide is at least 90% complementary to the target nucleic acid.

[0196] Embodiment 173. A conjugated antisense compound of any of Embodiments 1 to 171, wherein the antisense oligonucleotide is at least 95% complementary to the target nucleic acid.

[0197] Embodiment 174. A conjugated antisense compound according to any of Embodiments 1 to 171, wherein the antisense oligonucleotide is 100% complementary to the target nucleic acid.

[0198] Embodiment 175. A conjugated antisense compound according to any of Embodiments 166 to 174, wherein the target nucleic acid is premRNA.

[0199] Embodiment 176. A conjugated antisense compound according to any of Embodiments 166 to 174, wherein the target nucleic acid is mRNA.

[0200] Embodiment 177. A conjugated antisense compound according to any of Embodiments 166 to 176, wherein the target nucleic acid is expressed in the liver.

[0201] Embodiment 178. The conjugated antisense compound of Embodiment 177, wherein the target nucleic acid is expressed in hepatocytes.

[0202] Embodiment 179. A conjugated antisense compound of Embodiment 177 or 178, wherein the target nucleic acid encodes a protein selected from androgen receptor, apolipoprotein(a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, protein tyrosine phosphatase 1B, STAT3, and transthyretin.

[0203] Embodiment 180. The conjugated antisense compounds of Embodiments 166-179, wherein the target nucleic acid is a viral nucleic acid.

[0204] Embodiment 181. The conjugated antisense compound of Embodiment 180, wherein the viral nucleic acid is expressed in the liver.

[0205] Embodiment 182. The conjugated antisense compound of Embodiment 181, wherein the target nucleic acid is hepatitis B virus nucleic acid.

[0206] Embodiment 183. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, or 24.

[0207] Embodiment 184. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs. 25, 26, 27, 28, 29, or 30.

[0208] Embodiment 185. A conjugated antisense compound according to any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 31.

[0209] Embodiment 186. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 32.

[0210] Embodiment 187. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 33.

[0211] Embodiment 188. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 34.

[0212] Embodiment 189. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 35, 36, 37, 38, 39, 40, 41, 42, or 43.

[0213] Embodiment 190. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 44, 45, 46, 47, or 48.

[0214] Embodiment 191. A conjugated antisense compound according to any of Embodiments 1 to 179, wherein the antisense oligonucleotide contains one of the nucleic acid base sequences among SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[0215] Embodiment 192. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 60, 61, 62, 63, 64, 65, 66, or 67.

[0216] Embodiment 193. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 69, 70, 71, or 72.

[0217] Embodiment 194. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 73.

[0218] Embodiment 195. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences among SEQ ID NOs: 74, 75, 76, 77, 78, 79, 80, or 81.

[0219] Embodiment 196. A conjugated antisense compound of any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 68.

[0220] Embodiment 197. A conjugated antisense compound according to any of Embodiments 1 to 179, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences from SEQ ID NOs. 82 to 103.

[0221] Embodiment 198. A method for reducing the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a conjugated antisense compound of any of Embodiments 1 to 197.

[0222] Embodiment 199. The method of Embodiment 198, wherein the cells are liver cells.

[0223] Embodiment 200. The method of Embodiment 199, wherein the cells are hepatocytes.

[0224] Embodiment 201. Any of Embodiments 198 to 200, wherein the cells are present outside the body.

[0225] Embodiment 202. Any method of Embodiments 198 to 200, wherein the cells are present in an animal.

[0226] Embodiment 203. The method of Embodiment 202, wherein the animal is a mouse.

[0227] Embodiment 204. The method of Embodiment 202, wherein the animal is a human.

[0228] Embodiment 205. A pharmaceutical composition comprising a conjugated antisense compound according to any one of Embodiments 1 to 197 and a pharmaceutically acceptable carrier or diluent.

[0229] Embodiment 206. The pharmaceutical composition of Embodiment 205, wherein the pharmaceutically acceptable carrier or diluent is selected from sterile water and sterile physiological saline.

[0230] Embodiment 207. A method for treating a disease or condition in an animal, comprising administering a pharmaceutical composition of Embodiment 205 or 206 to the animal, thereby treating the disease or condition in the animal.

[0231] Embodiment 208. The method of Embodiment 207, wherein the animal is a mouse.

[0232] Embodiment 209. The method of Embodiment 207, wherein the animal is a human.

[0233] Embodiment 210. Any method of Embodiments 207 to 209, wherein the disease or condition is a liver disease or condition.

[0234] Embodiment 211. Any of the methods of Embodiments 207 to 210, wherein the administration is by parenteral administration.

[0235] Embodiment 212. The method of Embodiment 211, wherein the administration is by subcutaneous injection.

[0236] Embodiment 213. The method of Embodiment 211, wherein the administration is performed by intravenous infusion.

[0237] Embodiment 214. The method of Embodiment 211, wherein the administration is by intramuscular injection.

[0238] Embodiment 215. Any method of Embodiments 207 to 214, wherein the conjugated antisense compound is provided in a dose of 1 to 10 mg / kg.

[0239] Embodiment 216. Any method of Embodiments 207 to 214, wherein the conjugated antisense compound is provided in a dose of less than 1 mg / kg.

[0240] Embodiment 217. Any method of Embodiments 207 to 216, wherein the conjugated antisense compound is provided in a dose greater than 10 mg / kg.

[0241] Embodiment 218. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided for a drug administration period of at least two months.

[0242] Embodiment 219. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided for a period of at least four months.

[0243] Embodiment 220. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided for a period of at least 6 months.

[0244] Embodiment 221. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once a week.

[0245] Embodiment 222. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once every two weeks.

[0246] Embodiment 223. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once every three weeks.

[0247] Embodiment 224. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of once every four weeks.

[0248] Embodiment 225. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of once every five weeks.

[0249] Embodiment 226. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosing frequency of once every six weeks.

[0250] Embodiment 227. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of once every seven weeks.

[0251] Embodiment 228. Any method of Embodiments 207 to 217, wherein the conjugated antisense compound is provided at a dosage frequency of once every eight weeks.

[0252] Embodiment 229. A conjugated antisense compound comprising an antisense oligonucleotide containing 12 to 30 linked nucleosides, wherein the conjugated group contains at least one cell-targeting moiety.

[0253] Embodiment 230. The conjugated antisense compound of Embodiment 229, wherein the conjugated group comprises two cell-targeting moieties.

[0254] Embodiment 231. The conjugated antisense compound of Embodiment 229, wherein the conjugated group comprises three cell-targeting moieties.

[0255] Embodiment 232. The conjugated antisense compound of Embodiment 229, wherein the conjugated group comprises four cell-targeting moieties.

[0256] Embodiment 233. A conjugated antisense compound according to any of Embodiments 229-232, wherein each cell target moiety contains a cleavable bond.

[0257] Embodiment 234. A conjugated antisense compound of any of Embodiments 229-233, wherein each cell targeting portion comprises a tether and a ligand.

[0258] Embodiment 235. The conjugated antisense compound of Embodiment 234, wherein the ligand is a cell surface receptor ligand.

[0259] Embodiment 236. The conjugated antisense compound of Embodiment 235, wherein at least one tether contains a cleavable bond.

[0260] Embodiment 237. The conjugated antisense compound of Embodiment 235, wherein each tether contains a cleavable bond.

[0261] Embodiment 238. A conjugated antisense compound according to any of Embodiments 229 to 237, wherein the conjugated group includes a conjugated linker.

[0262] Embodiment 239. The conjugated antisense compound of Embodiment 238, wherein the conjugated linker contains one or more cleavable bonds.

[0263] Embodiment 240. A conjugated antisense compound according to any of Embodiments 229 to 239, wherein the conjugated group includes a branched group.

[0264] Embodiment 241. The conjugated antisense compound of Embodiment 240, wherein the branching group includes one or more cleavable bonds.

[0265] Embodiment 242. A conjugated antisense compound according to any of Embodiments 229 to 241, wherein the conjugated group includes a cleavable portion.

[0266] Embodiment 243. The conjugated antisense compound of Embodiment 242, wherein the cleavable portion comprises one or more cleavable bonds.

[0267] Embodiment 244. A conjugated antisense compound of any of Embodiments 229 to 243, wherein the conjugated group comprises at least one cleavable bond.

[0268] Embodiment 245. A conjugated antisense compound of any of Embodiments 229 to 243, wherein the conjugated group comprises at least two cleavable bonds.

[0269] Embodiment 246. A conjugated antisense compound of any of Embodiments 229 to 243, wherein the conjugated group comprises at least three cleavable bonds.

[0270] Embodiment 247. A conjugated antisense compound of any of Embodiments 229 to 243, wherein the conjugated group comprises at least four cleavable bonds.

[0271] Embodiment 248. A conjugated antisense compound of any of Embodiments 229 to 243, wherein the conjugated group comprises at least five cleavable bonds.

[0272] Embodiment 249. A conjugated antisense compound of any of Embodiments 229 to 248, comprising a cleavable bond selected from amides, polyamides, esters, ethers, phosphodiesters, phosphate esters, carbamates, disulfides, or peptides.

[0273] Embodiment 250. The conjugated antisense compound of Embodiment 249, wherein the peptide is a dipeptide.

[0274] Embodiment 251. The conjugated anticephaly of Embodiment 249, wherein the peptide is a tripeptide. A compound.

[0275] Embodiment 252. The conjugated antisense compound of Embodiment 249, wherein the peptide is lysine.

[0276] Embodiment 253. The conjugated antisense compound of Embodiment 249, wherein the peptide is a lysine derivative.

[0277] Embodiment 254. A conjugated antisense compound according to either Embodiment 250 or 251, wherein one or more peptides are lysine.

[0278] Embodiment 255. A conjugated antisense compound according to either Embodiment 250 or 251, wherein two or more peptides are lysine.

[0279] Embodiment 256. The conjugated group is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. A conjugated antisense compound according to any of embodiments 229 to 255, wherein each n is an integer from 1 to 20.

[0280] Embodiment 257. The conjugated group is [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound of any of embodiments 229 to 255, including the following:

[0281] Embodiment 258. The branching base is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. A conjugated antisense compound according to any of embodiments 229 to 257, wherein each n is an integer from 1 to 20.

[0282] Embodiment 259. The branching base is, [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound of any of embodiments 229 to 257, including the following:

[0283] Embodiment 260. A conjugated antisense compound according to any of Embodiments 229 to 259, wherein the cell targeting portion contains a carbohydrate.

[0284] Embodiment 261. A conjugated antisense compound according to any of Embodiments 229 to 259, wherein the cell targeting portion includes a carbohydrate cluster.

[0285] Embodiment 262. A conjugated antisense compound according to any of Embodiments 229 to 259, wherein the cell targeting portion includes a cell surface receptor ligand.

[0286] Embodiment 263. A conjugated antisense compound according to any of Embodiments 229 to 259, wherein the cell targeting moiety comprises at least one N-acetylgalactosamine (GalNAc).

[0287] Embodiment 264. The cleavable portion is covalently bonded to the antisense oligonucleotide, The conjugate linker is covalently bonded to the severable portion, The cell target portion is covalently bonded to the conjugated linker. A conjugated antisense compound according to any of embodiments 229 to 263.

[0288] Embodiment 265. A conjugated antisense compound according to any of Embodiments 229 to 264, wherein the cell targeting portion includes a branched group.

[0289] Embodiment 266. The conjugated antisense compound of Embodiment 265, wherein the branched group is covalently bonded to the conjugated linker.

[0290] Embodiment 267. A conjugated antisense compound of any of Embodiments 229 to 266, wherein the cell targeting portion comprises at least one tether.

[0291] Embodiment 268. A conjugated antisense compound according to any of Embodiments 229 to 267, wherein at least one tether is covalently bonded to the branching group.

[0292] Embodiment 269. A conjugated antisense compound according to any of Embodiments 229 to 267, wherein the cell targeting portion comprises at least one ligand.

[0293] Embodiment 270. The conjugated antisense compound of Embodiment 269, wherein each of the at least one ligands is covalently bonded to the tether.

[0294] Embodiment 271. The compound has a structure represented by the following formula I, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. A conjugated antisense compound according to any of embodiments 229 to 270.

[0295] Embodiment 272. A conjugated antisense compound according to any of Embodiments 229 to 271, wherein the cleavable portion comprises 1 to 4 linked cleavable nucleosides, and the bond between the antisense oligonucleotide and the first cleavable nucleoside is a phosphodiester nucleoside bond.

[0296] Embodiment 273. The conjugated antisense compound of Embodiment 272, wherein each internucleoside bond between each of the linked cleavable nucleosides is a phosphodiester internucleoside bond.

[0297] Embodiment 274. The conjugated antisense compound of Embodiment 271 or 272, wherein the cleavable portion comprises 1 to 3 linked cleavable portion nucleosides.

[0298] Embodiment 275. The conjugated antisense compound of Embodiment 271 or 272, wherein the cleavable portion comprises one or two linked cleavable portion nucleosides.

[0299] Embodiment 276. The conjugated antisense compound of Embodiment 271, wherein the cleavable portion comprises a nucleoside of one cleavable portion.

[0300] Embodiment 277. A conjugated antisense compound of any of Embodiments 229 to 276, wherein the cleavable portion is a nucleoside of a cleavable portion selected from the group consisting of purines, substituted purines, pyrimidines, or substituted pyrimidines.

[0301] Embodiment 278. A conjugated antisense compound of any of Embodiments 229 to 276, wherein the cleavable portion is a nucleoside of a cleavable portion selected from cytidine, uridine, adenosine, thymidine, and guanosine.

[0302] Embodiment 279. A conjugated antisense compound of any of Embodiments 229 to 276, wherein the cleavable portion is a deoxynucleoside of the cleavable portion selected from deoxyadenosine, deoxyguanosine, deoxyinosine, thymidine, deoxyuridine, and deoxycytidine.

[0303] Embodiment 280. A conjugated antisense compound of any of Embodiments 229 to 280, wherein the cleavable portion contains deoxyadenosine.

[0304] Embodiment 281. Embodiment 229~, wherein the cleavable portion is deoxyadenosine. Any of the 280 conjugated antisense compounds.

[0305] Embodiment 282. The severable portion has a structure selected from the following: [ka] In the formula, Bx, Bx1, Bx2, and Bx3 are each independently heterocyclic base parts. A conjugated antisense compound according to any of embodiments 229 to 276.

[0306] Embodiment 283. The conjugated antisense compound of Embodiment 282, wherein the heterocyclic base moiety is selected from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0307] Embodiment 284. A conjugated antisense compound according to any of Embodiments 229 to 276, wherein the cleavable portion has the following structure. [ka]

[0308] Embodiment 285. A conjugated antisense compound according to any of Embodiments 229 to 285, wherein the conjugated linker contains pyrrolidine.

[0309] Embodiment 286. A conjugated antisense compound according to any of Embodiments 229 to 286, wherein the conjugated linker contains PEG.

[0310] Embodiment 287. Any of Embodiments 229 to 287, wherein the conjugated linker includes an amide. Those conjugated antisense compounds.

[0311] Embodiment 288. A conjugated antisense compound according to any of Embodiments 229 to 288, wherein the conjugated linker comprises a polyamide.

[0312] Embodiment 289. A conjugated antisense compound according to any of Embodiments 229 to 289, wherein the conjugated linker contains an amine.

[0313] Embodiment 290. A conjugated antisense compound according to any of Embodiments 229 to 290, wherein the conjugated linker contains one or more disulfide bonds.

[0314] Embodiment 291. A conjugated antisense compound according to any of Embodiments 229 to 291, wherein the conjugated linker includes a protein-binding moiety.

[0315] Embodiment 292. The conjugated antisense compound of Embodiment 292, wherein the protein-binding portion contains a lipid.

[0316] Embodiment 293. The protein-binding portion is cholesterol, cholic acid, adamantane acetate, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethyltrityl, or phenoxazine), vitamin A conjugated antisense compound of Embodiment 293, selected from among (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosome lysants, steroids (e.g., ubaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friederin, epifriederanol-derived lithocholic acid), or cationic lipids.

[0317] Embodiment 294. A conjugated antisense compound according to any of Embodiments 229 to 293, wherein the protein-binding portion is a C16-C22 long-chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0318] Embodiment 295. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20, and p is between 1 and 6. A conjugated antisense compound according to any of embodiments 229 to 294.

[0319] Embodiment 296. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 229 to 295.

[0320] Embodiment 297. The conjugate linker has a structure selected from the following: [ka] A conjugated antisense compound of any of Embodiments 229 to 295, wherein each n is independently 1 to 20.

[0321] Embodiment 298. A conjugated antisense compound according to any of Embodiments 229 to 295, wherein the conjugated linker has a structure selected from the following. [ka]

[0322] Embodiment 299. A conjugated antisense compound according to any of Embodiments 229 to 295, wherein the conjugated linker has a structure selected from the following. [ka]

[0323] Embodiment 300. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any of embodiments 229 to 295.

[0324] Embodiment 301. A conjugated antisense compound according to any of Embodiments 229 to 295, wherein the conjugated linker has the following structure. [ka]

[0325] Embodiment 302. A conjugated antisense compound according to any of Embodiments 229 to 301, wherein the cell targeting portion contains a carbohydrate.

[0326] Embodiment 303. A conjugated antisense compound according to any of Embodiments 229 to 302, wherein the cell targeting portion includes a carbohydrate cluster.

[0327] Embodiment 304. A conjugated antisense compound according to any of Embodiments 229 to 303, wherein the cell targeting portion includes a cell surface receptor ligand.

[0328] Embodiment 305. A conjugated antisense compound of any of Embodiments 229 to 304, wherein the target portion comprises at least one N-acetylgalactosamine (GalNAc).

[0329] Embodiment 306. A conjugated antisense compound according to any of Embodiments 229 to 305, wherein the target portion includes a branched group.

[0330] Embodiment 307. The conjugated antisense compound of Embodiment 306, wherein the branched group contains an ether.

[0331] Embodiment 308. The branching base has the following structure: [ka] Each n is independently between 1 and 20. m is between 2 and 6. A conjugated antisense compound of embodiment 306 or 307.

[0332] Embodiment 309. The conjugated antisense compound of Embodiment 306 or 307, wherein the branched group has the following structure. [ka]

[0333] Embodiment 310. The branching base has the following structure: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. A conjugated antisense compound of embodiment 306 or 307.

[0334] Embodiment 311. The conjugated antisense compound of Embodiment 306 or 307, wherein the branched group has the following structure. [ka]

[0335] Embodiment 312. The branching base is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. In the formula, each n is an integer between 1 and 20. A conjugated antisense compound according to either embodiment 306 or 307.

[0336] Embodiment 313. The branching base is [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound comprising either embodiment 306 or 307.

[0337] Embodiment 314. A conjugated antisense compound according to any of Embodiments 229 to 313, wherein the cell targeting portion comprises one tether.

[0338] Embodiment 315. A conjugated antisense compound according to any of Embodiments 229 to 313, wherein the cell targeting portion comprises two tethers.

[0339] Embodiment 316. A conjugated antisense compound according to any of Embodiments 229 to 313, wherein the cell targeting portion comprises three tethers.

[0340] Embodiment 317. A conjugated antisense compound according to any of Embodiments 229 to 313, wherein the cell targeting moiety comprises four or more tethers.

[0341] Embodiment 318. A conjugated antisense compound of any of Embodiments 229 to 317, wherein at least one tether comprises PEG.

[0342] Embodiment 319. A conjugated antisense compound of any of Embodiments 229 to 318, wherein at least one tether comprises an amide.

[0343] Embodiment 320. A conjugated antisense compound of any of Embodiments 229 to 319, wherein at least one tether comprises a polyamide.

[0344] Embodiment 321. A conjugated antisense compound of any of Embodiments 229 to 320, wherein at least one tether contains an amine.

[0345] Embodiment 322. A conjugated antisense compound of any of Embodiments 229 to 321, wherein at least two tethers are different from each other.

[0346] Embodiment 323. A conjugated antisense compound of any of Embodiments 229 to 321, wherein all of the tethers are identical to each other.

