COMPOSITION AND METHOD FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION

Abstract

To provide an oligomer compound having a conjugated group targeting apolipoprotein (a) [apo(a)].SOLUTION: In a specific embodiment, an oligomer compound targeting apo(a) is conjugated to N-acetylgalactosamine. Also disclosed herein is a conjugated oligomer compound targeting apo(a) which is used in reducing apo(a), and treating, preventing or ameliorating a disease, disorder or condition associated with apo(a) and / or Lp(a). A specific disease, disorder or condition associates with apo(a) and / or Lp(a) includes inflammatory, cardiovascular, and / or metabolic diseases, disorders or conditions. By using the conjugated oligomer compound disclosed herein, such a disease, disorder, or condition in an individual who needs the compound can be treated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application has been filed in electronic format together with a sequence listing. The sequence listing was filed in electronic format as of May 2014. BIOL0250WOSEQ_ST25.txt, created on the 1st, with a size of 432Kb The information in this electronic sequence listing is provided as a file entitled "Sequence Listing 10.1 ... is incorporated herein in its entirety. [Background technology]

[0002] The principle behind antisense technology is that antisense compounds hybridize to target nucleic acids. The objective of this study is to regulate the amount, activity, and / or function of a target nucleic acid by adjusting the target nucleic acid. In certain cases, antisense compounds result in alterations in the transcription or translation of the target. Such regulation can be achieved, for example, by target mRNA degradation or occupancy-based inhibition. One example of modulation of RNA target function by degradation is the use of DNA-like antisense compounds. Upon hybridization, there is RNase H-based degradation of the target RNA. Another example of the regulation of gene expression by RNA is RNA interference (RNAi). i is an antisense molecule that mediates RNA-induced silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC). Further examples of the regulation of RNA target function include microRNAs and RNAi-mediated gene silencing. by occupancy-based mechanisms such as those naturally used by RNA. MicroRNAs are small non-coding RNAs that regulate the expression of protein-coding RNAs. The binding of an antisense compound to an RNA results in the transcription of that microRNA into its messenger RNA. A microRNA mimic prevents binding to the target and therefore interferes with the function of the microRNA. Certain antisense compounds can enhance native microRNA function. , altering pre-mRNA splicing. Regardless of the specific mechanism, sequence specificity is , a means of target validation and gene functioning, and expression of genes involved in disease pathogenesis This makes antisense compounds attractive as therapeutic agents that selectively modulate

[0003] Antisense technology is an effective means of regulating the expression of one or more specific gene products. and therefore uniquely useful for many therapeutic, diagnostic, and research applications. Chemically modified nucleosides can be incorporated into antisense compounds to target enhancing one or more properties of the target nucleic acid, such as nuclease resistance, pharmacokinetics, or affinity; In 1998, the antisense compound Vitravene® ( Mivirsen, Isis Pharmaceuticals Inc. (Carlsbad) ,CA) has received marketing approval from the U.S. Food and Drug Administration (FDA). It is the first antisense drug to be developed and is currently being used to treat cytomegalovirus ( It is a treatment for CMV-induced retinitis.

[0004] New chemical modifications have improved the potency and efficacy of antisense compounds, allowing for oral delivery Discover the potential for enhanced subcutaneous administration, reduced side effects, and improved patient convenience Chemical modifications that increase the potency of antisense compounds have led to lower doses. Increased resistance to degradation, reducing the potential for toxicity and overall treatment costs Modifications that result in slower elimination from the body, allowing for less frequent dosing. Different types of chemical modifications can be combined within a single compound to further optimize the efficacy of the compound. It is possible.

[0005] Lipoproteins are made up of amphiphilic coatings of proteins, phospholipids, and cholesterol. It consists of a non-polar core of acylglycerol and cholesteryl esters surrounded by a lining. Lipoproteins are spherical, micelle-like particles. Based on their functional and physical properties, Based on these, there are five broad categories: chylomicrons, very low density lipoproteins (VLDL), ), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) Chylomicrons are classified as high-density lipoproteins (HDL). VLDL, IDL, and LDL all contain triacylglycerol and HDL transports endogenous cholesterol from the liver to the tissues. It is transported to the liver.