[0347] Embodiment 324. Each tether is selected from the following: [ka] Each n is independently between 1 and 20. Each p is between 1 and approximately 6. A conjugated antisense compound according to any of embodiments 229 to 323.

[0348] Embodiment 325. Each tether is a conjugated antisense compound from any of Embodiments 229 to 324, selected from the following: [ka]

[0349] Embodiment 326. Each tether has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 229 to 324.

[0350] Embodiment 327. A conjugated antisense compound of any of Embodiments 229 to 324, wherein each tether has the following structure. [ka]

[0351] Embodiment 328. A conjugated antisense compound according to any of Embodiments 229 to 328, wherein the cell targeting portion comprises at least one ligand.

[0352] Embodiment 329. The conjugated antisense compound of Embodiment 328, wherein the cell targeting moiety contains one ligand.

[0353] Embodiment 330. The conjugated antisense compound of Embodiment 328, wherein the target portion comprises two ligands.

[0354] Embodiment 331. The conjugated antisense compound of Embodiment 328, wherein the target portion comprises three ligands.

[0355] Embodiment 332. A conjugated antisense compound according to any of Embodiments 328 to 331, wherein one ligand is covalently bound to each tether.

[0356] Embodiment 333. A conjugated antisense compound of any of Embodiments 229 to 332, wherein at least one ligand is N-acetylgalactosamine (GalNAc).

[0357] Embodiment 334. A conjugated antisense compound of any of Embodiments 229 to 332, wherein each ligand is N-acetylgalactosamine (GalNAc).

[0358] Embodiment 335. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose Lanose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[(R )-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6- A conjugated antisense compound according to any of embodiments 229 to 332, selected from O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0359] Embodiment 336. A conjugated antisense compound according to any of Embodiments 229 to 332, wherein the ligand is galactose.

[0360] Embodiment 337. A conjugated antisense compound of any of Embodiments 229 to 332, wherein the ligand is mannose-6-phosphate.

[0361] Embodiment 338. Each ligand is selected from the following: [ka] In the formula, each R1 is selected from OH and NHCOOH. A conjugated antisense compound according to any of embodiments 229 to 332.

[0362] Embodiment 339. A conjugated antisense compound of any of Embodiments 229 to 332, wherein each ligand is selected from the following. [ka]

[0363] Embodiment 340. A conjugated antisense compound of any of Embodiments 229 to 332, wherein each ligand has the following structure. [ka]

[0364] Embodiment 341. Each ligand has the following structure, one of Embodiments 229 to 332 One of the conjugated antisense compounds. [ka]

[0365] Embodiment 342. The cell target group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 229 to 332.

[0366] Embodiment 343. A conjugated antisense compound according to any of Embodiments 229 to 336, wherein the cell target group has the following structure. [ka]

[0367] Embodiment 344. The conjugate has the following structure: [ka] In the formula, each n is independently between 1 and 20. Z is H or a bonded solid support. Q is the antisense compound, X is either O or S, A conjugated antisense compound of any of embodiments 229 to 336, wherein Bx is a heterocyclic base moiety.

[0368] Embodiment 345. The conjugate has the following structure: [ka] In the formula, Z is H or a bonded solid support. Q is the antisense compound. A conjugated antisense compound according to any of embodiments 229 to 336.

[0369] Embodiment 346. A conjugated antisense compound according to any of Embodiments 229 to 345, wherein the conjugated group is bonded to the 2' position of the nucleoside of the antisense oligonucleotide.

[0370] Embodiment 347. A conjugated antisense compound according to any of Embodiments 229 to 345, wherein the conjugated group is bonded to the 3' position of the nucleoside of the antisense oligonucleotide.

[0371] Embodiment 348. The conjugated group is the nucleoside of the antisense oligonucleotide. A conjugated antisense compound of any of embodiments 229 to 345, bonded at the 5' position.

[0372] Embodiment 349. A conjugated antisense compound according to any of Embodiments 229 to 345, wherein the conjugated group is bonded to the 5' terminal nucleoside of the antisense oligonucleotide.

[0373] Embodiment 350. A conjugated antisense compound according to any of Embodiments 229 to 350, wherein the conjugated group is bonded to the 3' terminal nucleoside of the antisense oligonucleotide.

[0374] Embodiment 351. A conjugated antisense compound according to any of Embodiments 229 to 350, wherein the conjugated group is bonded to the internal nucleoside of the antisense oligonucleotide.

[0375] Embodiment 352. A conjugated antisense compound according to any of Embodiments 229 to 351, wherein the conjugated group increases the uptake of the conjugated antisense compound into hepatocytes compared to a non-conjugated antisense compound.

[0376] Embodiment 353. A conjugated antisense compound according to any of Embodiments 229 to 352, wherein the conjugated group increases the uptake of the conjugated antisense compound into liver cells compared to a non-conjugated antisense compound.

[0377] Embodiment 354. A conjugated antisense compound according to any of Embodiments 229 to 353, wherein the conjugated group increases the accumulation of the conjugated antisense compound in the liver compared to an unconjugated antisense compound.

[0378] Embodiment 355. A conjugated antisense compound according to any of Embodiments 229 to 354, wherein the conjugated group reduces the accumulation of the conjugated antisense compound in the kidney compared to a non-conjugated antisense compound.

[0379] Embodiment 356. A conjugated antisense compound according to any of Embodiments 229 to 355, wherein the antisense oligonucleotide is an RNase H-based antisense compound.

[0380] Embodiment 357. A conjugated antisense compound according to any of Embodiments 229 to 356, wherein the antisense oligonucleotide comprises at least one modified nucleoside.

[0381] Embodiment 358. A conjugated antisense compound according to any of Embodiments 229 to 357, wherein each nucleoside of the antisense oligonucleotide is a modified nucleoside.

[0382] Embodiment 359. A conjugated antisense compound according to any of Embodiments 229 to 358, wherein the antisense oligonucleotide is single-stranded.

[0383] Embodiment 360. A conjugated antisense compound of Embodiments 357-359, wherein at least one modified nucleoside contains a modified sugar moiety.

[0384] Embodiment 361. The antisense oligonucleotide is A 5' region consisting of 2 to 8 linked 5' region nucleosides, wherein at least 2 5' region nucleosides are modified nucleosides, and the 5' region nucleoside closest to the 3' side is a modified nucleoside, and A 3' region consisting of 2 to 8 linked 3' region nucleosides, wherein at least 2 of the 3' region nucleosides are modified nucleosides, and the 3' region nucleoside closest to the 5' side is a modified nucleoside, and The 5' region and the 3' region consist of 5 to 10 linked central nucleosides. A conjugated antisense compound of Embodiment 359 having a sugar motif comprising a central region, where each is independently selected from modified nucleosides and unmodified deoxynucleosides, with the central region nucleoside furthest 5' being an unmodified deoxynucleoside and the central region nucleoside furthest 3' being an unmodified deoxynucleoside.

[0385] Embodiment 362. The conjugated antisense compound of Embodiment 361, wherein the 5' region consists of two linked 5' region nucleosides.

[0386] Embodiment 363. The conjugated antisense compound of Embodiment 361, wherein the 5' region consists of three linked 5' region nucleosides.

[0387] Embodiment 364. The conjugated antisense compound of Embodiment 361, wherein the 5' region consists of four linked 5' region nucleosides.

[0388] Embodiment 365. The conjugated antisense compound of Embodiment 361, wherein the 5' region consists of five linked 5' region nucleosides.

[0389] Embodiment 366. A conjugated antisense compound according to any of Embodiments 361 to 365, wherein the 3' region consists of two linked 3' region nucleosides.

[0390] Embodiment 367. A conjugated antisense compound according to any of Embodiments 361 to 365, wherein the 3' region consists of three linked 3' region nucleosides.

[0391] Embodiment 368. A conjugated antisense compound according to any of Embodiments 361 to 365, wherein the 3' region consists of four linked 3' region nucleosides.

[0392] Embodiment 369. A conjugated antisense compound according to any of Embodiments 361 to 365, wherein the 3' region consists of five linked 3' region nucleosides.

[0393] Embodiment 370. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of five linked central region nucleosides.

[0394] Embodiment 371. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of six linked central region nucleosides.

[0395] Embodiment 372. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of seven linked central region nucleosides.

[0396] Embodiment 373. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of eight linked central region nucleosides.

[0397] Embodiment 374. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of nine linked central region nucleosides.

[0398] Embodiment 375. A conjugated antisense compound according to any of Embodiments 361 to 369, wherein the central region consists of 10 linked central region nucleosides.

[0399] Embodiment 376. A conjugated antisense compound according to any of Embodiments 229 to 376, wherein the antisense oligonucleotide consists of 14 to 26 linked nucleosides.

[0400] Embodiment 377. A conjugated antisense compound according to any of Embodiments 229 to 376, wherein the antisense oligonucleotide consists of a nucleoside linked with 15 to 25 units.

[0401] Embodiment 378. A conjugated antisense compound according to any of Embodiments 229 to 376, wherein the antisense oligonucleotide consists of 16 to 20 linked nucleosides.

[0402] Embodiment 379. A conjugated antisense compound of any of Embodiments 229 to 378, wherein each modified nucleoside independently comprises a 2'-substituted sugar moiety or a bicyclic sugar moiety.

[0403] Embodiment 380. The conjugated antisense compound of Embodiment 379, wherein the at least one modified nucleoside comprises a 2'-substituted sugar moiety.

[0404] Embodiment 381. Each modified nucleoside containing the 2'-substituted sugar moiety contains a 2' substituent independently selected from halogen, optionally substituted allyl, optionally substituted amino, azide, optionally substituted SH, CN, OCN, CF3, OCF3, O, S, or N(Rm)-alkyl; O, S, or N(Rm)-alkenyl; O, S, or N(Rm)-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted O-aralkyl, O(CH2)2SCH3, O-(CH2)2-ON(Rm)(Rn), or O-CH2-C(=O)-N(Rm)(Rn), wherein each Rm and Rn independently comprises H, an amino protecting group, or substituted or unsubstituted C1-C 10 It is alkyl, The conjugated antisense compound of Embodiment 380, wherein each optionally substituted group is optionally substituted with a substituent independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl, and alkynyl.

[0405] Embodiment 382. Each 2' substituent is halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-SCH3, O(CH2)2-OCF3, O(CH2)3-N(R1)(R2), O(CH2)2-ON(R1)(R2), O(CH2)2-O(CH2)2- A conjugated antisense compound of Embodiment 380, independently selected from N(R1)(R2), OCH2C(=O)-N(R1)(R2), OCH2C(=O)-N(R3)-(CH2)2-N(R1)(R2), and O(CH2)2-N(R3)-C(=NR4)[N(R1)(R2)], wherein R1, R2, R3, and R4 are each independently H or C1-C6 alkyl.

[0406] Embodiment 383. A conjugated antisense compound of Embodiment 380, wherein each 2' substituent is independently selected from halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3(MOE), O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

[0407] Embodiment 384. The conjugated antisense compound of Embodiment 380, wherein the at least one 2'-modified nucleoside contains a 2'-MOE sugar moiety.

[0408] Embodiment 385. The conjugated antisense compound of Embodiment 380, wherein the at least one 2'-modified nucleoside contains a 2'-OMe sugar moiety.

[0409] Embodiment 386. The conjugated antisense compound of Embodiment 380, wherein the at least one 2'-modified nucleoside contains a 2'-F sugar moiety.

[0410] Embodiment 387. A conjugated antisense compound of any of Embodiments 229 to 386, wherein the antisense oligonucleotide comprises at least one modified nucleoside containing a sugar substitute.

[0411] Embodiment 388. The conjugated antisense compound of Embodiment 387, wherein the modified nucleoside contains an F-HNA sugar moiety.

[0412] Embodiment 389. The conjugated antisense compound of Embodiment 387, wherein the modified nucleoside contains an HNA sugar moiety.

[0413] Embodiment 390. A conjugated antisense compound of any of Embodiments 229 to 389, wherein the antisense oligonucleotide comprises at least one modified nucleoside containing a bicyclic sugar moiety.

[0414] Embodiment 391. The conjugated antisense compound of Embodiment 390, wherein the bicyclic sugar portion is a cEt sugar portion.

[0415] Embodiment 392. A conjugated antisense compound of Embodiment 390, wherein the bicyclic sugar portion is an LNA sugar portion.

[0416] Embodiment 393. A conjugated antisense compound of any of Embodiments 1 to 392, wherein the antisense oligonucleotide contains at least one modified internucleoside bond.

[0417] Embodiment 394. The conjugated antisense compound of Embodiment 393, wherein each nucleoside bond in the antisense oligonucleotide is a modified nucleoside bond.

[0418] Embodiment 395. The conjugated antisense compound of Embodiment 394, wherein the antisense oligonucleotide comprises at least one modified bond and at least one unmodified phosphodiester nucleoside bond.

[0419] Embodiment 396. A conjugated antisense compound of any of Embodiments 393 to 395, wherein at least one modified nucleoside bond is a phosphosphorothioate nucleoside bond.

[0420] Embodiment 397. A conjugated antisense compound according to any of Embodiments 393 to 396, wherein each modified nucleoside bond is a phosphorothioate nucleoside bond.

[0421] Embodiment 398. A conjugated antisense compound according to any one of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least two phosphodiester nucleoside interbonding groups.

[0422] Embodiment 399. A conjugated antisense compound according to any one of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least three phosphodiester nucleoside interbonding groups.

[0423] Embodiment 400. The antisense oligonucleotide comprises at least four phosphodiester nucleoside interbondings, wherein the conjugated antisense oligonucleotide is one of any of Embodiments 393 to 396. A compound.

[0424] Embodiment 401. A conjugated antisense compound according to any one of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least five phosphodiester nucleoside interbondings.

[0425] Embodiment 402. A conjugated antisense compound according to any of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least six phosphodiester nucleoside interbondings.

[0426] Embodiment 403. A conjugated antisense compound according to any one of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least seven phosphodiester nucleoside interbondings.

[0427] Embodiment 404. A conjugated antisense compound of any of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least eight phosphodiester nucleoside interbondings.

[0428] Embodiment 405. A conjugated antisense compound according to any of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least nine phosphodiester nucleoside interbonding groups.

[0429] Embodiment 406. A conjugated antisense compound according to any one of Embodiments 393 to 396, wherein the antisense oligonucleotide contains at least 10 phosphodiester nucleoside interbonding groups.

[0430] Embodiment 407. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 16 phosphorothioate nucleoside bonds.

[0431] Embodiment 408. A conjugated antisense compound according to any one of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 15 phosphorothioate nucleoside bonds.

[0432] Embodiment 409. A conjugated antisense compound according to any one of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 14 phosphorothioate nucleoside bonds.

[0433] Embodiment 410. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 13 phosphorothioate nucleoside bonds.

[0434] Embodiment 411. A conjugated antisense compound according to any one of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 12 phosphorothioate nucleoside bonds.

[0435] Embodiment 412. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 11 phosphorothioate nucleoside bonds.

[0436] Embodiment 413. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than 10 phosphorothioate nucleoside bonds.

[0437] Embodiment 414. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than nine phosphorothioate nucleoside bonds.

[0438] Embodiment 415. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than eight phosphorothioate nucleoside bonds.

[0439] Embodiment 416. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than seven phosphorothioate nucleoside bonds.

[0440] Embodiment 417. A conjugated antisense compound according to any of Embodiments 393-396 or 398-406, wherein the antisense oligonucleotide contains fewer than six phosphorothioate nucleoside bonds.

[0441] Embodiment 418. A conjugated antisense compound according to any of Embodiments 393 to 418, wherein the internucleoside bonds between each terminal nucleoside of the antisense oligonucleotide are phosphorothioate nucleoside bonds.

[0442] Embodiment 419. A conjugated antisense compound according to any of Embodiments 393-396 or 398-418, wherein the internucleoside bonds connecting the two deoxynucleosides of the antisense oligonucleotide are phosphorothioate internucleoside bonds.

[0443] Embodiment 420. A conjugated antisense compound according to any of Embodiments 393-396 or 398-419, wherein each non-terminal nucleoside bond connecting the two modified nucleosides of the antisense oligonucleotide is a phosphodiester nucleoside bond.

[0444] Embodiment 421. A conjugated antisense compound of any of Embodiments 393-396 or 398-420, wherein each non-terminal nucleoside bond of the antisense oligonucleotide, which is the 3' of the modified nucleoside, is a phosphodiester nucleoside bond.

[0445] Embodiment 422. A conjugated antisense compound according to any of Embodiments 393-396 or 398-418, wherein each nucleoside bond of the antisense oligonucleotide that is the 3' of the deoxynucleoside is a phosphorothioate nucleoside bond.

[0446] Embodiment 423. The antisense oligonucleotide is MsMy(Ds) 0-1 (DsDs)(3-5)MsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMyMy(Ds)0-1 (DsDs) (3-5) MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM, and MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM It has a chemical motif selected from among them, A conjugated antisense compound according to any of Embodiments 229 to 422, wherein each M is independently a modified nucleoside, each D is a deoxynucleoside, each s is a phosphorothioate nucleoside bond, and each y is either a phosphodiester nucleoside bond or a phosphorothioate nucleoside bond, provided that at least one y is a phosphodiester nucleotide bond.

[0447] Embodiment 424. The antisense oligonucleotide is MsMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMo(Ds) 0-1(DsDs) (3-5) MoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM, and MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM having a chemical motif selected from among In the formula, each M is, independently, a modified nucleoside, each D is a deoxynucleoside, each o is a phosphodiester nucleoside internucleoside linkage, and each s is a phosphorothioate nucleoside internucleoside linkage, the conjugate antisense compound of any of Embodiments 229 to 422.

[0448] Embodiment 425. The conjugate antisense compound of Embodiment 423 or 424, wherein each M is independently selected from among 2'-MOE nucleosides and bicyclic nucleosides.

[0449] Embodiment 426. The conjugate antisense compound of Embodiment 425, wherein each M is independently selected from among 2'-MOE nucleosides, cEt nucleosides, and LNA nucleosides.

[0450] Embodiment 427. The conjugate antisense compound of Embodiment 425 or 426, wherein each M is a 2'-MOE nucleoside.

[0451] Embodiment 428. A conjugated antisense compound of Embodiment 425 or 426, wherein each M is a cEt nucleoside.

[0452] Embodiment 429. A combination of Embodiment 425 or 426, where each M is an LNA nucleoside. Antisense compound.

[0453] Embodiment 430. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least eight nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0454] Embodiment 431. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 10 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0455] Embodiment 432. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 12 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0456] Embodiment 433. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 14 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0457] Embodiment 434. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 16 nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0458] Embodiment 435. A conjugated antisense compound according to any of Embodiments 229 to 429, wherein the antisense oligonucleotide has a nucleic acid base sequence comprising at least 18 nucleic acid base moieties complementary to the isolength portion of the target nucleic acid.

[0459] Embodiment 436. A conjugated antisense compound according to any of Embodiments 229 to 435, wherein the antisense oligonucleotide is at least 90% complementary to the target nucleic acid.

[0460] Embodiment 437. A conjugated antisense compound according to any of Embodiments 229 to 435, wherein the antisense oligonucleotide is at least 95% complementary to the target nucleic acid.

[0461] Embodiment 438. A conjugated antisense compound according to any of Embodiments 229 to 435, wherein the antisense oligonucleotide is 100% complementary to the target nucleic acid.

[0462] Embodiment 439. A conjugated antisense compound according to any of Embodiments 430 to 438, wherein the target nucleic acid is premRNA.

[0463] Embodiment 440. A conjugated antisense compound according to any of Embodiments 430 to 438, wherein the target nucleic acid is mRNA.

[0464] Embodiment 441. A conjugated antisense compound according to any of Embodiments 430 to 440, wherein the target nucleic acid is expressed in the liver.

[0465] Embodiment 442. The conjugated antisense compound of Embodiment 441, wherein the target nucleic acid is expressed in hepatocytes.

[0466] Embodiment 443. The target nucleic acid is androgen receptor, apolipoprotein (a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, tan A conjugated antisense compound of Embodiment 441 or 442 encoding a protein selected from protein tyrosine phosphatase 1B, STAT3, and transthyretin.

[0467] Embodiment 444. The conjugated antisense compounds of Embodiments 430-440, wherein the target nucleic acid is a viral nucleic acid.

[0468] Embodiment 445. The conjugated antisense compound of Embodiment 444, wherein the viral nucleic acid is expressed in the liver.

[0469] Embodiment 446. The conjugated antisense compound of Embodiment 445, wherein the target nucleic acid is hepatitis B virus nucleic acid.

[0470] Embodiment 447. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, or 24.

[0471] Embodiment 448. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises one nucleic acid base sequence from SEQ ID NOs: 25, 26, 27, 28, 29, or 30.

[0472] Embodiment 449. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 31.

[0473] Embodiment 450. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 32.

[0474] Embodiment 451. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 33.

[0475] Embodiment 452. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 34.

[0476] Embodiment 453. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs: 35, 36, 37, 38, 39, 40, 41, 42, or 43.

[0477] Embodiment 454. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of SEQ ID NOs: 44, 45, 46, 47, or 48.

[0478] Embodiment 455. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide contains one of the nucleic acid base sequences among SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[0479] Embodiment 456. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 60, 61, 62, 63, 64, 65, 66, or 67.

[0480] Embodiment 457. Any of Embodiments 229 to 443, wherein the antisense oligonucleotide contains one of the nucleic acid base sequences of SEQ ID NOs. 69, 70, 71, or 72. Those conjugated antisense compounds.

[0481] Embodiment 458. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 73.

[0482] Embodiment 459. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs: 74, 75, 76, 77, 78, 79, 80, or 81.

[0483] Embodiment 460. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide comprises the nucleic acid base sequence of Sequence ID No. 68.

[0484] Embodiment 461. A conjugated antisense compound according to any of Embodiments 229 to 443, wherein the antisense oligonucleotide contains any nucleic acid base sequence from SEQ ID NOs. 82 to 103.

[0485] Embodiment 462. A method for reducing the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with a conjugated antisense compound of any of Embodiments 229 to 461.

[0486] Embodiment 463. The method of Embodiment 462, wherein the cells are liver cells.

[0487] Embodiment 464. The method of Embodiment 462, wherein the cells are hepatocytes.

[0488] Embodiment 465. Any of the methods of Embodiments 462 to 464, wherein the cells are present outside the body.

[0489] Embodiment 466. Any method according to Embodiments 462 to 464, wherein the cells are present within an animal.

[0490] Embodiment 467. The method of Embodiment 466, wherein the animal is a mouse.

[0491] Embodiment 468. The method of Embodiment 466, wherein the animal is a human.

[0492] Embodiment 469. A pharmaceutical composition comprising a conjugated antisense compound according to any one of Embodiments 229 to 469 and a pharmaceutically acceptable carrier or diluent.

[0493] Embodiment 470. The pharmaceutical composition of Embodiment 469, wherein the pharmaceutically acceptable carrier or diluent is selected from sterile water and sterile physiological saline.

[0494] Embodiment 471. A method for treating a disease or condition in an animal, comprising administering a pharmaceutical composition of Embodiment 469 or 470 to the animal, thereby treating the disease or condition in the animal.

[0495] Embodiment 472. The method of Embodiment 471, wherein the animal is a mouse.

[0496] Embodiment 473. The method of Embodiment 471, wherein the animal is a human.

[0497] Embodiment 474. Any method of Embodiments 471 to 473, wherein the disease or condition is a liver disease or condition.

[0498] Embodiment 475. Any of the methods in Embodiments 471 to 474, wherein the administration is by parenteral administration.

[0499] Embodiment 476. The method of Embodiment 475, wherein the administration is by subcutaneous injection.

[0500] Embodiment 477. The method of Embodiment 475, wherein the administration is by intravenous infusion.

[0501] Embodiment 478. The method of Embodiment 475, wherein the administration is by intramuscular injection.

[0502] Embodiment 479. Any method according to Embodiments 471 to 478, wherein the conjugated antisense compound is provided in a dose of 1 to 10 mg / kg.

[0503] Embodiment 480. Any method of Embodiments 471 to 478, wherein the conjugated antisense compound is provided in a dose of less than 1 mg / kg.

[0504] Embodiment 481. Any method of Embodiments 471 to 480, wherein the conjugated antisense compound is provided in a dose greater than 10 mg / kg.

[0505] Embodiment 482. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided for a drug administration period of at least two months.

[0506] Embodiment 483. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided for a period of at least four months.

[0507] Embodiment 484. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided for a period of at least 6 months.

[0508] Embodiment 485. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once a week.

[0509] Embodiment 486. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once every two weeks.

[0510] Embodiment 487. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided at a dosage frequency of approximately once every three weeks.

[0511] Embodiment 488. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided in a dose frequency of once every four weeks.

[0512] Embodiment 489. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided in a dose frequency of once every five weeks.

[0513] Embodiment 490. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided at a dosing frequency of once every six weeks.

[0514] Embodiment 491. Any method of Embodiments 471 to 481, wherein the conjugated antisense compound is provided at a dosage frequency of once every seven weeks.

[0515] Embodiment 492. The conjugated antisense compound is provided in a dosing frequency of once every 8 weeks. The method described in any of embodiments 471 to 481.

[0516] Embodiment 493. A conjugated compound comprising at least one phosphorus-binding group or neutral-binding group and one or more ligands.

[0517] Embodiment 494. The conjugated compound of Embodiment 493, comprising two or more ligands.

[0518] Embodiment 495. The conjugated compound of Embodiment 493, comprising three ligands.

[0519] Embodiment 496. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mann Pyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O- [(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl2,3,4-tri-O-acetyl-1- A conjugated compound according to any of embodiments 493 to 495, selected from thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0520] Embodiment 497. A conjugated compound of any of Embodiments 493 to 495, wherein the ligand is N-acetylgalactoseamine.

[0521] Embodiment 498. A conjugated compound according to any of Embodiments 493 to 497, wherein the conjugated group comprises a structure selected from the following. [ka] [ka]

[0522] Embodiment 499. The conjugated compound has a tether having a structure selected from the following: [ka] In the formula, L is either a phosphorus-binding group or a neutral-binding group. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. A conjugated compound of any of embodiments 493 to 498, wherein each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether.

[0523] Embodiment 500. The tether has a structure selected from the following: [ka] In the formula, Z2 is either H or CH3. The conjugated compound of Embodiment 499, wherein each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether.

[0524] Embodiment 501. A conjugated compound according to any of Embodiments 493 to 500, wherein the conjugated compound is covalently bonded to an oligonucleotide.

[0525] Embodiment 502. An oligomeric compound comprising at least one conjugated oligonucleotide group, wherein the at least one conjugated group is a conjugated compound of any of Embodiments 493 to 500.

[0526] Embodiment 503. A compound having formula (I), [Chemical formula] In the formula, Bx is a heterocyclic base moiety, T1 is a hydroxyl group, hydrogen, a hydroxyl protecting group, a phosphorus moiety, or a reactive phosphorus group, a compound.

[0527] Embodiment 504. A compound having formula (II), [Chemical formula] In the formula, Bx is a heterocyclic base moiety, T1 is a hydroxyl group, hydrogen, a hydroxyl protecting group, a phosphorus moiety, or a reactive phosphorus group, a compound.

[0528] Embodiment 505. The phosphorus moiety has the following formula, [Chemical formula] In the formula, n is 0 or 1, R a and R c are each independently OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino, or substituted amino, R b is O or S, A compound according to any of Embodiment 503 or 504.

[0529] Embodiment 506. An oligonucleotide and an oligomeric compound comprising at least one conjugate group, wherein the at least one conjugate group is a conjugate compound of formula (III), [Chemical formula] In the formula, Bx is a heterocyclic base moiety, An oligomeric compound in which T2 is an internucleoside binding group that is bound to a nucleoside, nucleotide, oligonucleoside, oligonucleotide, monomeric subunit, or oligomeric compound.

[0530] Embodiment 507. An oligomeric compound comprising an oligonucleotide and at least one conjugated group, wherein the at least one conjugated group is a conjugated compound of formula (IV), [ka] During the ceremony, Bx is the heterocyclic base portion, An oligomeric compound in which T2 is an internucleoside binding group that is bound to a nucleoside, nucleotide, oligonucleoside, oligonucleotide, monomeric subunit, or oligomeric compound.

[0531] Embodiment 508. A compound or oligomer compound of any of Embodiments 503 to 507, wherein the heterocyclic base portion is a pyrimidine, a substituted pyrimidine, a purine, or a substituted purine.

[0532] Embodiment 509. A compound or oligomer compound of any of Embodiments 503 to 507, wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0533] Embodiment 510. A compound or oligomer compound of any of Embodiments 503 to 507, wherein Bx is adenine.

[0534] Embodiment 511. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0535] Embodiment 512. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, n1 is 0 or 1, q is an integer between 1 and 5. Conjugated antisense compounds.

[0536] Embodiment 513. The conjugate linker has a structure selected from the following: [ka] In the formula, each L is independently either a phosphorus bond group or a neutral bond group. Each n is independently between 1 and 20. A conjugated antisense compound of Embodiment 511 or 512.

[0537] Embodiment 514. The conjugated antisense compound of Embodiment 511 or 512, wherein the conjugated linker has a structure selected from the following. [ka]

[0538] Embodiment 515. The conjugated antisense compound of Embodiment 511 or 512, wherein the conjugated linker has the following structure. [ka]

[0539] Embodiment 516. The conjugated antisense compound of Embodiment 511 or 512, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0540] Embodiment 517. The conjugated antisense compound of Embodiment 511 or 512, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0541] Embodiment 518. The conjugated antisense compound of Embodiment 511 or 512, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0542] Embodiment 519. A conjugated antisense compound according to either Embodiment 511 or 518, wherein the conjugated linker contains pyrrolidine.

[0543] Embodiment 520. A conjugated antisense compound of either Embodiment 511 or 519, wherein the conjugated linker does not contain pyrrolidine.

[0544] Embodiment 521. A conjugated antisense compound according to either Embodiment 511 or 520, wherein the conjugated linker comprises PEG.

[0545] Embodiment 522. A conjugated antisense compound according to either Embodiment 511 or 521, wherein the conjugated linker comprises an amide.

[0546] Embodiment 523. A conjugated antisense compound according to either Embodiment 511 or 522, wherein the conjugated linker does not contain an amide.

[0547] Embodiment 524. Embodiment 511 or 523, wherein the conjugated linker contains polyamide. One of the following conjugated antisense compounds.

[0548] Embodiment 525. A conjugated antisense compound according to either Embodiment 511 or 524, wherein the conjugated linker contains an amine.

[0549] Embodiment 526. A conjugated antisense compound according to either Embodiment 511 or 525, wherein the conjugated linker contains one or more disulfide bonds.

[0550] Embodiment 527. A conjugated antisense compound according to either Embodiment 511 or 526, wherein the conjugated linker includes a protein-binding moiety.

[0551] Embodiment 528. The conjugated antisense compound of Embodiment 527, wherein the protein-binding portion contains a lipid.

[0552] Embodiment 529. The protein binding portion is cholesterol, cholic acid, adamantane acetate, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine), vitamin A conjugated antisense compound of Embodiment 528, selected from among ions (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosome lysants, steroids (e.g., ubaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friederin, epifriederanol-derived lithocholic acid), or cationic lipids.

[0553] Embodiment 530. A conjugated antisense compound according to any of Embodiments 527 to 529, wherein the protein-binding portion is a C16-C22 long-chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0554] Embodiment 531. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20, and p is between 1 and 6. A conjugated antisense compound according to either embodiment 511 or 512.

[0555] Embodiment 532. The conjugate linker has a structure selected from the following: [ka] A conjugated antisense compound of either Embodiment 511 or 512, wherein each n is independently 1 to 20.

[0556] Embodiment 533. A conjugated antisense compound according to either Embodiment 511 or 512, wherein the conjugated linker has a structure selected from the following. [ka]

[0557] Embodiment 534. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to either embodiment 511 or 512.

[0558] Embodiment 535. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0559] Embodiment 536. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, D is the branching base, Each E is a tether, Each F is an ligand, A conjugated antisense compound where q is an integer between 1 and 5.

[0560] Embodiment 537. The branching base has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. Conjugated antisense compounds of embodiments 511 to 536.

[0561] Embodiment 538. The branching base has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. Conjugated antisense compounds of embodiments 511 to 536.

[0562] Embodiment 539. The conjugated antisense compounds of Embodiments 511 to 536, wherein the branched group has the following structure. [ka]

[0563] Embodiment 540. The conjugated antisense compounds of Embodiments 511 to 536, wherein the branched group has the following structure. [ka]

[0564] Embodiment 541. A conjugated antisense compound of any of Embodiments 511 to 536, wherein the branched group contains an ether.

[0565] Embodiment 542. The branching base has the following structure: [ka] Each n is independently between 1 and 20. m is between 2 and 6. Conjugated antisense compounds of embodiments 511 to 536.

[0566] Embodiment 543. The conjugated antisense compounds of Embodiments 511 to 536, wherein the branched group has the following structure. [ka]

[0567] Embodiment 544. The conjugated antisense compounds of Embodiments 511 to 536, wherein the branched group has the following structure. [ka]

[0568] Embodiment 545. The branching base is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. In the formula, each n is an integer between 1 and 20. A conjugated antisense compound according to any of embodiments 511 to 536.

[0569] Embodiment 546. The branching base is [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound of any of embodiments 511 to 536, including the following:

[0570] Embodiment 547. Each tether is selected from the following: [ka] In the formula, L is selected from phosphorus-binding groups and neutral-binding groups. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. Conjugated antisense compounds of embodiments 511 to 546.

[0571] Embodiment 548. Each tether is selected from the following: [ka] In the formula, Z2 is either H or CH3. Each m2 is independently between 0 and 20, and at least one m2 is greater than 0 for each tether. Conjugated antisense compounds according to claims 511 to 546.

[0572] Embodiment 549. A conjugated antisense compound of any of Embodiments 511 to 546, wherein at least one tether comprises PEG.

[0573] Embodiment 550. A conjugated antisense compound of any of Embodiments 511 to 546, wherein at least one tether comprises an amide.

[0574] Embodiment 551. A conjugated antisense compound of any of Embodiments 511 to 546, wherein at least one tether comprises a polyamide.

[0575] Embodiment 552. A conjugated antisense compound of any of Embodiments 511 to 546, wherein at least one tether contains an amine.

[0576] Embodiment 553. A conjugated antisense compound of any of Embodiments 511 to 546, wherein at least two tethers are different from each other.

[0577] Embodiment 554. A conjugated antisense compound according to any of Embodiments 511 to 546, wherein all of the tethers are identical to each other.

[0578] Embodiment 555. Each tether is selected from the following: [ka] Each n is independently between 1 and 20. Each p is between 1 and approximately 6. A conjugated antisense compound according to any of embodiments 511 to 546.

[0579] Embodiment 556. Each tether is a conjugated antisense compound from any of Embodiments 511 to 546, selected from the following: [ka]

[0580] Embodiment 557. Each tether has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 511 to 546.

[0581] Embodiment 558. A conjugated antisense compound of any of Embodiments 511 to 546, wherein each tether has the following structure. [ka]

[0582] Embodiment 559. A conjugated antisense compound according to any of Embodiments 493-502 or 511-558, wherein the cell targeting portion has the following structure. [ka]

[0583] Embodiment 560. A conjugated antisense compound according to any of Embodiments 493-502 or 511-558, wherein the cell targeting portion has the following structure. [ka]

[0584] Embodiment 561. A conjugated antisense compound according to any of Embodiments 493-502 or 511-558, wherein the cell targeting moiety comprises at least one ligand.

[0585] Embodiment 562. A conjugated antisense compound of Embodiments 493-502 or 511-558, wherein the cell targeting portion contains one ligand.

[0586] Embodiment 563. A conjugated antisense compound of Embodiments 493-502 or 511-558, wherein the target portion comprises two ligands.

[0587] Embodiment 564. A conjugated antisense compound of Embodiments 493-502 or 511-558, wherein the target portion comprises three ligands.

[0588] Embodiment 565. A conjugated antisense compound according to any of Embodiments 561 to 564, wherein each ligand is covalently bonded to each tether.

[0589] Embodiment 566. A conjugated antisense compound of any of Embodiments 561 to 564, wherein at least one ligand is N-acetylgalactosamine (GalNAc).

[0590] Embodiment 567. A conjugated antisense compound according to any of Embodiments 561 to 564, wherein each ligand is N-acetylgalactosamine (GalNAc).

[0591] Embodiment 568. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glu Copiranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamine A conjugated antisense compound of any of embodiments 561 to 564, selected from no-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranose, 4-thio-β-D-galactopyranoose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0592] Embodiment 569. A conjugated antisense compound according to any of Embodiments 561 to 564, wherein the ligand is galactose.

[0593] Embodiment 570. A conjugated antisense compound of any of Embodiments 561 to 564, wherein the ligand is mannose-6-phosphate.

[0594] Embodiment 571. Each ligand is selected from the following: [ka] In the formula, each R1 is selected from OH and NHCOOH. A conjugated antisense compound according to any of embodiments 561 to 564.

[0595] Embodiment 572. A conjugated antisense compound of any of Embodiments 561 to 564, wherein each ligand is selected from the following. [ka]

[0596] Embodiment 573. A conjugated antisense compound according to any of Embodiments 561 to 564, wherein each ligand has the following structure. [ka]

[0597] Embodiment 574. A conjugated antisense compound according to any of Embodiments 561 to 564, wherein each ligand has the following structure. [ka]

[0598] Embodiment 575. The cell target portion has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0599] Embodiment 576. A conjugated antisense compound according to any of Embodiments 493-502 or 511-574, wherein the cell targeting portion has the following structure. [ka]

[0600] Embodiment 577. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q is the antisense compound, Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0601] Embodiment 578. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q is the antisense compound, Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0602] Embodiment 579. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q is the antisense compound, Z is H or a bonded solid support. A conjugated antisense compound according to any of embodiments 493-502 or 511-574, wherein Bx is a heterocyclic base moiety.

[0603] Embodiment 580. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q is the antisense compound, Z is H or a bonded solid support. Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0604] Embodiment 581. The conjugated group has the following structure: [ka] In the formula, Q is the antisense compound. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0605] Embodiment 582. The conjugated group has the following structure: [ka] In the formula, Q is the antisense compound. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0606] Embodiment 583. The conjugated group has the following structure: [ka] In the formula, Q is the antisense compound, Z is H or a bonded solid support. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0607] Embodiment 584. The conjugated group has the following structure: [ka] In the formula, Q is the antisense compound, Z is H or a bonded solid support. A conjugated antisense compound according to any of embodiments 493-502 or 511-574.

[0608] Embodiment 585. A conjugated oligonucleotide comprising an oligonucleotide and a conjugated group, wherein the conjugated group is any conjugated group from any of Embodiments 493 to 584.

[0609] Embodiment 586. The conjugated oligonucleotide of Embodiment 585, wherein the oligonucleotide comprises at least one modified nucleoside.

[0610] Embodiment 587. The conjugated oligonucleotide of Embodiment 586, wherein the at least one modified nucleoside comprises a modified base.

[0611] Embodiment 588. A conjugated oligonucleotide of Embodiment 586 or 587, wherein the at least one modified nucleoside comprises a sugar substitute.

[0612] Embodiment 589. The conjugated form of Embodiment 588, wherein the sugar substitute is tetrahydropyran. Ligonucleotide.

[0613] Embodiment 590. A conjugated oligonucleotide according to any of Embodiments 589, wherein the tetrahydropyran is F-HNA.

[0614] Embodiment 591. A conjugated oligonucleotide of any of Embodiments 586 to 590, wherein the remainder of the oligonucleotide comprises at least one nucleoside containing a modified sugar.

[0615] Embodiment 592. The conjugated oligonucleotide of Embodiment 591, wherein the at least one modified nucleoside containing a modified sugar is selected from bicyclic nucleosides and 2'-modified nucleosides.