[0006] Lipoprotein particles undergo successive metabolic processes and have variable properties and compositions. Protein density is determined by the particle size because the density of their outer coating is less than that of the inner core. The protein component of lipoproteins is apolipoproteins. At least nine apolipoproteins are known as apolipoproteins. It is distributed in significant amounts between tissues.

[0007] Lipoprotein(a) [Lp(a)] particles were identified approximately 50 years ago and are highly unique. It consists of a specific LDL particle, which contains one apolipoprotein B (apoB) protein. The protein is bound to a single apolipoprotein (a) [apo(a)] protein via disulfide bonds. The apo(a) protein is linked to the protein, particularly the kringle IV type 2 repeat domain. It shares a high degree of homology with plasminogen in the blood. The level of circulating Lp(a) varies depending on the molecule. The co-occurrence of both alleles in an individual is inversely proportional to the number of kringle type IV2 variable repeats present. To reveal the heterozygous plasma isoform profile, raft et al.,Eur J Hum Genet,1996;4(2):74 -87). This kringle repeat domain in apo(a) may be responsible for its prothrombotic properties. may be involved in the anti-fibrinolytic and anti-arteriosclerotic properties and may enhance atherosclerosis progression. It is thought that this is the case.

[0008] Apo(a) is transcriptionally regulated by IL-6 and inhibited by the IL-6 inhibitor tocilizumab. In a study in treated rheumatoid arthritis patients, plasma levels were measured after 3 months of treatment. later decreased by 30% (Schultz et al., PLoS One 2010;5 :e14328).

[0009] Apo(a) has been shown to preferentially bind to oxidized phospholipids and enhance vascular inflammation. (Bergmark et al., J Lipid Res 2008;49 :2230-2239, Tsimikas et al.,Circulation.2 009;119(13):1711-1719).

[0010] Furthermore, studies have shown that Lp(a) particles stimulate endothelial permeability and act as plasminogen activators. It can induce type 1 expression of IL-1 receptor agonist and activate macrophage interleukin-8 secretion. This suggests that (Pin Lipidol 2004;15:167-174). Importantly, Gene association studies have linked Lp(a) to myocardial infarction, stroke, peripheral vascular disease, and abdominal aortic aneurysm. It has been shown to be an independent risk factor (Rifai et al., Clin Che m 2004;50:1364-71, Erqou et al., JAMA 2009 ;302:412-23, Kamstrup et al.,Circulation 2008;117:176-84). Furthermore, in recent years, the incidence of premature coronary artery disease (PROCARD) In the IS study, Clarke et al. (Clarke et al., NE JM(2009)361;2518-2528) has been shown to be associated with coronary heart disease and plasma Lp( a) describes a strong and independent association between the concentration of et al. reported that elevated serum Lp(a) is associated with increased risk of Alzheimer's disease (AD). (Solfrizzi et al., J Neurol Neu Rosurg Psychiatry 2002,72:732-736). Currently, In this context, examples of indirect apo(a) inhibitors for treating cardiovascular disease include: Plasma Lp(a) levels were 18%, 39%, 32%, 36%, 43%, and 17% reduction in vasopressin, aspirin, niacin, mipomersen, anacetrapib, and eprotipine Lp(a) apheresis is also used to treat Lp( a) It is used in the clinic to reduce apo(a) containing particles.

[0011] To date, direct targeting of apo(a) levels has been used to treat cardiovascular disease. Therapeutic strategies are limited. Ribozyme oligonucleotides (U.S. Pat. No. 5,877 ,022) and antisense oligonucleotides (International Publication No. WO2005 / 0002 01, International Publication No. WO2003 / 014397, International Publication No. WO2013 / 1774 No. 68, U.S. Patent No. 20040242516, U.S. Patent No. 8,138,328, U.S. Patent No. Nos. 8,673,632 and 7,259,150, Merki et al., J Am Coll Cardiol 2011;57:1611-1621 (each publication Although several patents have been developed, none of which are approved for commercial use, It has not been approved.

[0012] Therefore, the risk of cardiovascular events due to chronically elevated plasma Lp(a) levels is unclear. Potently and selectively reduces apo(a) levels in high-risk patients There remains a clear unmet medical need for new agents. Summary of the Invention

[0013] Compositions and methods for modulating apo(a) mRNA and protein expression are provided herein. In certain embodiments, the apo(a)-specific inhibitor is Decreases the expression of o(a) mRNA and protein. Regulates the expression of Lp(a) levels. Compositions and methods for doing so are provided herein.