[0616] Embodiment 593. The conjugated oligonucleotide of Embodiment 586, wherein at least one modified nucleoside is a bicyclic nucleoside.

[0617] Embodiment 594. The conjugated oligonucleotide of Embodiment 593, wherein the bicyclic nucleoside is a (4'-CH2-O-2')BNA nucleoside.

[0618] Embodiment 595. The conjugated oligonucleotide of Embodiment 593, wherein the bicyclic nucleoside is (4'-(CH2)2-O-2')BNA nucleoside.

[0619] Embodiment 596. The conjugated oligonucleotide of Embodiment 593, wherein the bicyclic nucleoside is (4'-C(CH3)HO-2')BNA nucleoside.

[0620] Embodiment 597. The conjugated oligonucleotide of Embodiment 586, wherein at least one modified nucleoside is a 2'-modified nucleoside.

[0621] Embodiment 598. The conjugated oligonucleotide of Embodiment 597, wherein the at least one 2'-modified nucleoside is selected from a 2'-F nucleoside, a 2'-OCH3 nucleoside, and a 2'-O(CH2)2OCH3 nucleoside.

[0622] Embodiment 599. The conjugated oligonucleotide of Embodiment 598, wherein at least one 2'-modified nucleoside is a 2'-F nucleoside.

[0623] Embodiment 600. The conjugated oligonucleotide of Embodiment 598, wherein the at least one 2'-modified nucleoside is a 2'-OCH3 nucleoside.

[0624] Embodiment 601. The conjugated oligonucleotide of Embodiment 598, wherein the at least one 2'-modified nucleoside is a 2'-O(CH2)2OCH3 nucleoside.

[0625] Embodiment 602. A conjugated oligonucleotide according to any one of Embodiments 585 to 601, wherein the oligonucleotide comprises at least one unmodified nucleoside.

[0626] Embodiment 603. The conjugated oligonucleotide of Embodiment 602, wherein the unmodified nucleoside is a ribonucleoside.

[0627] Embodiment 604. The conjugated oligonucleotide of Embodiment 602, wherein the unmodified nucleoside is a deoxyribonucleoside.

[0628] Embodiment 605. The oligonucleotide comprises at least two modified nucleosides. or a conjugated oligonucleotide according to any of embodiments 585 to 604.

[0629] Embodiment 606. The conjugated oligonucleotide of Embodiment 605, wherein at least two modified nucleosides contain the same modification.

[0630] Embodiment 607. The conjugated oligonucleotide of Embodiment 605, wherein the at least two modified nucleosides include different modifications.

[0631] Embodiment 608. A conjugated oligonucleotide of any of Embodiments 605 to 607, wherein at least one of the at least two modified nucleosides comprises a sugar substitute.

[0632] Embodiment 609. A conjugated oligonucleotide according to any one of Embodiments 605 to 608, wherein at least one of the at least two modified nucleosides includes a 2'-modification.

[0633] Embodiment 610. The conjugated oligonucleotide of Embodiment 609, wherein each of the at least two modified nucleosides is independently selected from 2'-F nucleosides, 2'-OCH3 nucleosides, and 2'-O(CH2)2OCH3 nucleosides.

[0634] Embodiment 611. The conjugated oligonucleotide of Embodiment 610, wherein each of the at least two modified nucleosides is a 2'-F nucleoside.

[0635] Embodiment 612. The conjugated oligonucleotide of Embodiment 610, wherein each of the at least two modified nucleosides is a 2'-OCH3 nucleoside.

[0636] Embodiment 613. The conjugated oligonucleotide of Embodiment 610, wherein each of the at least two modified nucleosides is a 2'-O(CH2)2OCH3 nucleoside.

[0637] Embodiment 614. A conjugated oligonucleotide of any of Embodiments 586 to 613, wherein essentially all nucleosides of the oligonucleotide are modified nucleosides.

[0638] Embodiment 615. A conjugated oligonucleotide according to any of Embodiments 586-601 or 606-613, wherein all nucleosides of the oligonucleotide are modified nucleosides.

[0639] Embodiment 616. A conjugated oligonucleotide according to any of Embodiments 586 to 615, wherein the oligonucleotide is single-stranded.

[0640] Embodiment 617. A conjugated oligonucleotide according to any of Embodiments 586 to 615, wherein the oligonucleotide is double-stranded.

[0641] Embodiment 618. A conjugated oligonucleotide according to any of Embodiments 586 to 615, wherein the oligonucleotide is an antisense compound.

[0642] Embodiment 619. A conjugated oligonucleotide according to any of Embodiments 586 to 615, wherein the oligonucleotide is a RISC-based oligonucleotide.

[0643] Embodiment 620. A conjugated oligonucleotide according to any of Embodiments 586 to 615, wherein the oligonucleotide activates the RISC pathway.

[0644] Embodiment 621. The oligonucleotide is an RNase H-based antisense compound A conjugated oligonucleotide of any of embodiments 586 to 615, which is a substance.

[0645] Embodiment 622. A conjugated oligonucleotide compound according to any of Embodiments 586 to 621, wherein the conjugated group is bonded to the 5' terminal nucleoside of the antisense oligonucleotide.

[0646] Embodiment 623. A conjugated oligonucleotide compound according to any of Embodiments 586 to 621, wherein the conjugated group is bonded to the 3' terminal nucleoside of the antisense oligonucleotide.

[0647] Embodiment 624. A conjugated oligonucleotide compound according to any of Embodiments 586 to 621, wherein the conjugated group is bonded to the internal nucleoside of the antisense oligonucleotide.

[0648] Embodiment 625. A conjugated oligonucleotide compound according to any of Embodiments 586 to 624, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into hepatocytes compared with a non-conjugated oligonucleotide compound.

[0649] Embodiment 626. A conjugated oligonucleotide compound according to any of Embodiments 586 to 624, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into liver cells compared to a non-conjugated oligonucleotide compound.

[0650] Embodiment 627. A conjugated oligonucleotide compound according to any of Embodiments 586 to 626, wherein the conjugated group increases the accumulation of the conjugated oligonucleotide compound in the liver compared to a non-conjugated oligonucleotide compound.

[0651] Embodiment 628. A conjugated oligonucleotide compound according to any of Embodiments 586 to 627, wherein the conjugated group reduces the accumulation of the conjugated oligonucleotide compound in the kidney compared to a non-conjugated oligonucleotide compound.

[0652] Embodiment 629. The conjugated oligonucleotide is A 5' region consisting of 2 to 8 linked 5' region nucleosides, wherein at least 2 5' region nucleosides are modified nucleosides, and the 5' region nucleoside closest to the 3' side is a modified nucleoside, and A 3' region consisting of 2 to 8 linked 3' region nucleosides, wherein at least 2 of the 3' region nucleosides are modified nucleosides, and the 3' region nucleoside closest to the 5' side is a modified nucleoside, and A central region between the 5' region and the 3' region, each consisting of 5 to 10 linked central region nucleosides, wherein each is independently selected from modified nucleosides and unmodified deoxynucleosides, the central region nucleoside furthest to the 5' side is an unmodified deoxynucleoside, and the central region nucleoside furthest to the 3' side is an unmodified deoxynucleoside. Conjugated oligonucleotide compounds of embodiments 586 to 628 having a sugar motif including the sugar motif.

[0653] Embodiment 630. The conjugated oligonucleotide compound of Embodiment 629, wherein the 5' region consists of two linked 5' region nucleosides.

[0654] Embodiment 631. The conjugated oligonucleotide compound of Embodiment 629, wherein the 5' region consists of three linked 5' region nucleosides.

[0655] Embodiment 632. The conjugated oligonucleotide compound of Embodiment 629, wherein the 5' region consists of four linked 5' region nucleosides.

[0656] Embodiment 633. The conjugated oligonucleotide compound of Embodiment 629, wherein the 5' region consists of five linked 5' region nucleosides.

[0657] Embodiment 634. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the 3' region consists of two linked 3' region nucleosides.

[0658] Embodiment 635. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the 3' region consists of three linked 3' region nucleosides.

[0659] Embodiment 636. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the 3' region consists of four linked 3' region nucleosides.

[0660] Embodiment 637. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the 3' region consists of a 3' region nucleoside in which five 3' regions are linked together.

[0661] Embodiment 638. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of five linked central region nucleosides.

[0662] Embodiment 639. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of six linked central region nucleosides.

[0663] Embodiment 640. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of seven linked central region nucleosides.

[0664] Embodiment 641. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of eight linked central region nucleosides.

[0665] Embodiment 642. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of nine linked central region nucleosides.

[0666] Embodiment 643. A conjugated oligonucleotide compound according to any of Embodiments 629 to 633, wherein the central region consists of 10 linked central region nucleosides.

[0667] Embodiment 644. A conjugated oligonucleotide compound according to any of Embodiments 629 to 644, wherein the conjugated oligonucleotide consists of 14 to 26 linked nucleosides.

[0668] Embodiment 645. A conjugated oligonucleotide compound according to any of Embodiments 629 to 644, wherein the conjugated oligonucleotide consists of 15 to 25 linked nucleosides.

[0669] Embodiment 646. A conjugated oligonucleotide compound according to any of Embodiments 629 to 644, wherein the conjugated oligonucleotide consists of 16 to 20 linked nucleosides.

[0670] Embodiment 647. A conjugated oligonucleotide compound of any of Embodiments 629 to 644, wherein each modified nucleoside independently comprises a 2'-substituted sugar moiety or a bicyclic sugar moiety.

[0671] Embodiment 648. The conjugated oligonucleotide compound of Embodiment 647, wherein the at least one modified nucleoside comprises a 2'-substituted sugar moiety.

[0672] Embodiment 649. Each modified nucleoside containing the 2'-substituted sugar moiety contains a 2' substituent independently selected from halogen, optionally substituted allyl, optionally substituted amino, azide, optionally substituted SH, CN, OCN, CF3, OCF3, O, S, or N(Rm)-alkyl; O, S, or N(Rm)-alkenyl; O, S, or N(Rm)-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted O-aralkyl, O(CH2)2SCH3, O-(CH2)2-ON(Rm)(Rn), or O-CH2-C(=O)-N(Rm)(Rn), wherein each Rm and Rn independently comprises H, an amino protecting group, or substituted or unsubstituted C1-C 10 It is alkyl, The conjugated oligonucleotide compound of Embodiment 648, wherein each optionally substituted group is optionally substituted with a substituent independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl, and alkynyl.

[0673] Embodiment 650. Each 2' substituent is halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-SCH3, O(CH2)2-OCF3, O(CH2)3-N(R1)(R2), O(CH2)2-ON(R1)(R2), O(CH2)2-O(CH2)2-N( A conjugated oligonucleotide compound of Embodiment 648, independently selected from R1)(R2), OCH2C(=O)-N(R1)(R2), OCH2C(=O)-N(R3)-(CH2)2-N(R1)(R2), and O(CH2)2-N(R3)-C(=NR4)[N(R1)(R2)], wherein R1, R2, R3, and R4 are each independently H or C1-C6 alkyl.

[0674] Embodiment 651. A conjugated oligonucleotide compound of Embodiment 648, wherein each 2' substituent is independently selected from halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3(MOE), O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

[0675] Embodiment 652. The conjugated oligonucleotide compound of Embodiment 648, wherein the at least one 2'-modified nucleoside contains a 2'-MOE sugar moiety.

[0676] Embodiment 653. The conjugated oligonucleotide compound of Embodiment 648, wherein the at least one 2'-modified nucleoside contains a 2'-OMe sugar moiety.

[0677] Embodiment 654. The conjugated oligonucleotide compound of Embodiment 648, wherein the at least one 2'-modified nucleoside contains a 2'-F sugar moiety.

[0678] Embodiment 655. A conjugated oligonucleotide compound according to any one of Embodiments 629 to 644, wherein the conjugated oligonucleotide comprises at least one modified nucleoside containing a sugar substitute.

[0679] Embodiment 656. The conjugated oligonucleotide compound of Embodiment 655, wherein the modified nucleoside contains an F-HNA sugar moiety.

[0680] Embodiment 657. The conjugated form of Embodiment 655, wherein the modified nucleoside includes an HNA sugar moiety. Oligonucleotide compounds.

[0681] Embodiment 658. A conjugated oligonucleotide compound according to any one of Embodiments 629 to 657, wherein the conjugated oligonucleotide comprises at least one modified nucleoside containing a bicyclic sugar moiety.

[0682] Embodiment 659. The conjugated oligonucleotide compound of Embodiment 658, wherein the bicyclic sugar portion is a cEt sugar portion.

[0683] Embodiment 660. A conjugated oligonucleotide compound of Embodiment 658, wherein the bicyclic sugar portion is an LNA sugar portion.

[0684] Embodiment 661. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 660, wherein the conjugated oligonucleotide contains at least one modified internucleoside bond.

[0685] Embodiment 662. The conjugated oligonucleotide compound of Embodiment 661, wherein each nucleoside bond in the conjugated oligonucleotide is a modified nucleoside bond.

[0686] Embodiment 663. The conjugated oligonucleotide compound of Embodiment 661, wherein the conjugated oligonucleotide comprises at least one modified bond and at least one unmodified phosphodiester nucleoside bond.

[0687] Embodiment 664. A conjugated oligonucleotide compound of any of Embodiments 661 to 663, wherein at least one modified nucleoside bond is a phosphosphorothioate nucleoside bond.

[0688] Embodiment 665. A conjugated oligonucleotide compound according to any of Embodiments 661 to 663, wherein each modified nucleoside bond is a phosphorothioate nucleoside bond.

[0689] Embodiment 666. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide comprises at least two phosphodiester nucleoside interbonding groups.

[0690] Embodiment 667. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least three phosphodiester nucleoside interbonding groups.

[0691] Embodiment 668. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide comprises at least four phosphodiester nucleoside interbonding groups.

[0692] Embodiment 669. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least five phosphodiester nucleoside interbonding groups.

[0693] Embodiment 670. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least six phosphodiester nucleoside interbonding bonds.

[0694] Embodiment 671. The conjugated oligonucleotide comprises at least 7 phosphodiesternes A conjugated oligonucleotide compound according to either embodiment 661 or 662, comprising a cleosidic bond.

[0695] Embodiment 672. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least eight phosphodiester nucleoside interbondings.

[0696] Embodiment 673. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least nine phosphodiester nucleoside interbonding bonds.

[0697] Embodiment 674. A conjugated oligonucleotide compound according to either Embodiment 661 or 662, wherein the conjugated oligonucleotide contains at least 10 phosphodiester nucleoside interbonding groups.

[0698] Embodiment 675. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 16 phosphorothioate nucleoside bonds.

[0699] Embodiment 676. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 15 phosphorothioate nucleoside bonds.

[0700] Embodiment 677. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 14 phosphorothioate nucleoside bonds.

[0701] Embodiment 678. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 13 phosphorothioate nucleoside bonds.

[0702] Embodiment 679. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 12 phosphorothioate nucleoside bonds.

[0703] Embodiment 680. A conjugated oligonucleotide compound according to any one of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 11 phosphorothioate nucleoside bonds.

[0704] Embodiment 681. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than 10 phosphorothioate nucleoside bonds.

[0705] Embodiment 682. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than nine phosphorothioate nucleoside bonds.

[0706] Embodiment 683. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than eight phosphorothioate nucleoside bonds.

[0707] Embodiment 684. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than seven phosphorothioate nucleoside bonds.

[0708] Embodiment 685. A conjugated oligonucleotide compound according to any of Embodiments 661 or 663-674, wherein the conjugated oligonucleotide contains fewer than six phosphorothioate nucleoside bonds.

[0709] Embodiment 686. A conjugated oligonucleotide compound according to any of Embodiments 585 to 685, wherein the internucleoside bonds between each terminal nucleoside of the conjugated oligonucleotide are phosphorothioate nucleoside bonds.

[0710] Embodiment 687. A conjugated oligonucleotide compound according to any of Embodiments 585-662 or 665-686, wherein the internucleoside bonds connecting the two deoxynucleosides of the conjugated oligonucleotide are phosphorothioate internucleoside bonds.

[0711] Embodiment 688. A conjugated oligonucleotide compound according to any of Embodiments 585-662 or 665-687, wherein each non-terminal nucleoside bond connecting the two modified nucleosides of the conjugated oligonucleotide is a phosphodiester nucleoside bond.

[0712] Embodiment 689. A conjugated oligonucleotide compound according to any of Embodiments 585-662 or 665-688, wherein each non-terminal nucleoside bond of the conjugated oligonucleotide, which is the 3' of the modified nucleoside, is a phosphodiester nucleoside bond.

[0713] Embodiment 690. A conjugated oligonucleotide compound according to any of Embodiments 585-662 or 665-689, wherein each nucleoside bond of the conjugated oligonucleotide that is the 3' of the deoxynucleoside is a phosphorothioate nucleoside bond.

[0714] Embodiment 691. The conjugated oligonucleotide is MsMy(Ds) 0-1 (DsDs) (3-5) MsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM, and MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each s is a phosphorothioate nucleoside bond, and each y is either a phosphodiester nucleoside bond or a phosphorothioate nucleoside bond. However, provided that at least one y is a phosphodiester nucleotide bond, A conjugated oligonucleotide compound according to any of embodiments 585-662 or 665-690.

[0715] Embodiment 692. The conjugated oligonucleotide is MsMo(Ds)0-1 (DsDs) (3-5) MoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM, and MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each o is a phosphodiester nucleoside bond, and each s is a phosphorothioate nucleoside bond. A conjugated oligonucleotide compound according to any of embodiments 585-662 or 665-690.

[0716] Embodiment 693. A conjugated oligonucleotide compound of Embodiment 691 or 692, wherein each M is independently selected from 2'-MOE nucleosides and bicyclic nucleosides.

[0717] Embodiment 694. The conjugated oligonucleotide compound of Embodiment 693, wherein each M is independently selected from 2'-MOE nucleoside, cEt nucleoside, and LNA nucleoside.

[0718] Embodiment 695. A conjugated oligonucleotide compound of Embodiment 693 or 694, wherein each M is a 2'-MOE nucleoside.

[0719] Embodiment 696. A conjugated oligonucleotide compound of Embodiment 693 or 694, wherein each M is a cEt nucleoside.

[0720] Embodiment 697. A conjugated oligonucleotide compound of Embodiment 693 or 694, wherein each M is an LNA nucleoside.

[0721] Embodiment 698. A conjugated oligonucleotide compound according to any of Embodiments 585 to 697, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least eight nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0722] Embodiment 699. The conjugated oligonucleotide has a nucleic acid base sequence that includes at least 10 nucleic acid base portions complementary to the isolength portion of the target nucleic acid, as in Embodiments 585 to 697. One of the conjugated oligonucleotide compounds.

[0723] Embodiment 700. A conjugated oligonucleotide compound according to any of Embodiments 585 to 697, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 12 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0724] Embodiment 701. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 697, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 14 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0725] Embodiment 702. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 697, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 16 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0726] Embodiment 703. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 697, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 18 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[0727] Embodiment 704. A conjugated oligonucleotide compound according to any of Embodiments 585 to 697, wherein the conjugated oligonucleotide is at least 90% complementary to the target nucleic acid.

[0728] Embodiment 705. A conjugated oligonucleotide compound according to any of Embodiments 585 to 697, wherein the conjugated oligonucleotide is at least 95% complementary to the target nucleic acid.

[0729] Embodiment 706. A conjugated oligonucleotide compound according to any of Embodiments 585 to 697, wherein the conjugated oligonucleotide is 100% complementary to the target nucleic acid.

[0730] Embodiment 707. A conjugated oligonucleotide compound according to any of Embodiments 698 to 706, wherein the target nucleic acid is premRNA.

[0731] Embodiment 708. A conjugated oligonucleotide compound according to any of Embodiments 698 to 706, wherein the target nucleic acid is mRNA.

[0732] Embodiment 709. A conjugated oligonucleotide compound according to any of Embodiments 698 to 706, wherein the target nucleic acid is a microRNA.