[0014] In certain embodiments, the composition is an apo(a)-specific inhibitor. In this embodiment, the apo(a)-specific inhibitor is a nucleic acid, a protein, or a small molecule. In certain embodiments, the apo(a)-specific inhibitor is an apo(a)-containing inhibitor. In certain embodiments, the antisense oligonucleotide targets o(a). In this regard, apo(a)-specific inhibitors are modified oligonucleotides and conjugates, and modified The oligonucleotide consists of 12 to 30 linked nucleosides and is represented by SEQ ID NO: 1. At least eight consecutive nucleobases complementary to an isometric portion of nucleobases 3901 to 3920 of and the nucleobase sequence of the modified oligonucleotide comprises a nucleobase sequence comprising a portion of SEQ ID NO: 1. In certain embodiments, the apo(a)-specific The inhibitors are modified oligonucleotides and conjugates, and the modified oligonucleotides are Consisting of 2 to 30 linked nucleosides, and SEQ ID NOs: 1 to 130, 133, 134 At least 8, at least 9, at least 10, at least 11, at least 12, at least 1 3, at least 14, at least 15, at least 16, minimum 17, minimum 18, minimum 19 or a nucleobase sequence comprising 20 consecutive nucleobases. In this context, the apo(a)-specific inhibitors are modified oligonucleotides and conjugates, The decorated oligonucleotide consists of 20 linked nucleosides and is represented by SEQ ID NO: 58. and a nucleic acid sequence containing at least 8 consecutive nucleic acid bases of any one of the following: A oligonucleotide is (a) a gap-separating oligonucleotide consisting of 10 linked deoxynucleosides. (b) a 5' wing segment consisting of five linked nucleosides; (c) It contains a 3' wing segment consisting of five linked nucleosides and a gap segment. The 5' wing segment is positioned between the 5' wing segment and the 3' wing segment, and each wing Each nucleoside in the binding segment contains a 2'-O-methoxyethyl sugar and at least one The internucleoside linkages are phosphorothioate linkages, and each cytosine residue is a 5-methyl It is thyrcytosine.

[0015] Certain embodiments include a conjugated antisense compound described herein, or a salt thereof, and and a pharmaceutically acceptable carrier or diluent.

[0016] In certain embodiments, the modulation of apo(a) expression occurs in a cell or tissue. In certain embodiments, the modulation occurs within a cell or tissue in an animal. In certain embodiments, the animal is a human. In certain embodiments, the modulation is a reduction in apo(a) mRNA levels. In certain embodiments, apo(a)m protein levels are reduced. Both RNA levels and apo(a) protein levels are reduced. In this study, the modulation is a decrease in Lp(a) levels. Such a decrease may be time-dependent or may occur in a dose-dependent manner.

[0017] Certain embodiments provide conjugated antisense compositions and methods for use in therapy. Certain embodiments provide methods for preventing apo(a)-related diseases, disorders, and conditions. and methods for treating, retarding, slowing the progression of, and / or ameliorating, inflammatory bowel disease - Patents.com Certain embodiments provide a method for preventing Lp(a)-related diseases, disorders, and conditions, Compositions and methods for treating, retarding, slowing the progression of, and / or ameliorating In certain embodiments, such diseases, disorders, and conditions are inflammatory diseases, disorders, and conditions. , cardiovascular, and / or metabolic diseases, disorders, and conditions. In the present invention, therapeutic compositions and methods are provided that provide an apo(a)-specific inhibitor In certain embodiments, the apo(a)-specific inhibitor is In certain embodiments, the nucleic acid is an antisense compound. In certain embodiments, the antisense compounds are modified oligonucleotides. In certain embodiments, the antisense compound comprises a modified oligonucleotide having a conjugate. It is Do.