[0733] Embodiment 710. A conjugated oligonucleotide compound according to any of Embodiments 698 to 709, wherein the target nucleic acid is expressed in the liver.

[0734] Embodiment 711. A conjugated oligonucleotide compound according to any of Embodiments 698 to 709, wherein the target nucleic acid is expressed in hepatocytes.

[0735] Embodiment 712. A conjugated oligonucleotide compound according to any of Embodiments 698 to 709, wherein the target nucleic acid encodes a protein selected from androgen receptor, apolipoprotein (a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, protein tyrosine phosphatase 1B, STAT3, and transthyretin.

[0736] Embodiment 713. The embodiment of Embodiments 698 to 709, wherein the target nucleic acid is a viral nucleic acid. One of the conjugated oligonucleotide compounds.

[0737] Embodiment 714. The conjugated oligonucleotide compound of Embodiment 713, wherein the viral nucleic acid is expressed in the liver.

[0738] Embodiment 715. The conjugated oligonucleotide compound of Embodiment 714, wherein the target nucleic acid is hepatitis B virus nucleic acid.

[0739] Embodiment 716. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, or 24.

[0740] Embodiment 717. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 25, 26, 27, 28, 29, or 30.

[0741] Embodiment 718. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 31.

[0742] Embodiment 719. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 32.

[0743] Embodiment 720. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 33.

[0744] Embodiment 721. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 34.

[0745] Embodiment 722. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences of SEQ ID NOs: 35, 36, 37, 38, 39, 40, 41, 42, or 43.

[0746] Embodiment 723. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 44, 45, 46, 47, or 48.

[0747] Embodiment 724. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences among SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[0748] Embodiment 725. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 60, 61, 62, 63, 64, 65, 66, or 67.

[0749] Embodiment 726. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 69, 70, 71, or 72.

[0750] Embodiment 727. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 73.

[0751] Embodiment 728. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs: 74, 75, 76, 77, 78, 79, 80, or 81.

[0752] Embodiment 729. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 68.

[0753] Embodiment 730. A conjugated oligonucleotide compound according to any of Embodiments 585 to 708, wherein the conjugated oligonucleotide contains any nucleic acid base sequence from SEQ ID NOs. 82 to 103.

[0754] Embodiment 731. A conjugated oligonucleotide compound according to any one of Embodiments 585 to 731, wherein the conjugated oligonucleotide is an antisense oligonucleotide.

[0755] Embodiment 732. A method for reducing the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with any of the compounds or conjugated antisense compounds of Embodiments 493 to 731.

[0756] Embodiment 733. The method of Embodiment 732, wherein the cells are liver cells.

[0757] Embodiment 734. The method of Embodiment 732, wherein the cells are hepatocytes.

[0758] Embodiment 735. Any of Embodiments 732 to 734, wherein the cells are present outside the body.

[0759] Embodiment 736. Any of Embodiments 732 to 734, wherein the cells are present within an animal.

[0760] Embodiment 737. The method of Embodiment 736, wherein the animal is a mouse.

[0761] Embodiment 738. The method of Embodiment 736, wherein the animal is a human.

[0762] Embodiment 739. A pharmaceutical composition comprising a compound or conjugated oligonucleotide according to any of Embodiments 493 to 731, and a pharmaceutically acceptable carrier or diluent.

[0763] Embodiment 740. The pharmaceutical composition of Embodiment 739, wherein the pharmaceutically acceptable carrier or diluent is selected from sterile water and sterile physiological saline.

[0764] Embodiment 741. A method for treating a disease or condition in an animal, comprising administering a pharmaceutical composition of Embodiment 739 or 740 to the animal, thereby treating the disease or condition in the animal.

[0765] Embodiment 742. The method of Embodiment 741, wherein the animal is a mouse.

[0766] Embodiment 743. The method of Embodiment 741, wherein the animal is a human.

[0767] Embodiment 744. Any method of Embodiments 741 to 743, wherein the disease or condition is a liver disease or condition.

[0768] Embodiment 745. Any of the methods in Embodiments 741 to 743, wherein the administration is by parenteral administration.

[0769] Embodiment 746. The method of Embodiment 745, wherein the administration is by subcutaneous injection.

[0770] Embodiment 747. The method of Embodiment 745, wherein the administration is by intravenous infusion.

[0771] Embodiment 748. The method of Embodiment 745, wherein the administration is by intramuscular injection.

[0772] Embodiment 749. Any method according to Embodiments 741 to 748, wherein the conjugated oligonucleotide is provided in a dose of 1 to 10 mg / kg.

[0773] Embodiment 750. Any method of Embodiments 741 to 748, wherein the conjugated oligonucleotide is provided in a dose of less than 1 mg / kg.

[0774] Embodiment 751. Any method of Embodiments 741 to 748, wherein the conjugated oligonucleotide is provided in a dose greater than 10 mg / kg.

[0775] Embodiment 752. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided for a drug administration period of at least two months.

[0776] Embodiment 753. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided for a period of at least four months.

[0777] Embodiment 754. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided over a treatment period of at least 6 months.

[0778] Embodiment 755. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once a week.

[0779] Embodiment 756. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once every two weeks.

[0780] Embodiment 757. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once every three weeks.

[0781] Embodiment 758. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided in a dose frequency of once every four weeks.

[0782] Embodiment 759. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every five weeks.

[0783] Embodiment 760. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every six weeks.

[0784] Embodiment 761. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every seven weeks.

[0785] Embodiment 762. Any method of Embodiments 741 to 751, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every 8 weeks.

[0786] Embodiment 763. A conjugated antisense compound comprising an antisense oligonucleotide containing 12 to 30 linked nucleosides, wherein the conjugated group contains at least one cell-targeting moiety.

[0787] Embodiment 764. A method for reducing the activity or amount of apolipoprotein C-III protein in cells, comprising contacting the cells with at least one conjugated antisense compound from any of Embodiments 493 to 731, thereby reducing the activity or amount of the apolipoprotein C-III protein in the cells.

[0788] Embodiment 765. A method for lowering total cholesterol, comprising contacting cells with at least one compound from any of Embodiments 493 to 731, thereby lowering total cholesterol.

[0789] Embodiment 766. A method for reducing triglycerides, comprising contacting cells with at least one compound from any of Embodiments 493 to 731, thereby reducing triglycerides.

[0790] Embodiment 767. A method for reducing LDL, comprising contacting cells with at least one compound from any of Embodiments 493 to 731, thereby reducing LDL.

[0791] Embodiment 768. A method for increasing HDL, comprising contacting cells with at least one compound from any of Embodiments 493 to 731, thereby increasing HDL.

[0792] Embodiment 769. Any of the methods of Embodiments 764 to 768, wherein the cells are present outside the body.

[0793] Embodiment 770. Any method according to Embodiments 764 to 768, wherein the cells are present in an animal.

[0794] Embodiment 771. Any of Embodiments 764 to 768, wherein the animal is a human.

[0795] Embodiment 772. A compound or conjugated oligonucleotide of any of Embodiments 1 to 771, or a prodrug thereof.

[0796] Embodiment 773. A prodrug of an antisense compound comprising the following structure: [ka] A prodrug wherein ASO represents an antisense oligonucleotide of any of embodiments 1 to 771.

[0797] Embodiment 774. A prodrug of an antisense compound comprising the following structure, wherein one or more metabolites of the prodrug have the following structure, [ka] A prodrug wherein ASO represents an antisense oligonucleotide of any of embodiments 1 to 771.

[0798] Embodiment 775. A prodrug of an antisense compound, wherein one or more metabolites of the prodrug contain an antisense oligonucleotide of any of Embodiments 1 to 771.

[0799] Embodiment 776. A prodrug, [ka] Includes, A prodrug wherein ASO represents an antisense oligonucleotide of any of claims 1 to 731.

[0800] Embodiment 777. A method for producing an antisense oligonucleotide according to any of Embodiments 1 to 771.

[0801] Embodiment 778. A method for preparing an antisense oligonucleotide according to any of Embodiments 1 to 771.

[0802] Embodiment 779. A conjugated compound comprising at least one phosphorus-binding group or neutral-binding group and one or more ligands.

[0803] Embodiment 780. A conjugated compound of Embodiment 779 comprising two or more ligands.

[0804] Embodiment 781. A conjugated compound of Embodiment 779, comprising three ligands.

[0805] Embodiment 782. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mann Pyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O- [(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl2,3,4-tri-O-acetyl-1- A conjugated compound according to any of embodiments 779 to 781, selected from thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0806] Embodiment 783. A conjugated compound of any of Embodiments 779 to 781, wherein the ligand is N-acetylgalactoseamine.

[0807] Embodiment 784. A conjugated compound according to any of Embodiments 779 to 783, wherein the conjugated group comprises a structure selected from the following. [ka] [ka]

[0808] Embodiment 785. The conjugated compound has a tether having a structure selected from the following: [ka] In the formula, L is either a phosphorus-binding group or a neutral-binding group. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. A conjugated compound according to any of embodiments 779 to 784.

[0809] Embodiment 786. The tether has a structure selected from the following: [ka] In the formula, Z2 is either H or CH3. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. Conjugated compound of Embodiment 785.

[0810] Embodiment 787. A conjugated compound according to any of Embodiments 779 to 786, wherein the conjugated compound is covalently bonded to an oligonucleotide.

[0811] Embodiment 788. An oligomeric compound comprising an oligonucleotide and at least one conjugated group, wherein at least one conjugated group is a conjugated compound of any of Embodiments 780 to 786.

[0812] Embodiment 789. A compound having formula (V), [ka] In the formula, either T3 or T4 is selected from GalNAc3-1a, GalNAc3-2a, GalNAc3-3a, GalNAc3-4a, GalNAc3-5a, GalNAc3-6a, GalNAc3-7a, GalNAc3-8a, GalNAc3-9a, GalNAc3-10a, or GalNAc3-11a. A compound in which the other of T3 or T4 is selected from hydroxyl, hydroxyl protecting group, nucleoside, oligonucleotide, monomeric subunit, or oligomeric compound, and Bx is a heterocyclic base moiety.

[0813] Embodiment 790. A compound having formula (VIII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0814] Embodiment 791. A compound having formula (IX), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0815] Embodiment 792. A compound having formula (X), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0816] Embodiment 793. A compound having formula (XI), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0817] Embodiment 794. A compound having formula (XII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0818] Embodiment 795. A compound having formula (XIII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0819] Embodiment 796. A compound having formula (XIV), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0820] Embodiment 797. A compound having formula (XV), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[0821] Embodiment 798. A compound having the following formula (I), [ka] During the ceremony, Bx is the heterocyclic base portion, A compound in which T1 is a hydroxyl group, a hydrogen atom, a hydroxyl protecting group, a phosphorus moiety, or a reactive phosphorus group.

[0822] Embodiment 799. A compound having the following formula (II), [ka] During the ceremony, Bx is the heterocyclic base portion, A compound in which T1 is a hydroxyl group, a hydrogen atom, a hydroxyl protecting group, a phosphorus moiety, or a reactive phosphorus group.

[0823] Embodiment 800. The phosphorus portion has the following formula: [ka] During the ceremony, n is 0 or 1, R a and R c Each of these is independently OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino, or substituted amino. R b However, it is either O or S. A compound according to either embodiment 798 or 799.

[0824] Embodiment 801. An oligomeric compound comprising an oligonucleotide and at least one conjugated group, wherein the at least one conjugated group is a conjugated compound of the following formula (III). the law of nature, [ka] During the ceremony, Bx is the heterocyclic base portion, An oligomeric compound in which T2 is an internucleoside binding group that is bound to a nucleoside, nucleotide, oligonucleoside, oligonucleotide, monomeric subunit, or oligomeric compound.

[0825] Embodiment 802. An oligomeric compound comprising an oligonucleotide and at least one conjugated group, wherein the at least one conjugated group is a conjugated compound of the following formula (IV): [ka] Bx is the heterocyclic base portion, An oligomeric compound in which T2 is an internucleoside binding group that is bound to a nucleoside, nucleotide, oligonucleoside, oligonucleotide, monomeric subunit, or oligomeric compound.

[0826] Embodiment 803. A compound or oligomer compound of any of Embodiments 798 to 802, wherein the heterocyclic base portion is a pyrimidine, a substituted pyrimidine, a purine, or a substituted purine.

[0827] Embodiment 804. A compound or oligomer compound of any of Embodiments 798 to 802, wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

[0828] Embodiment 805. A compound or oligomer compound of any of Embodiments 798 to 802, wherein Bx is adenine.

[0829] Embodiment 806. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0830] Embodiment 807. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, n1 is 0 or 1, q is an integer between 1 and 5. Conjugated antisense compounds.

[0831] Embodiment 808. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0832] Embodiment 809. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0833] Embodiment 810. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, C is the conjugate linker, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0834] Embodiment 811. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0835] Embodiment 812. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0836] Embodiment 813. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[0837] Embodiment 814. The conjugate linker has a structure selected from the following: [ka] and In the formula, each L is independently either a phosphorus bond group or a neutral bond group. Each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 810.

[0838] Embodiment 815. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker has a structure selected from the following. [ka]

[0839] Embodiment 816. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker has the following structure. [ka]

[0840] Embodiment 817. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0841] Embodiment 818. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0842] Embodiment 819. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker has one of the structures selected from the following. [ka]

[0843] Embodiment 820. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker contains pyrrolidine.

[0844] Embodiment 821. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker does not contain pyrrolidine.

[0845] Embodiment 822. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker contains PEG.

[0846] Embodiment 823. A conjugated antisense compound of any of Embodiments 806 to 810, wherein the conjugated linker comprises an amide.

[0847] Embodiment 824. The conjugated linker does not contain an amide, as in Embodiments 806-810. Any of the conjugated antisense compounds.

[0848] Embodiment 825. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker comprises a polyamide.

[0849] Embodiment 826. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker contains an amine.

[0850] Embodiment 827. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker contains one or more disulfide bonds.

[0851] Embodiment 828. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker includes a protein-binding moiety.

[0852] Embodiment 829. The conjugated antisense compound of Embodiment 828, wherein the protein-binding portion contains a lipid.

[0853] Embodiment 830. The protein binding portion is cholesterol, cholic acid, adamantane acetate, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethyltrityl, or phenoxazine), vitamin A conjugated antisense compound of Embodiment 829, selected from among (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosome lysants, steroids (e.g., ubaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friederin, epifriederanol-derived lithocholic acid), or cationic lipids.

[0854] Embodiment 831. A conjugated antisense compound according to any of Embodiments 828 to 830, wherein the protein-binding portion is a C16-C22 long-chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0855] Embodiment 832. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20, and p is between 1 and 6. A conjugated antisense compound according to any of embodiments 806 to 810.

[0856] Embodiment 833. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 810.

[0857] Embodiment 834. A conjugated antisense compound according to any of Embodiments 806 to 810, wherein the conjugated linker has a structure selected from the following. [ka]

[0858] Embodiment 835. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 810.

[0859] Embodiment 836. The branching base has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. Conjugated antisense compounds of embodiments 806 to 835.

[0860] Embodiment 837. The branching base has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. Conjugated antisense compounds of embodiments 806 to 835.

[0861] Embodiment 838. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0862] Embodiment 839. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0863] Embodiment 840. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0864] Embodiment 841. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0865] Embodiment 842. A conjugated antisense compound of any of Embodiments 806 to 835, wherein the branched group contains an ether.

[0866] Embodiment 843. The branching base has the following structure: [ka] Each n is independently between 1 and 20. m is between 2 and 6. Conjugated antisense compounds of embodiments 806 to 835.

[0867] Embodiment 844. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0868] Embodiment 845. The conjugated antisense compounds of Embodiments 806 to 835, wherein the branched group has the following structure. [ka]

[0869] Embodiment 846. The branching base is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. In the formula, each n is an integer between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 835.

[0870] Embodiment 847. The branching base is [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound of any of embodiments 806 to 835, including the following:

[0871] Embodiment 848. Each tether is selected from the following: [ka] In the formula, L is selected from phosphorus-binding groups and neutral-binding groups. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. Conjugated antisense compounds of embodiments 806-847.

[0872] Embodiment 849. Each tether is selected from the following: [ka] In the formula, Z2 is either H or CH3. Each m2 is independently between 0 and 20, and at least one m2 is greater than 0 for each tether. Conjugated antisense compounds of embodiments 806-847.

[0873] Embodiment 850. A conjugated antisense compound of any of Embodiments 806 to 847, wherein at least one tether contains PEG.

[0874] Embodiment 851. A conjugated antisense compound of any of Embodiments 806 to 847, wherein at least one tether comprises an amide.

[0875] Embodiment 852. A conjugated antisense compound of any of Embodiments 806 to 847, wherein at least one tether comprises a polyamide.

[0876] Embodiment 853. A conjugated antisense compound of any of Embodiments 806 to 847, wherein at least one tether contains an amine.

[0877] Embodiment 854. A conjugated antisense compound of any of Embodiments 806 to 847, wherein at least two tethers are different from each other.

[0878] Embodiment 855. A conjugated antisense compound according to any of Embodiments 806 to 847, wherein all of the tethers are identical to each other.

[0879] Embodiment 856. Each tether is selected from the following: [ka] Each n is independently between 1 and 20. Each p is between 1 and approximately 6. A conjugated antisense compound according to any of embodiments 806 to 847.

[0880] Embodiment 857. Each tether is a conjugated antisense compound from any of Embodiments 806 to 847, selected from the following: [ka]

[0881] Embodiment 858. Each tether has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 847.

[0882] Embodiment 859. A conjugated antisense compound of any of Embodiments 806 to 847, wherein each tether has the following structure. [ka]

[0883] Embodiment 860. A conjugated antisense compound according to any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0884] Embodiment 861. A conjugated antisense compound according to any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0885] Embodiment 862. A conjugated antisense compound according to any of Embodiments 806 to 859, wherein the cell targeting moiety comprises at least one ligand.

[0886] Embodiment 863. A conjugated antisense compound according to any of Embodiments 806 to 859, wherein the cell targeting portion contains one ligand.

[0887] Embodiment 864. A conjugated antisense compound according to any of Embodiments 806 to 859, wherein the target portion comprises two ligands.

[0888] Embodiment 865. A conjugated antisense compound according to any of Embodiments 806 to 859, wherein the target portion comprises three ligands.

[0889] Embodiment 866. A conjugated antisense compound according to any of Embodiments 806 to 859, wherein each ligand is covalently bonded to each tether.

[0890] Embodiment 867. A conjugated antisense compound of any of Embodiments 862 to 866, wherein at least one ligand is N-acetylgalactosamine (GalNAc).

[0891] Embodiment 868. A conjugated antisense compound according to any of Embodiments 862 to 866, wherein each ligand is N-acetylgalactosamine (GalNAc).

[0892] Embodiment 869. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glu Copiranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamine A conjugated antisense compound of any of embodiments 862 to 866, selected from no-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranose, 4-thio-β-D-galactopyranoose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0893] Embodiment 870. A conjugated antisense compound according to any of Embodiments 862 to 866, wherein the ligand is galactose.

[0894] Embodiment 871. A conjugated antisense compound according to any of Embodiments 862 to 866, wherein the ligand is mannose-6-phosphate.

[0895] Embodiment 872. Each ligand is selected from the following: [ka] In the formula, each R1 is selected from OH and NHCOOH. A conjugated antisense compound according to any of embodiments 862 to 866.

[0896] Embodiment 873. A conjugated antisense compound according to any of Embodiments 862 to 866, wherein each ligand is selected from the following. [ka]

[0897] Embodiment 874. A conjugated antisense compound of any of Embodiments 862 to 866, wherein each ligand has the following structure. [ka]

[0898] Embodiment 875. A conjugated antisense compound according to any of Embodiments 862 to 866, wherein each ligand has the following structure. [ka]

[0899] Embodiment 876. The conjugated group comprises a cell targeting moiety having the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any of embodiments 806 to 860.