[0018] In certain embodiments, the present disclosure provides conjugated antisense compounds. In certain embodiments, the present disclosure provides an antisense oligonucleotide complementary to a nucleic acid transcript. In certain embodiments, the present disclosure provides conjugated antisense compounds comprising: Conjugating cells with antisense oligonucleotides complementary to nucleic acid transcripts In certain embodiments, the present disclosure provides a method comprising contacting a compound comprising: contacting the cell with a conjugated antisense compound comprising an antisense oligonucleotide and reducing the amount or activity of a nucleic acid transcript in the cell.

[0019] The asialoglycoprotein receptor (ASGP-R) has been previously described. rk et al.,PNAS vol.102,No.47,pp17125-171 29 (2005). Such receptors are expressed in liver cells, particularly hepatocytes. Furthermore, three N-acetylgalactosamine (GalNAc) ligands are expressed on the Compounds containing clusters can bind to ASGP-R, and their uptake into cells is For example, Khorev et al., Bior ganic and Medicinal Chemistry,16,9,pp5216- 5231 (May 2008). Conjugates containing raster can be used to deliver certain compounds to liver cells, specifically hepatocytes. For example, certain GalNAc-containing conjugates are transported by liver cells in vivo. It has been shown that these compounds increase the activity of double-stranded siRNA compounds in cells. In this case, the GalNAc-containing conjugate is typically attached to the sense strand of the siRNA duplex. The sense strand is processed before the antisense strand finally hybridizes to the target nucleic acid. Because the conjugates are separated, there is little concern that they will interfere with activity. is attached to the 3' end of the sense strand of the siRNA. 22. Certain conjugate groups described herein may be used in combination with previously described conjugate groups. are more active and / or easier to synthesize than

[0020] In certain embodiments of the invention, the conjugate inhibits splicing of a pre-mRNA target nucleic acid. RNase H-based antisense compounds and antisense compounds that alter Such an embodiment is linked to a single-stranded antisense compound, including, but not limited to, In embodiments, the conjugate is administered for a period of time sufficient to provide a benefit (e.g., improved cellular uptake). The target protein should remain bound to the antisense compound during the binding period, but be cleaved or otherwise otherwise, hybridization to a target nucleic acid associated with splicing or splicing regulation. Subsequent steps required for activity, such as cleavage and interaction with RNase H or enzymes The balance of these properties is important for siR This is more important in the context of single-stranded antisense compounds than NA compounds, and the conjugates The conjugate may be attached to the sense strand only. Conjugated single-stranded antisense compounds with improved potency in liver cells within the Considering the balance of properties required for these compounds, The improvement is astonishing.

[0021] In certain embodiments, the conjugate groups herein comprise a cleavable moiety. As mentioned above, without wishing to be bound by the mechanism, the conjugates may be used to enhance uptake. It should remain in the compound long enough to provide the desired effect, but then one of the conjugates The conjugate is then cleaved to release the parent compound (e.g., antisense It is logical to desire to release the compound in its most active form. In some embodiments, the cleavable moiety is a cleavable nucleoside. Embodiments include those in which nucleosides are linked by one or more cleavable bonds, such as phosphodiester bonds. Attaching the remainder of the conjugate (cluster) to the antisense oligonucleotide via In certain embodiments, the method takes advantage of endogenous nucleases in cells. , the cluster is linked to a scissile nucleoside by a phosphodiester bond. In certain embodiments, the cleavable nucleoside is linked by a phosphodiester bond. Antisense oligonucleotides (antisense compounds) are attached to the target site. In embodiments, the conjugate group may include two or three cleavable nucleosides. In such embodiments, such cleavable nucleosides may have a cleavable bond (phosphoryl). to each other, to the antisense compounds, and / or to the clusters Certain conjugates herein include a cleavable nucleoside. Instead, it contains a cleavable bond. provided by at least one bond that is vulnerable to cleavage in the cell (a cleavable bond) It is shown that this will be the case.

[0022] In certain embodiments, the conjugated antisense compound is a prodrug. Such prodrugs are administered to animals and ultimately metabolized to a more active form. The conjugated antisense compound may be cleaved to remove all or part of the conjugate, and (b) providing an active (or more active) form of the antisense compound lacking all or part of the vinegar.