[0900] Embodiment 877. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0901] Embodiment 878. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0902] Embodiment 879. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0903] Embodiment 880. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0904] Embodiment 881. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0905] Embodiment 882. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0906] Embodiment 883. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0907] Embodiment 884. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0908] Embodiment 885. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0909] Embodiment 886. A conjugated antisense compound of any of Embodiments 806 to 860, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[0910] Embodiment 887. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 779 to 789.

[0911] Embodiment 888. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 779 to 789.

[0912] Embodiment 889. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A is the antisense oligonucleotide, Z is H or a bonded solid support. Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 779 to 789.

[0913] Embodiment 890. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. A is the antisense oligonucleotide, Z is H or a bonded solid support. Bx is the heterocyclic base portion. A conjugated antisense compound according to any of embodiments 779 to 789.

[0914] Embodiment 891. The conjugated group has the following structure: [ka] In the formula, A is the antisense oligonucleotide. A conjugated antisense compound according to any of embodiments 779 to 789.

[0915] Embodiment 892. The conjugated group has the following structure: [ka] In the formula, A is the antisense oligonucleotide. A conjugated antisense compound according to any of embodiments 779 to 789.

[0916] Embodiment 893. The conjugated group has the following structure: [ka] In the formula, A is the antisense oligonucleotide, Z is H or a bonded solid support. A conjugated antisense compound according to any of embodiments 779 to 789.

[0917] Embodiment 894. The conjugated group has the following structure: [ka] In the formula, A is the antisense oligonucleotide, Z is H or a bonded solid support. A conjugated antisense compound according to any of embodiments 779 to 789.

[0918] Embodiment 895. The conjugated group has the following structure: [ka] A is the antisense oligonucleotide, a conjugated antisense compound according to any of embodiments 779 to 789.

[0919] Embodiment 896. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0920] Embodiment 897. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0921] Embodiment 898. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide.

[0922] Embodiment 899. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0923] Embodiment 900. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0924] Embodiment 901. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0925] Embodiment 902. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0926] Embodiment 903. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0927] Embodiment 904. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0928] Embodiment 905. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0929] Embodiment 906. The conjugated group has the following structure: [ka] A conjugated antisense compound according to any one of embodiments 779 to 789, wherein A is the antisense oligonucleotide in the formula.

[0930] Embodiment 907. A conjugated oligonucleotide comprising an oligonucleotide and a conjugated group, wherein the conjugated group is any conjugated group from any of Embodiments 779 to 907.

[0931] Embodiment 908. The conjugated oligonucleotide of Embodiment 907, wherein the oligonucleotide comprises at least one modified nucleoside.

[0932] Embodiment 909. The conjugated oligonucleotide of Embodiment 908, wherein at least one modified nucleoside comprises a modified base.

[0933] Embodiment 910. A conjugated oligonucleotide of Embodiment 908 or 909, wherein the at least one modified nucleoside comprises a sugar substitute.

[0934] Embodiment 911. The conjugated oligonucleotide of Embodiment 910, wherein the sugar substitute is tetrahydropyran.

[0935] Embodiment 912. A conjugated oligonucleotide according to any of Embodiment 911, wherein the tetrahydropyran is F-HNA.

[0936] Embodiment 913. A conjugated oligonucleotide according to any one of Embodiments 908 to 912, wherein the remainder of the oligonucleotide comprises at least one nucleoside containing a modified sugar.

[0937] Embodiment 914. The at least one modified nucleoside containing the modified sugar is selected from bicyclic nucleosides and 2'-modified nucleosides, and is a conjugated oligonucleotide of Embodiment 913. Cleotide.

[0938] Embodiment 915. The conjugated oligonucleotide of Embodiment 914, wherein at least one modified nucleoside is a bicyclic nucleoside.

[0939] Embodiment 916. The conjugated oligonucleotide of Embodiment 915, wherein the bicyclic nucleoside is a (4'-CH2-O-2')BNA nucleoside.

[0940] Embodiment 917. The conjugated oligonucleotide of Embodiment 915, wherein the bicyclic nucleoside is (4'-(CH2)2-O-2')BNA nucleoside.

[0941] Embodiment 918. The conjugated oligonucleotide of Embodiment 915, wherein the bicyclic nucleoside is (4'-C(CH3)HO-2')BNA nucleoside.

[0942] Embodiment 919. The conjugated oligonucleotide of Embodiment 914, wherein at least one modified nucleoside is a 2'-modified nucleoside.

[0943] Embodiment 920. The conjugated oligonucleotide of Embodiment 919, wherein the at least one 2'-modified nucleoside is selected from a 2'-F nucleoside, a 2'-OCH3 nucleoside, and a 2'-O(CH2)2OCH3 nucleoside.

[0944] Embodiment 921. The conjugated oligonucleotide of Embodiment 920, wherein at least one 2'-modified nucleoside is a 2'-F nucleoside.

[0945] Embodiment 922. The conjugated oligonucleotide of Embodiment 920, wherein the at least one 2'-modified nucleoside is a 2'-OCH3 nucleoside.

[0946] Embodiment 923. The conjugated oligonucleotide of Embodiment 920, wherein the at least one 2'-modified nucleoside is a 2'-O(CH2)2OCH3 nucleoside.

[0947] Embodiment 924. A conjugated oligonucleotide according to any one of Embodiments 907 to 923, wherein the oligonucleotide comprises at least one unmodified nucleoside.

[0948] Embodiment 925. The conjugated oligonucleotide of Embodiment 924, wherein the unmodified nucleoside is a ribonucleoside.

[0949] Embodiment 926. The conjugated oligonucleotide of Embodiment 924, wherein the unmodified nucleoside is a deoxyribonucleoside.

[0950] Embodiment 927. A conjugated oligonucleotide according to any one of Embodiments 907 to 926, wherein the oligonucleotide comprises at least two modified nucleosides.

[0951] Embodiment 928. The conjugated oligonucleotide of Embodiment 927, wherein at least two of the modified nucleosides contain the same modification.

[0952] Embodiment 929. The conjugated oligonucleotide of Embodiment 927, wherein the at least two modified nucleosides include different modifications.

[0953] Embodiment 930. A conjugated oligonucleotide of any of Embodiments 927 to 929, wherein at least one of the at least two modified nucleosides comprises a sugar substitute.

[0954] Embodiment 931. A conjugated oligonucleotide of any of Embodiments 927 to 930, wherein at least one of the at least two modified nucleosides includes a 2'-modification.

[0955] Embodiment 932. The conjugated oligonucleotide of Embodiment 931, wherein each of the at least two modified nucleosides is independently selected from 2'-F nucleosides, 2'-OCH3 nucleosides, and 2'-O(CH2)2OCH3 nucleosides.

[0956] Embodiment 933. The conjugated oligonucleotide of Embodiment 932, wherein each of the at least two modified nucleosides is a 2'-F nucleoside.

[0957] Embodiment 934. The conjugated oligonucleotide of Embodiment 932, wherein each of the at least two modified nucleosides is a 2'-OCH3 nucleoside.

[0958] Embodiment 935. The conjugated oligonucleotide of Embodiment 932, wherein each of the at least two modified nucleosides is a 2'-O(CH2)2OCH3 nucleoside.

[0959] Embodiment 936. A conjugated oligonucleotide of any of Embodiments 907 to 935, wherein essentially all nucleosides of the oligonucleotide are modified nucleosides.

[0960] Embodiment 937. A conjugated oligonucleotide according to any one of Embodiments 907-927 or 930-936, wherein all nucleosides of the oligonucleotide are modified nucleosides.

[0961] Embodiment 938. A conjugated oligonucleotide according to any of Embodiments 907 to 937, wherein the oligonucleotide is single-stranded.

[0962] Embodiment 939. A conjugated oligonucleotide according to any of Embodiments 907 to 937, wherein the oligonucleotide is double-stranded.

[0963] Embodiment 940. A conjugated oligonucleotide according to any of Embodiments 907 to 937, wherein the oligonucleotide is an antisense compound.

[0964] Embodiment 941. A conjugated oligonucleotide according to any of Embodiments 907 to 937, wherein the oligonucleotide is a RISC-based oligonucleotide.

[0965] Embodiment 942. A conjugated oligonucleotide according to any of Embodiments 907 to 937, wherein the oligonucleotide activates the RISC pathway.

[0966] Embodiment 943. A conjugated oligonucleotide according to any one of Embodiments 907 to 937, wherein the oligonucleotide is an RNase H-based antisense compound.

[0967] Embodiment 944. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group is bonded to the 5' terminal nucleoside of the antisense oligonucleotide.

[0968] Embodiment 945. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group is bonded to the 3' terminal nucleoside of the antisense oligonucleotide.

[0969] Embodiment 946. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group is bonded to the internal nucleoside of the antisense oligonucleotide.

[0970] Embodiment 947. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into hepatocytes compared with a non-conjugated oligonucleotide compound.

[0971] Embodiment 948. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into liver cells compared to a non-conjugated oligonucleotide compound.

[0972] Embodiment 949. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group increases the accumulation of the conjugated oligonucleotide compound in the liver compared to a non-conjugated oligonucleotide compound.

[0973] Embodiment 950. A conjugated oligonucleotide compound according to any of Embodiments 907 to 943, wherein the conjugated group reduces the accumulation of the conjugated oligonucleotide compound in the kidney compared to a non-conjugated oligonucleotide compound.

[0974] Embodiment 951. The conjugated oligonucleotide is A 5' region consisting of 2 to 8 linked 5' region nucleosides, wherein at least 2 5' region nucleosides are modified nucleosides, and the 5' region nucleoside closest to the 3' side is a modified nucleoside, and A 3' region consisting of 2 to 8 linked 3' region nucleosides, wherein at least 2 of the 3' region nucleosides are modified nucleosides, and the 3' region nucleoside closest to the 5' side is a modified nucleoside, and A central region between the 5' region and the 3' region, each consisting of 5 to 10 linked central region nucleosides, wherein each is independently selected from modified nucleosides and unmodified deoxynucleosides, the central region nucleoside furthest to the 5' side is an unmodified deoxynucleoside, and the central region nucleoside furthest to the 3' side is an unmodified deoxynucleoside. Conjugated oligonucleotide compounds of embodiments 907-935 or 938-950 having a sugar motif containing a sugar motif.

[0975] Embodiment 952. The conjugated oligonucleotide compound of Embodiment 951, wherein the 5' region consists of two linked 5' region nucleosides.

[0976] Embodiment 953. The conjugated oligonucleotide compound of Embodiment 951, wherein the 5' region consists of three linked 5' region nucleosides.

[0977] Embodiment 954. The conjugated oligonucleotide compound of Embodiment 951, wherein the 5' region consists of four linked 5' region nucleosides.

[0978] Embodiment 955. The conjugated oligonucleotide compound of Embodiment 951, wherein the 5' region consists of five linked 5' region nucleosides.

[0979] Embodiment 956. A conjugated oligonucleotide compound according to any of Embodiments 951 to 955, wherein the 3' region consists of two linked 3' region nucleosides.

[0980] Embodiment 957. A conjugated oligonucleotide compound according to any of Embodiments 951 to 955, wherein the 3' region consists of three linked 3' region nucleosides.

[0981] Embodiment 958. A conjugated oligonucleotide compound according to any of Embodiments 951 to 955, wherein the 3' region consists of four linked 3' region nucleosides.

[0982] Embodiment 959. A conjugated oligonucleotide compound according to any of Embodiments 951 to 955, wherein the 3' region consists of five linked 3' region nucleosides.

[0983] Embodiment 960. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of five linked central region nucleosides.

[0984] Embodiment 961. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of six linked central region nucleosides.

[0985] Embodiment 962. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of seven linked central region nucleosides.

[0986] Embodiment 963. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of eight linked central region nucleosides.

[0987] Embodiment 964. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of nine linked central region nucleosides.

[0988] Embodiment 965. A conjugated oligonucleotide compound according to any of Embodiments 951 to 959, wherein the central region consists of 10 linked central region nucleosides.

[0989] Embodiment 966. A conjugated oligonucleotide compound according to any of Embodiments 951 to 965, wherein the conjugated oligonucleotide consists of 14 to 26 linked nucleosides.

[0990] Embodiment 967. A conjugated oligonucleotide compound according to any of Embodiments 951 to 965, wherein the conjugated oligonucleotide consists of 15 to 25 linked nucleosides.

[0991] Embodiment 968. A conjugated oligonucleotide compound according to any of Embodiments 951 to 965, wherein the conjugated oligonucleotide consists of 16 to 20 linked nucleosides.

[0992] Embodiment 969. A conjugated oligonucleotide compound of any of Embodiments 951 to 968, wherein each modified nucleoside independently comprises a 2'-substituted sugar moiety or a bicyclic sugar moiety.

[0993] Embodiment 970. The conjugated oligonucleotide compound of Embodiment 969, wherein the at least one modified nucleoside comprises a 2'-substituted sugar moiety.

[0994] Embodiment 971. Each modified nucleoside containing the 2'-substituted sugar moiety is independently selected from halogen, optionally substituted allyl, optionally substituted amino, azide, optionally substituted SH, CN, OCN, CF3, OCF3, O, S, or N(Rm)-alkyl; O, S, or N(Rm)-alkenyl; O, S, or N(Rm)-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkyl, optionally substituted O-alkyl, optionally substituted O-aralkyl, O(CH2)2SCH3, O-(CH2)2-ON(Rm)(Rn), or O-CH2-C(=O)-N(Rm)(Rn) The compound contains substituents, where each Rm and Rn independently represents H, an amino protecting group, or substituted or unsubstituted C1-C1. 10 It is alkyl, The conjugated oligonucleotide compound of Embodiment 970, wherein each optionally substituted group is optionally substituted with a substituent independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl, and alkynyl.

[0995] Embodiment 972. Each 2' substituent is halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-SCH3, O(CH2)2-OCF3, O(CH2)3-N(R1)(R2), O(CH2)2-ON(R1)(R2), O(CH2)2-O(CH2)2-N( A conjugated oligonucleotide compound of Embodiment 970, independently selected from R1)(R2), OCH2C(=O)-N(R1)(R2), OCH2C(=O)-N(R3)-(CH2)2-N(R1)(R2), and O(CH2)2-N(R3)-C(=NR4)[N(R1)(R2)], wherein R1, R2, R3, and R4 are each independently H or C1-C6 alkyl.

[0996] Embodiment 973. A conjugated oligonucleotide compound of Embodiment 970, wherein each 2' substituent is independently selected from halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3(MOE), O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

[0997] Embodiment 974. The conjugated oligonucleotide compound of Embodiment 970, wherein the at least one 2'-modified nucleoside contains a 2'-MOE sugar moiety.

[0998] Embodiment 975. The conjugated oligonucleotide compound of Embodiment 970, wherein the at least one 2'-modified nucleoside contains a 2'-OMe sugar moiety.

[0999] Embodiment 976. The conjugated oligonucleotide compound of Embodiment 970, wherein the at least one 2'-modified nucleoside contains a 2'-F sugar moiety.

[1000] Embodiment 977. A conjugated oligonucleotide compound according to any one of Embodiments 951 to 968, wherein the conjugated oligonucleotide comprises at least one modified nucleoside containing a sugar substitute.

[1001] Embodiment 978. The conjugated oligonucleotide compound of Embodiment 977, wherein the modified nucleoside contains an F-HNA sugar moiety.

[1002] Embodiment 979. The conjugated oligonucleotide compound of Embodiment 977, wherein the modified nucleoside contains an HNA sugar moiety.

[1003] Embodiment 980. A conjugated oligonucleotide compound according to any one of Embodiments 951 to 968, wherein the conjugated oligonucleotide comprises at least one modified nucleoside containing a bicyclic sugar moiety.

[1004] Embodiment 981. The conjugated oligonucleotide compound of Embodiment 980, wherein the bicyclic sugar portion is a cEt sugar portion.

[1005] Embodiment 982. A conjugated oligonucleotide compound of Embodiment 980, wherein the bicyclic sugar portion is an LNA sugar portion.

[1006] Embodiment 983. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 982, wherein the conjugated oligonucleotide contains at least one modified internucleoside bond.

[1007] Embodiment 984. The conjugated oligonucleotide compound of Embodiment 908, wherein each nucleoside bond in the conjugated oligonucleotide is a modified nucleoside bond.

[1008] Embodiment 985. The conjugated oligonucleotide compound of Embodiment 983, wherein the conjugated oligonucleotide comprises at least one modified bond and at least one unmodified phosphodiester nucleoside bond.

[1009] Embodiment 986. A conjugated oligonucleotide compound of any of Embodiments 983 to 985, wherein at least one modified nucleoside bond is a phosphosulfothioate nucleoside bond.

[1010] Embodiment 987. A conjugated oligonucleotide compound according to any of Embodiments 983 to 985, wherein each modified nucleoside bond is a phosphorothioate nucleoside bond.

[1011] Embodiment 988. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least two phosphodiester nucleoside interbonding bonds.

[1012] Embodiment 989. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least three phosphodiester nucleoside interbonding bonds.

[1013] Embodiment 990. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least four phosphodiester nucleoside interbonding bonds.

[1014] Embodiment 991. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least five phosphodiester nucleoside interbonding groups.

[1015] Embodiment 992. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least six phosphodiester nucleoside interbonding bonds.

[1016] Embodiment 993. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least seven phosphodiester nucleoside interbonding bonds.

[1017] Embodiment 994. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least eight phosphodiester nucleoside interbonding bonds.

[1018] Embodiment 995. A conjugated oligonucleotide from any of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least nine phosphodiester nucleoside interbonding groups. compound.

[1019] Embodiment 996. A conjugated oligonucleotide compound according to any one of Embodiments 983 to 984, wherein the conjugated oligonucleotide contains at least 10 phosphodiester nucleoside interbonding bonds.

[1020] Embodiment 997. A conjugated oligonucleotide compound according to any one of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 16 phosphorothioate nucleoside bonds.

[1021] Embodiment 998. A conjugated oligonucleotide compound according to any one of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 15 phosphorothioate nucleoside bonds.

[1022] Embodiment 999. A conjugated oligonucleotide compound according to any one of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 14 phosphorothioate nucleoside bonds.

[1023] Embodiment 1000. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 13 phosphorothioate nucleoside bonds.

[1024] Embodiment 1001. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 12 phosphorothioate nucleoside bonds.

[1025] Embodiment 1002. A conjugated oligonucleotide compound according to any one of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 11 phosphorothioate nucleoside bonds.

[1026] Embodiment 1003. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than 10 phosphorothioate nucleoside bonds.

[1027] Embodiment 1004. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than nine phosphorothioate nucleoside bonds.

[1028] Embodiment 1005. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than eight phosphorothioate nucleoside bonds.

[1029] Embodiment 1006. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than seven phosphorothioate nucleoside bonds.

[1030] Embodiment 1007. A conjugated oligonucleotide compound according to any of Embodiments 983 or 985-996, wherein the conjugated oligonucleotide contains fewer than six phosphorothioate nucleoside bonds.

[1031] Embodiment 1008. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1007, wherein the internucleoside bonds between each terminal nucleoside of the conjugated oligonucleotide are phosphorothioate nucleoside bonds.

[1032] Embodiment 1009. A conjugated oligonucleotide compound according to any of Embodiments 907-984 or 997-1008, wherein the internucleoside bonds connecting the two deoxynucleosides of the conjugated oligonucleotide are phosphorothioate internucleoside bonds.

[1033] Embodiment 1010. A conjugated oligonucleotide compound according to any of Embodiments 907-984 or 997-1009, wherein each non-terminal nucleoside bond connecting the two modified nucleosides of the conjugated oligonucleotide is a phosphodiester nucleoside bond.

[1034] Embodiment 1011. A conjugated oligonucleotide compound according to any of Embodiments 907-984 or 997-1010, wherein each non-terminal nucleoside bond of the conjugated oligonucleotide, which is the 3' of the modified nucleoside, is a phosphodiester nucleoside bond.

[1035] Embodiment 1012. A conjugated oligonucleotide compound according to any of Embodiments 907-984 or 997-1011, wherein the internucleoside bonds of each nucleoside bond in the conjugated oligonucleotide that is the 3' of the deoxynucleoside are phosphorothioate nucleoside bonds.

[1036] Embodiment 1013. The conjugated oligonucleotide is MsMy(Ds) 0-1 (DsDs) (3-5) MsM MsMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My MyMsM MsMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMsM MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) MyMyMsM, and MsMyMyMyMy(Ds) 0-1 (DsDs) (3-5) My My MyMsM It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each s is a phosphorothioate nucleoside bond, and each y is either a phosphodiester nucleoside bond or a phosphorothioate nucleoside bond, provided that at least one y is a phosphodiester nucleotide bond. A conjugated oligonucleotide compound according to any of embodiments 907-984 or 997-1012.

[1037] Embodiment 1014. The conjugated oligonucleotide is MsMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM MsMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMsM MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMsM, and MsMoMoMoMo(Ds) 0-1 (DsDs) (3-5) MoMoMoMsM It has a chemical motif selected from among them, In the formula, each M is independently a modified nucleoside, each D is a deoxynucleoside, each o is a phosphodiester nucleoside bond, and each s is a phosphorothioate nucleoside bond. A conjugated oligonucleotide compound according to any of embodiments 907-984 or 997-1012.

[1038] Embodiment 1015. A conjugated oligonucleotide compound of Embodiment 1013 or 1014, wherein each M is independently selected from 2'-MOE nucleosides and bicyclic nucleosides.

[1039] Embodiment 1016. The conjugated oligonucleotide compound of Embodiment 1015, wherein each M is independently selected from 2'-MOE nucleoside, cEt nucleoside, and LNA nucleoside.

[1040] Embodiment 1017. A conjugated oligonucleotide compound of Embodiment 1015 or 1016, wherein each M is a 2'-MOE nucleoside.

[1041] Embodiment 1018. A conjugated oligonucleotide compound of Embodiment 1015 or 1016, wherein each M is a cEt nucleoside.

[1042] Embodiment 1019. A conjugated oligonucleotide compound of Embodiment 1015 or 1016, wherein each M is an LNA nucleoside.

[1043] Embodiment 1020. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence comprising at least eight nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[1044] Embodiment 1021. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 10 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[1045] Embodiment 1022. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 12 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[1046] Embodiment 1023. Embodiments 907-1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 14 nucleic acid base portions complementary to the isolength portion of the target nucleic acid. One of the following conjugated oligonucleotide compounds.

[1047] Embodiment 1024. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 16 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[1048] Embodiment 1025. A conjugated oligonucleotide compound according to any one of Embodiments 907 to 1019, wherein the conjugated oligonucleotide has a nucleic acid base sequence that includes at least 18 nucleic acid base portions complementary to the isolength portion of the target nucleic acid.

[1049] Embodiment 1026. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1019, wherein the conjugated oligonucleotide is at least 90% complementary to the target nucleic acid.

[1050] Embodiment 1027. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1019, wherein the conjugated oligonucleotide is at least 95% complementary to the target nucleic acid.

[1051] Embodiment 1028. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1019, wherein the conjugated oligonucleotide is 100% complementary to the target nucleic acid.

[1052] Embodiment 1029. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1028, wherein the target nucleic acid is premRNA.

[1053] Embodiment 1030. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1028, wherein the target nucleic acid is mRNA.

[1054] Embodiment 1031. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1030, wherein the target nucleic acid is a microRNA.

[1055] Embodiment 1032. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1030, wherein the target nucleic acid is expressed in the liver.

[1056] Embodiment 1033. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1030, wherein the target nucleic acid is expressed in hepatocytes.

[1057] Embodiment 1034. A conjugated oligonucleotide compound of any of Embodiments 1020 to 1030, wherein the target nucleic acid encodes a protein selected from androgen receptor, apolipoprotein (a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, protein tyrosine phosphatase 1B, STAT3, SRB-1, and transthyretin.

[1058] Embodiment 1035. A conjugated oligonucleotide compound according to any of Embodiments 1020 to 1031, wherein the target nucleic acid is a viral nucleic acid.

[1059] Embodiment 1036. The conjugated oligonucleotide compound of Embodiment 1035, wherein the viral nucleic acid is expressed in the liver.

[1060] Embodiment 1037. The conjugated oligonucleotide compound of Embodiment 1036, wherein the target nucleic acid is hepatitis B virus nucleic acid.

[1061] Embodiment 1038. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 17, 18, 19, 20, 21, 22, 23, or 24.

[1062] Embodiment 1039. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one nucleic acid base sequence from SEQ ID NOs: 25, 26, 27, 28, 29, or 30.

[1063] Embodiment 1040. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 31.

[1064] Embodiment 1041. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 32.

[1065] Embodiment 1042. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 33.

[1066] Embodiment 1043. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 34.

[1067] Embodiment 1044. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences of SEQ ID NOs: 35, 36, 37, 38, 39, 40, 41, 42, or 43.

[1068] Embodiment 1045. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 44, 45, 46, 47, or 48.

[1069] Embodiment 1046. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences among SEQ ID NOs: 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[1070] Embodiment 1047. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences of SEQ ID NOs. 60, 61, 62, 63, 64, 65, 66, or 67.

[1071] Embodiment 1048. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide comprises one of the nucleic acid base sequences of SEQ ID NOs. 69, 70, 71, or 72.

[1072] Embodiment 1049. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 73.

[1073] Embodiment 1050. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains one of the nucleic acid base sequences of SEQ ID NOs: 74, 75, 76, 77, 78, 79, 80, or 81.

[1074] Embodiment 1051. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains the nucleic acid base sequence of SEQ ID NO: 68.

[1075] Embodiment 1052. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1030, wherein the conjugated oligonucleotide contains any nucleic acid base sequence among SEQ ID NOs. 82 to 103, 111, or 113.

[1076] Embodiment 1053. A conjugated oligonucleotide compound according to any of Embodiments 907 to 1052, wherein the conjugated oligonucleotide is an antisense oligonucleotide.

[1077] Embodiment 1054. A pharmaceutical composition comprising a compound or conjugated oligonucleotide according to any of Embodiments 779 to 1053, and a pharmaceutically acceptable carrier or diluent.

[1078] Embodiment 1055. The pharmaceutical composition of Embodiment 1054, wherein the pharmaceutically acceptable carrier or diluent is selected from sterile water and sterile physiological saline.

[1079] Embodiment 1056. A method for reducing the amount or activity of a target nucleic acid in a cell, comprising contacting the cell with any of the compounds or conjugated antisense compounds of Embodiments 779 to 1053, or the pharmaceutical composition of Embodiment 1054 or 1055.

[1080] Embodiment 1057. The method of Embodiment 1056, wherein the cells are liver cells.

[1081] Embodiment 1058. The method of Embodiment 1056, wherein the cells are hepatocytes.

[1082] Embodiment 1059. Any of the methods of Embodiments 1056 to 1058, wherein the cells are present outside the body.

[1083] Embodiment 1060. Any method according to Embodiments 1056 to 1058, wherein the cells are present in an animal.

[1084] Embodiment 1061. The method of Embodiment 1060, wherein the animal is a mouse.

[1085] Embodiment 1062. The method of Embodiment 1060, wherein the animal is a human.

[1086] Embodiment 1063. A method for treating a disease or condition in an animal, comprising administering a pharmaceutical composition of Embodiment 1054 or 1056 to the animal, thereby treating the disease or condition in the animal.

[1087] Embodiment 1064. The method of Embodiment 1063, wherein the animal is a mouse.

[1088] Embodiment 1065. The method of Embodiment 1063, wherein the animal is a human.

[1089] Embodiment 1066. Any method of Embodiments 1063 to 1065, wherein the disease or condition is a liver disease or condition.

[1090] Embodiment 1067. Any of the methods of Embodiments 1063 to 1065, wherein the administration is by parenteral administration.

[1091] Embodiment 1068. The method of Embodiment 1067, wherein the administration is by subcutaneous injection.

[1092] Embodiment 1069. The method of Embodiment 1067, wherein the administration is performed by intravenous infusion.

[1093] Embodiment 1070. The method of Embodiment 1067, wherein the administration is by intramuscular injection.

[1094] Embodiment 1071. Any method of Embodiments 741 to 748, wherein the conjugated oligonucleotide is provided in a dose of 1 to 10 mg / kg.

[1095] Embodiment 1072. Any method of Embodiments 1056 to 1070, wherein the conjugated oligonucleotide is provided in a dose of less than 1 mg / kg.

[1096] Embodiment 1073. Any method of Embodiments 1056 to 1070, wherein the conjugated oligonucleotide is provided in a dose greater than 10 mg / kg.

[1097] Embodiment 1074. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided for a drug administration period of at least two months.

[1098] Embodiment 1075. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided for a period of at least four months.

[1099] Embodiment 1076. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided for a period of at least 6 months.

[1100] Embodiment 1077. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once a week.

[1101] Embodiment 1078. Any method according to Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once every two weeks.

[1102] Embodiment 1079. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of approximately once every three weeks.

[1103] Embodiment 1080. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every four weeks.

[1104] Embodiment 1081. Any method according to Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every five weeks.

[1105] Embodiment 1082. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every six weeks.

[1106] Embodiment 1083. Any method according to Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every seven weeks.

[1107] Embodiment 1084. Any method of Embodiments 1056 to 1073, wherein the conjugated oligonucleotide is provided at a dosage frequency of once every 8 weeks.

[1108] Embodiment 1085. A conjugated antisense compound comprising 12 to 30 linked nucleosides and an antisense oligonucleotide containing a conjugated group, wherein the conjugated group contains at least one cell-targeting moiety.

[1109] Embodiment 1086. A method for reducing the activity or amount of apolipoprotein C-III protein in cells, comprising contacting the cells with at least one conjugated antisense compound of any of Embodiments 779 to 1055, thereby reducing the activity or amount of apolipoprotein C-III protein in the cells. A method for reducing the activity or amount of the apolipoprotein C-III protein.

[1110] Embodiment 1087. A method for lowering total cholesterol, comprising contacting cells with at least one compound from any of Embodiments 779 to 1055, thereby lowering total cholesterol.

[1111] Embodiment 1088. A method for reducing triglycerides, comprising contacting cells with at least one compound from any of Embodiments 779 to 1055, thereby reducing triglycerides.

[1112] Embodiment 1089. A method for reducing LDL, comprising contacting cells with at least one compound from any of Embodiments 779 to 1055, thereby reducing LDL.

[1113] Embodiment 1090. A method for increasing HDL, comprising contacting cells with at least one compound from any of Embodiments 779 to 1055, thereby increasing HDL.

[1114] Embodiment 1091. Any of the methods of Embodiments 1086 to 1090, wherein the cells are present outside the body.

[1115] Embodiment 1092. Any method according to Embodiments 1086 to 1090, wherein the cells are present within an animal.

[1116] Embodiment 1093. Any method of Embodiments 1086 to 1090, wherein the animal is a human.

[1117] Embodiment 1094. A compound or conjugated oligonucleotide according to any of Embodiments 1 to 1055, or a prodrug thereof.

[1118] Embodiment 1095. A method for producing an antisense oligonucleotide according to any of Embodiments 1 to 1055.

[1119] Embodiment 1096. A method for preparing an antisense oligonucleotide according to any of Embodiments 1 to 1055.

[1120] Embodiment 1097. A step for producing any one of the conjugated antisense compounds of Embodiments 1 to 1055, wherein the step comprises: formulating the conjugated antisense compound for human use; performing chromatographic analysis of the formulated conjugated antisense compound; and packaging the conjugated antisense compound in preparation for sale.

[1121] Embodiment 1098. A conjugated compound comprising at least one phosphorus-binding group or neutral-binding group and one or more ligands.

[1122] Embodiment 1099. The conjugated compound of claim 1098, comprising two or more ligands.

[1123] Embodiment 1100. The conjugated compound of claim 1098, comprising three ligands.

[1124] Embodiment 1101. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, ma Mannopyranose derivatives, galactose derivatives, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannopyranose, β-D-mannopyranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl] -2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6-O-tri A conjugated compound according to any of claims 1098 to 1100, selected from tyl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[1125] Embodiment 1102. A conjugated compound according to any one of claims 1098 to 1101, wherein the ligand is N-acetylgalactoseamine.

[1126] Embodiment 1103. The conjugated group includes a structure selected from the following: [ka] [ka] [ka] In the formula, n is between 1 and 12. m is between 1 and 12. A conjugated compound according to any one of claims 1098 to 1102.

[1127] Embodiment 1104. The conjugated compound has a tether having a structure selected from the following: [ka] In the formula, L is either a phosphorus-binding group or a neutral-binding group. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. A conjugated compound according to any one of claims 1098 to 1102.

[1128] Embodiment 1105. The tether has a structure selected from the following: [ka] In the formula, Z2 is either H or CH3. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. The conjugated compound of claim 1104.

[1129] Embodiment 1106. The tether has a structure selected from the following: [ka] In the formula, n is between 1 and 12. m is between 1 and 12. A conjugated compound according to any one of claims 1098 to 1102.

[1130] Embodiment 1107. A conjugated compound according to any one of claims 1098 to 1106, wherein the conjugated compound is covalently bonded to an oligonucleotide.

[1131] Embodiment 1108. An oligomeric compound comprising an oligonucleotide and at least one conjugated group, wherein at least one conjugated group is any of claims 1098 to 1108. Conjugated compounds, or oligomeric compounds.

[1132] Embodiment 1109. A compound having formula (V), [ka] In the formula, either T3 or T4 is selected from GalNAc3-1a, GalNAc3-2a, GalNAc3-3a, GalNAc3-4a, GalNAc3-5a, GalNAc3-6a, GalNAc3-7a, GalNAc3-8a, GalNAc3-9a, GalNAc3-10a, GalNAc3-11a, GalNAc3-12a, GalNAc3-13a, GalNAc3-14a, GalNAc3-15a, GalNAc3-16a, GalNAc3-17a, GalNAc3-18a, GalNAc3-19a, GalNAc3-20a, GalNAc3-21a, or GalNAc3-22a. A compound in which the other of T3 or T4 is selected from hydroxyl, hydroxyl protecting group, nucleoside, oligonucleotide, monomeric subunit, or oligomeric compound, and Bx is a heterocyclic base moiety.

[1133] Embodiment 1110. A compound having formula (Va), [ka] In the formula, either T3 or T4 is selected from GalNAc3-1a, GalNAc3-2a, GalNAc3-3a, GalNAc3-4a, GalNAc3-5a, GalNAc3-6a, GalNAc3-7a, GalNAc3-8a, GalNAc3-9a, GalNAc3-10a, GalNAc3-11a, GalNAc3-12a, GalNAc3-13a, GalNAc3-14a, GalNAc3-15a, GalNAc3-16a, GalNAc3-17a, GalNAc3-18a, GalNAc3-19a, GalNAc3-20a, GalNAc3-21a, or GalNAc3-22a. The other of T3 or T4 is selected from hydroxyl, hydroxyl protecting group, nucleoside, oligonucleotide, monomer subunit, or oligomeric compound, and Bx is a heterocyclic base moiety, Q 13 A compound selected from halogens, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3(MOE), O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

[1134] Embodiment 1111. B x The compound according to claim 1109 or 1110, selected from adenine, guanine, thymine, uracil, or cytosine.

[1135] Embodiment 1112. Q 13 A compound of any of claims 1109 to 1111, wherein the compound is O(CH2)2-OCH3.

[1136] Embodiment 1113. A compound having formula (XVI), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1137] Embodiment 1114. A compound having formula (XVII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1138] Embodiment 1115. A compound having formula (XVIII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1139] Embodiment 1116. A compound having formula (XIX), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1140] Embodiment 1117. A compound having formula (XX), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1141] Embodiment 1118. A compound having formula (XXI), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1142] Embodiment 1119. A compound having formula (XXII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1143] Embodiment 1120. A compound having formula (XXIII), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1144] Embodiment 1121. A compound having formula (XXIIIa), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1145] Embodiment 1122. A compound having formula (XXIV), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1146] Embodiment 1123. A compound having formula (XXIVa), [ka] During the ceremony, A compound in which T2 is a nucleoside, nucleotide, monomeric subunit, or oligomeric compound.

[1147] Embodiment 1124. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1148] Embodiment 1125. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, n1 is 0 or 1, q is an integer between 1 and 5. Conjugated antisense compounds.

[1149] Embodiment 1126. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, C is the conjugate linker, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1150] Embodiment 1127. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, C is the conjugate linker, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1151] Embodiment 1128. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, C is the conjugate linker, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1152] Embodiment 1129. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1153] Embodiment 1130. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, B is the portion that can be cut, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1154] Embodiment 1131. A conjugated antisense compound having a structure represented by the following formula, [ka] During the ceremony, A is the antisense oligonucleotide, D is the branching base, Each E is a tether, Each F is an ligand, q is an integer between 1 and 5. Conjugated antisense compounds.

[1155] Embodiment 1132. The conjugate linker has a structure selected from the following: [ka] In the formula, each L is independently either a phosphorus bond group or a neutral bond group. Each n is independently between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1156] Embodiment 1133. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker has a structure selected from the following. [ka]

[1157] Embodiment 1134. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker has the following structure. [ka]

[1158] Embodiment 1135. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker has one of the structures selected from the following. [ka]

[1159] Embodiment 1136. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker has one of the structures selected from the following. [ka]

[1160] Embodiment 1137. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker has one of the structures selected from the following. [ka]

[1161] Embodiment 1138. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker comprises pyrrolidine.

[1162] Embodiment 1139. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker does not contain pyrrolidine.

[1163] Embodiment 1140. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker comprises PEG.

[1164] Embodiment 1141. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker comprises an amide.

[1165] Embodiment 1142. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker does not contain an amide.

[1166] Embodiment 1143. Claims 1124-1131, wherein the conjugated linker comprises a polyamide. One of the following conjugated antisense compounds.

[1167] Embodiment 1144. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker contains an amine.

[1168] Embodiment 1145. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker comprises one or more disulfide bonds.

[1169] Embodiment 1146. A conjugated antisense compound according to any one of claims 1124 to 1131, wherein the conjugated linker includes a protein-binding moiety.

[1170] Embodiment 1147. The conjugated antisense compound of claim 1146, wherein the protein-binding portion comprises a lipid.

[1171] Embodiment 1148. The protein binding portion is cholesterol, cholic acid, adamantane acetate, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethyltrityl, or phenoxazine), vitamin A conjugated antisense compound according to claim 1146, selected from (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosome lysants, steroids (e.g., ubaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friederin, epifriederanol-derived lithocholic acid), or cationic lipids.

[1172] Embodiment 1149. The conjugated antisense compound of claim 1146 or 1147, wherein the protein-binding portion is a C16-C22 long-chain saturated or unsaturated fatty acid, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[1173] Embodiment 1150. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20, and p is between 1 and 6. A conjugated antisense compound according to any one of claims 1124 to 1128.

[1174] Embodiment 1151. The conjugate linker has a structure selected from the following: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1128.

[1175] Embodiment 1152. A conjugated antisense compound according to any one of claims 1124 to 1128, wherein the conjugated linker has a structure selected from the following. [ka]

[1176] Embodiment 1153. The conjugate linker has a structure selected from the following: [ka] In the formula, n is between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1128.

[1177] Embodiment 1154. The branching group has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. The conjugated antisense compounds of claims 1124 to 1154.

[1178] Embodiment 1155. The branching base has one of the following structures: [ka] In the formula, each A1 is independently O, S, C=O, or NH. Each n is independently between 1 and 20. The conjugated antisense compounds of claims 1124 to 1154.

[1179] Embodiment 1156. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1180] Embodiment 1157. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1181] Embodiment 1158. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1182] Embodiment 1159. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1183] Embodiment 1160. A conjugated antisense compound according to any one of claims 1124 to 1154, wherein the branched group comprises an ether.

[1184] Embodiment 1161. The branching base has the following structure: [ka] Each n is independently between 1 and 20. m is between 2 and 6. The conjugated antisense compounds of claims 1124 to 1154.

[1185] Embodiment 1162. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1186] Embodiment 1163. The conjugated antisense compound of claims 1124-1154, wherein the branched group has the following structure. [ka]

[1187] Embodiment 1164. The branching base is [ka] [ka] [ka] [ka] or [ka] Includes, In the formula, each j is an integer between 1 and 3. In the formula, each n is an integer between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1154.

[1188] Embodiment 1165. The branching base is, [ka] [ka] [ka] [ka] or [ka] A conjugated antisense compound, comprising any of claims 1124 to 1154.

[1189] Embodiment 1166. Each tether is selected from the following: [ka] In the formula, L is selected from phosphorus-binding groups and neutral-binding groups. Z1 is C(=O)O-R2, Z2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. R2 is H, C1-C6 alkyl, or substituted C1-C6 alkyl. Each m1 is independently between 0 and 20, and at least one m1 is greater than 0 for each tether. The conjugated antisense compounds of claims 1124 to 1165.

[1190] Embodiment 1167. Each tether is selected from the following: [ka] In the formula, Z2 is either H or CH3. Each m2 is independently between 0 and 20, and at least one m2 is greater than 0 for each tether. The conjugated antisense compounds of claims 1124 to 1165.

[1191] Embodiment 1168. Each tether is selected from the following: [ka] In the formula, n is between 1 and 12. m is between 1 and 12. The conjugated antisense compounds of claims 1124 to 1165.

[1192] Embodiment 1169. A conjugated antisense compound of any of claims 1124 to 1165, wherein at least one tether comprises PEG.

[1193] Embodiment 1170. A conjugated antisense compound of any of claims 1124 to 1165, wherein at least one tether comprises an amide.

[1194] Embodiment 1171. A conjugated antisense compound of any of claims 1124 to 1165, wherein at least one tether comprises a polyamide.

[1195] Embodiment 1172. A conjugated antisense compound of any of claims 1124 to 1165, wherein at least one tether comprises an amine.

[1196] Embodiment 1173. A conjugated antisense compound according to any of claims 1124 to 1165, wherein at least two tethers are different from each other.

[1197] Embodiment 1174. A conjugated antisense compound according to any one of claims 1124 to 1165, wherein all of the tethers are identical to each other.

[1198] Embodiment 1175. Each tether is selected from the following: [ka] Each n is independently between 1 and 20. Each p is between 1 and approximately 6. A conjugated antisense compound according to any one of claims 1124 to 1165.

[1199] Embodiment 1176. A conjugated antisense compound according to any of claims 1124 to 1165, wherein each tether is selected from the following: [ka]

[1200] Embodiment 1177. Each tether has the following structure: [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1165.

[1201] Embodiment 1178. A conjugated antisense compound according to any one of claims 1124 to 1165, wherein each tether has the following structure. [ka]

[1202] Embodiment 1179. A conjugated antisense compound according to any one of claims 1124 to 1178, wherein the cell targeting portion comprises at least one ligand.

[1203] Embodiment 1180. A conjugated antisense compound according to any one of claims 1124 to 1178, wherein the cell targeting portion comprises one ligand.

[1204] Embodiment 1181. A conjugated antisense compound according to any one of claims 1124 to 1178, wherein the target portion comprises two ligands.

[1205] Embodiment 1182. A conjugated antisense compound according to any one of claims 1124 to 1178, wherein the target portion comprises three ligands.

[1206] Embodiment 1183. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein each ligand is covalently bonded to each tether.

[1207] Embodiment 1184. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein at least one ligand is N-acetylgalactosamine (GalNAc).

[1208] Embodiment 1185. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein each ligand is N-acetylgalactosamine (GalNAc).

[1209] Embodiment 1186. The ligand is a polysaccharide, modified polysaccharide, mannose, galactose, mannose derivative, galactose derivative, D-mannopyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose North, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-amino-3-O-[(R)] -1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamide-2,3-di-O-methyl-D-mannopyranoose, 2-deoxy-2-sulfamino-D-glucopyranose, N-glycoyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6-O A conjugated antisense compound according to any of claims 1179 to 1182, selected from -trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranoside, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside, 2,5-anhydro-D-alononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[1210] Embodiment 1187. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein the ligand is galactose.

[1211] Embodiment 1188. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein the ligand is mannose-6-phosphate.

[1212] Embodiment 1189. Each ligand is selected from the following: [ka] In the formula, each R1 is selected from OH and NHCOOH. A conjugated antisense compound according to any one of claims 1179 to 1182.

[1213] Embodiment 1190. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein each ligand is selected from the following. [ka]

[1214] Embodiment 1191. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein each ligand has the following structure. [ka]

[1215] Embodiment 1192. A conjugated antisense compound according to any one of claims 1179 to 1182, wherein each ligand has the following structure. [ka]

[1216] Embodiment 1193. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1217] Embodiment 1194. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1218] Embodiment 1195. The conjugated group comprises a cell target moiety having the following structure, [ka] In the formula, each n is independently between 1 and 20. A conjugated antisense compound according to any one of claims 1124 to 1153.

[1219] Embodiment 1196. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1220] Embodiment 1197. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1221] Embodiment 1198. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1222] Embodiment 1199. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1223] Embodiment 1200. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1224] Embodiment 1201. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1225] Embodiment 1202. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1226] Embodiment 1203. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1227] Embodiment 1204. Claim 1, wherein the conjugated group comprises a cell targeting moiety having the following structure. A conjugated antisense compound from 124 to 1153. [ka]

[1228] Embodiment 1205. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1229] Embodiment 1206. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1230] Embodiment 1207. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1231] Embodiment 1208. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1232] Embodiment 1209. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1233] Embodiment 1210. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1234] Embodiment 1211. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1235] Embodiment 1212. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1236] Embodiment 1213. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1237] Embodiment 1214. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1238] Embodiment 1215. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1239] Embodiment 1216. A conjugated antisense compound according to any one of claims 1124 to 1153, wherein the conjugated group comprises a cell-targeting moiety having the following structure. [ka]

[1240] Embodiment 1217. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1241] Embodiment 1218. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1242] Embodiment 1219. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Z is H or a bonded solid support. Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1243] Embodiment 1220. The conjugated group has the following structure: [ka] In the formula, each n is independently between 1 and 20. Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Z is H or a bonded solid support. Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1244] Embodiment 1221. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1245] Embodiment 1222. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1246] Embodiment 1223. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1247] Embodiment 1224. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1248] Embodiment 1225. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1249] Embodiment 1226. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1250] Embodiment 1227. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1251] Embodiment 1228. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1252] Embodiment 1229. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1253] Embodiment 1230. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1254] Embodiment 1231. The conjugated group has the following structure: [ka] In the formula, Q 13 However, it is either H or O(CH2)2-OCH3, A is the antisense oligonucleotide, Bx is the heterocyclic base portion. A conjugated antisense compound according to any one of claims 1124 to 1131.

[1255] Embodiment 1232. B x A compound according to any of claims 1217 to 1231, selected from adenine, guanine, thymine, uracil, or cytosine.

[1256] Embodiment 1233. B x A compound of any of claims 1217 to 1231, wherein is adenine.

[1257] Embodiment 1234. B x A compound according to any one of claims 1217 to 1231, wherein the compound is thymine.

[1258] Embodiment 1235. Q 13 A compound according to any one of claims 1217 to 1234, wherein is O(CH2)2-OCH3.

[1259] Embodiment 1236. Q 13 A compound according to any of claims 1217 to 1234, wherein is H.

[1260] Embodiment 1237. A conjugated oligonucleotide comprising an oligonucleotide and a conjugated group, wherein the conjugated group is any conjugated group according to any of claims 1098 to 1236.

[1261] Embodiment 1238. The conjugated oligonucleotide of claim 1237, wherein the oligonucleotide comprises at least one modified nucleoside.

[1262] Embodiment 1239. The conjugated oligonucleotide of claim 1237, wherein the at least one modified nucleoside comprises a modified base.

[1263] Embodiment 1240. The conjugated oligonucleotide of claim 1238 or 1239, wherein the at least one modified nucleoside comprises a sugar substitute.

[1264] Embodiment 1241. The conjugated oligonucleotide of claim 1240, wherein the sugar substitute is tetrahydropyran.

[1265] Embodiment 1242. The conjugated oligonucleotide according to any of claim 1241, wherein the tetrahydropyran is F-HNA.

[1266] Embodiment 1243. A conjugated oligonucleotide according to any one of claims 1238 to 1242, wherein the remainder of the oligonucleotide comprises at least one nucleoside containing a modified sugar.

[1267] Embodiment 1244. The conjugated oligonucleotide of claim 1243, wherein the at least one modified nucleoside comprising a modified sugar is selected from bicyclic nucleosides and 2'-modified nucleosides.

[1268] Embodiment 1245. The conjugated oligonucleotide of claim 1244, wherein the at least one modified nucleoside is a bicyclic nucleoside.

[1269] Embodiment 1246. The conjugated oligonucleotide of claim 1245, wherein the bicyclic nucleoside is a (4'-CH2-O-2')BNA nucleoside.

[1270] Embodiment 1247. The conjugated oligonucleotide of claim 1245, wherein the bicyclic nucleoside is a (4'-(CH2)2-O-2')BNA nucleoside.

[1271] Embodiment 1248. The conjugated oligonucleotide of claim 1245, wherein the bicyclic nucleoside is (4'-C(CH3)HO-2')BNA nucleoside.

[1272] Embodiment 1249. The conjugated oligonucleotide of claim 1244, wherein the at least one modified nucleoside is a 2'-modified nucleoside.

[1273] Embodiment 1250. The conjugated oligonucleotide of claim 1249, wherein the at least one 2'-modified nucleoside is selected from a 2'-F nucleoside, a 2'-OCH3 nucleoside, and a 2'-O(CH2)2OCH3 nucleoside.

[1274] Embodiment 1251. The conjugated oligonucleotide of claim 1250, wherein the at least one 2'-modified nucleoside is a 2'-F nucleoside.

[1275] Embodiment 1252. The conjugated oligonucleotide of claim 1250, wherein the at least one 2'-modified nucleoside is a 2'-OCH3 nucleoside.

[1276] Embodiment 1253. The conjugated oligonucleotide of claim 1250, wherein the at least one 2'-modified nucleoside is a 2'-O(CH2)2OCH3 nucleoside.

[1277] Embodiment 1254. A conjugated oligonucleotide according to any one of claims 1237 to 1253, wherein the oligonucleotide comprises at least one unmodified nucleoside.

[1278] Embodiment 1255. The conjugated oligonucleotide of claim 1254, wherein the unmodified nucleoside is a ribonucleoside.

[1279] Embodiment 1256. The conjugated oligonucleotide of claim 1254, wherein the unmodified nucleoside is a deoxyribonucleoside.

[1280] Embodiment 1257. A conjugated oligonucleotide according to any one of claims 1237 to 1256, wherein the oligonucleotide comprises at least two modified nucleosides.

[1281] Embodiment 1258. The conjugated oligonucleotide of claim 1257, wherein the at least two modified nucleosides include the same modification.

[1282] Embodiment 1259. The conjugated oligonucleotide of claim 1257, wherein the at least two modified nucleosides comprise different modifications.

[1283] Embodiment 1260. A conjugated oligonucleotide according to any one of claims 1257 to 1259, wherein at least one of the at least two modified nucleosides comprises a sugar substitute.

[1284] Embodiment 1261. A conjugated oligonucleotide according to any one of claims 1257 to 1260, wherein at least one of the at least two modified nucleosides includes a 2'-modification.

[1285] Embodiment 1262. The conjugated oligonucleotide of claim 1261, wherein each of the at least two modified nucleosides is independently selected from a 2'-F nucleoside, a 2'-OCH3 nucleoside, and a 2'-O(CH2)2OCH3 nucleoside.

[1286] Embodiment 1263. The conjugated oligonucleotide of claim 1262, wherein each of the at least two modified nucleosides is a 2'-F nucleoside.

[1287] Embodiment 1264. The conjugated oligonucleotide of claim 1262, wherein each of the at least two modified nucleosides is a 2'-OCH3 nucleoside.

[1288] Embodiment 1265. The conjugated oligonucleotide of claim 1262, wherein each of the at least two modified nucleosides is a 2'-O(CH2)2OCH3 nucleoside.

[1289] Embodiment 1266. A conjugated oligonucleotide according to any one of claims 1237 to 1265, wherein essentially all nucleosides of the oligonucleotide are modified nucleosides.

[1290] Embodiment 1267. A conjugated oligonucleotide according to any one of claims 1237-1257 or 1260-1266, wherein all nucleosides of the oligonucleotide are modified nucleosides.

[1291] Embodiment 1268. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide is single-stranded.

[1292] Embodiment 1269. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide is double-stranded.

[1293] Embodiment 1270. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide is an antisense compound.

[1294] Embodiment 1271. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide is a RISC-based oligonucleotide.

[1295] Embodiment 1272. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide activates the RISC pathway.

[1296] Embodiment 1273. A conjugated oligonucleotide according to any one of claims 1237 to 1267, wherein the oligonucleotide is an RNase H-based antisense compound.

[1297] Embodiment 1274. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group is bonded to the 5' terminal nucleoside of the antisense oligonucleotide.

[1298] Embodiment 1275. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group is bonded to the 3' terminal nucleoside of the antisense oligonucleotide.

[1299] Embodiment 1276. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group is bonded to the internal nucleoside of the antisense oligonucleotide.

[1300] Embodiment 1277. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into hepatocytes compared with a non-conjugated oligonucleotide compound.

[1301] Embodiment 1278. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group increases the uptake of the conjugated oligonucleotide compound into liver cells compared to an unconjugated oligonucleotide compound.

[1302] Embodiment 1279. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group increases the accumulation of the conjugated oligonucleotide compound in the liver compared to a non-conjugated oligonucleotide compound.

[1303] Embodiment 1280. A conjugated oligonucleotide compound according to any one of claims 1237 to 1273, wherein the conjugated group reduces the accumulation of the conjugated oligonucleotide compound in the kidney compared to a non-conjugated oligonucleotide compound.

[1304] Embodiment 1281. The conjugated oligonucleotide is A 5' region consisting of 2 to 8 linked 5' region nucleosides, wherein at least 2 5' region nucleosides are modified nucleosides, and the 5' region nucleoside closest to the 3' side is a modified nucleoside, and A 3' region consisting of 2 to 8 linked 3' region nucleosides, wherein at least 2 of the 3' region nucleosides are modified nucleosides, and the 3' region nucleoside closest to the 5' side is a modified nucleoside, and A central region between the 5' region and the 3' region, each consisting of 5 to 10 linked central region nucleosides, wherein each is independently selected from modified nucleosides and unmodified deoxynucleosides, the central region nucleoside furthest to the 5' side is an unmodified deoxynucleoside, and the central region nucleoside furthest to the 3' side is an unmodified deoxynucleoside. A conjugated oligonucleotide compound according to claims 1237-1265 or 1268-1280, having a sugar motif containing a sugar motif.

[1305] Embodiment 1282. The conjugated oligonucleotide compound of claim 1281, wherein the 5' region consists of two linked 5' region nucleosides.

[1306] Embodiment 1283. The conjugated oligonucleotide compound of claim 1281, wherein the 5' region consists of three linked 5' region nucleosides.

[1307] Embodiment 1284. The conjugated oligonucleotide compound of claim 1281, wherein the 5' region consists of four linked 5' region nucleosides.

[1308] Embodiment 1285. The conjugated oligonucleotide compound of claim 1281, wherein the 5' region consists of five linked 5' region nucleosides.

[1309] Embodiment 1286. A conjugated oligonucleotide compound according to any one of claims 1281 to 1285, wherein the 3' region consists of two linked 3' region nucleosides.

[1310] Embodiment 1287. A conjugated oligonucleotide compound according to any one of claims 1281 to 1285, wherein the 3' region consists of three linked 3' region nucleosides.

[1311] Embodiment 1288. A conjugated oligonucleotide compound according to any one of claims 1281 to 1285, wherein the 3' region consists of four linked 3' region nucleosides.

[1312] Embodiment 1289. A conjugated oligonucleotide compound according to any one of claims 1281 to 1285, wherein the 3' region consists of five linked 3' region nucleosides.

[1313] Embodiment 1290. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of five linked central region nucleosides.

[1314] Embodiment 1291. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of six linked central region nucleosides.

[1315] Embodiment 1292. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of seven linked central region nucleosides.

[1316] Embodiment 1293. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of eight linked central region nucleosides.

[1317] Embodiment 1294. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of nine linked central region nucleosides.

[1318] Embodiment 1295. A conjugated oligonucleotide compound according to any one of claims 1281 to 1289, wherein the central region consists of 10 linked central region nucleosides.

[1319] Embodiment 1296. A conjugated oligonucleotide compound according to any one of claims 1281 to 1295, wherein the conjugated oligonucleotide consists of 14 to 26 linked nucleosides.

[1320] Embodiment 1297. A conjugated oligonucleotide compound according to any one of claims 1281 to 1295, wherein the conjugated oligonucleotide consists of 15 to 25 linked nucleosides.

[1321] Embodiment 129...

Claims

1. A conjugated oligonucleotide comprising an oligonucleotide and a conjugated group, Here, the conjugated group is given by the following formula: 【Chemistry 1】 During the ceremony, C is the aforementioned conjugate linker; D is the branching base; Each E is a tether; Each F is a ligand; and, q is an integer between 1 and 5. It has a structure represented by, Here, (i) The branching group has the following structure: 【Chemistry 2】 Having; (ii) The conjugated group comprises three ligands, where each ligand has the following structure: 【Transformation 3】 Having; (iii) The oligonucleotide comprises at least one modified nucleoside, wherein the oligonucleotide is double-stranded or activates the RISC pathway; and, (iv) The oligonucleotide has a nucleic acid base sequence comprising at least eight nucleic acid base portions complementary to the isolength portion of the target nucleic acid, wherein the target nucleic acid encodes a protein selected from androgen receptor, apolipoprotein (a), apolipoprotein B, apolipoprotein C-III, C-reactive protein, eIF-4E, factor VII, factor XI, glucocorticoid receptor, glucagon receptor, protein tyrosine phosphatase 1B, STAT3, SRB-1, and transthyretin. The aforementioned conjugated oligonucleotide.

2. The conjugated oligonucleotide according to claim 1, wherein the tether contains PEG.

3. The conjugated oligonucleotide according to claim 1 or 2, wherein the linker comprises at least one phosphorus-binding group.

4. The conjugated oligonucleotide according to any one of claims 1 to 3, wherein the oligonucleotide includes a monomeric subunit that is not linked to the heterocyclic base portion, thereby providing a debase site.

5. The conjugated oligonucleotide according to any one of claims 1 to 4, wherein each nucleoside bond of the oligonucleotide is selected from phosphodiesters and phosphorothioates, and at least one nucleoside bond is a phosphorothioate.

6. The conjugated oligonucleotide according to any one of claims 1 to 5, wherein the oligonucleotide is paired with a second oligomer compound to form siRNA.

7. The conjugated oligonucleotide according to any one of claims 1 to 6, wherein the oligonucleotide is the antisense strand in a siRNA compound.

8. The conjugated oligonucleotide according to any one of claims 1 to 7, wherein the oligonucleotide comprises at least one modified nucleoside.

9. The conjugated oligonucleotide according to claim 8, wherein the at least one modified nucleoside is a 2'-modified nucleoside.

10. The aforementioned at least one 2'-modified nucleoside is a 2'-F nucleoside, a 2'-OCH ３ Nucleosides, and 2'-O(CH ２ ) ２ OCH ３ A conjugated oligonucleotide according to claim 9, selected from nucleosides.

11. The conjugated oligonucleotide according to any one of claims 1 to 10, wherein the oligonucleotide has a nucleic acid base sequence comprising at least eight nucleic acid base portions complementary to the isolength portion of the target nucleic acid, and wherein the target nucleic acid encodes apolipoprotein C-III.

12. A method for reducing the activity or amount of apolipoprotein C-III protein in cells, comprising contacting the cells with the conjugated antisense compound; thereby reducing the activity or amount of apolipoprotein C-III protein in the cells, A conjugated oligonucleotide according to any one of claims 1-11, for use in the following:

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