[0023] In certain embodiments, the conjugate is attached to the 5' end of the oligonucleotide. Certain such 5' conjugates have corresponding conjugate groups attached to the 3' terminus. In certain embodiments, improved activity is achieved by improved cleavage. In certain embodiments, an oligonucleotide comprising a conjugate at the 5' end may be The efficacy of the oligonucleotides is higher than that of oligonucleotides containing conjugates at the 3' end (see, e.g., Example 1). 56, 81, 83, and 84). In addition, the 5' linkage is Typically, oligonucleotides are synthesized in a 3' to 5' direction. To make 3' conjugated oligonucleotides, they are typically synthesized on a solid support. To do this, a pre-conjugated 3' nucleoside is attached to a solid support, followed by the addition of an oligonucleotide. However, the conjugated nucleoside is attached to a solid support. Furthermore, by using this procedure, the conjugate is then It is present throughout the synthesis of oligonucleotides and can be degraded during subsequent steps. or limit the types of reactants and reagents that can be used. By using conjugated oligonucleotide structures and techniques, it is possible to carry out the synthesis of nucleotides using standard automated techniques. The oligonucleotide is synthesized using the 5'-nucleotide conjugate. Alternatively, the oligonucleotides can be cleaved from the solid support and then reassembled. Nucleotides can be synthesized.

[0024] In view of the art and this disclosure, one of ordinary skill in the art would be able to readily identify the conjugates and conjugate o- Furthermore, any of the oligonucleotides described herein can be readily produced. The synthesis of certain such conjugates and conjugated oligonucleotides disclosed has been previously described. The synthesis of the disclosed conjugates is easier and / or requires fewer steps. They are therefore inexpensive and offer advantages in manufacturing. The synthesis involves fewer synthetic steps and increased yields compared to previously described conjugate groups. GalNAc3-10 in Example 46 and GalNAc3- Conjugated groups such as 7 require the construction of more chemical intermediates. U.S. Patent No. 8,106,022 Previously described conjugates, such as those described in U.S. Pat. No. 2 or U.S. Pat. No. 7,262,177 These and other conjugates described herein are therefore much simpler than single-stranded oligonucleotides and double-stranded oligonucleotides (e.g., siRNA) When used in conjunction with any oligonucleotide containing either strand of It is more advantageous than the compound.

[0025] Similarly, conjugate groups having only one or two GalNAc ligands are disclosed herein. As shown, such conjugate groups improve the activity of the antisense compounds. Such compounds are easier to prepare than conjugates containing three GalNAc ligands. Conjugate groups containing one or two GalNAc ligands are used in single-stranded oligonucleotides and and any amplicon containing either strand of a double-stranded oligonucleotide (e.g., siRNA). The nucleotide sequence can be linked to a cis-sense compound.

[0026] In certain embodiments, the conjugates herein substantially improve the tolerability to some extent. For example, the immunogenicity of a conjugated antisense compound does not change the immunogenicity of the unconjugated parent compound. It is shown herein that the strength is lower than that of the conventional steroids. (or even if there is only a slight decrease in tolerance compared to the increase in intensity) Some embodiments have improved therapeutic properties.

[0027] In certain embodiments, the conjugate may be a less attractive result in the absence of the conjugate. This allows the antisense compound to be altered in a manner that has a beneficial effect. For example, In some embodiments, one or more phosphothioates of a fully phosphorothioate antisense compound may be present. Substitution of the thiolate bond with a phosphodiester bond may improve tolerability to some extent. For example, in certain cases, the The immunogenicity of such antisense compounds is enhanced by the use of identical nucleotides in which each linkage is a phosphorothioate linkage. However, in certain cases, the immunogenicity of the compound is lower than that of the compound shown in Example 26. Similar substitution of one or more phosphorothioate linkages for phosphodiester linkages is also possible, as shown in Conversion also results in reduced cellular uptake and / or loss of strength. In the present invention, the conjugated antisense compounds are fully phosphorothioate conjugated pairs. Such a compound can be produced with little or no loss of uptake and strength compared to the reactant. Indeed, in certain embodiments, e.g., Examples 44, 57, 59, and 86, the conjugate and at least one phosphodiester nucleoside Oligonucleotides containing inter-mer linkages are also fully phosphorothioated containing the same conjugate. They also demonstrate increased in vivo potency when compared to their hydroxyl counterparts. results in a substantial increase in uptake / intensity, so the small loss of that substantial increase is It may be acceptable to achieve improved tolerability. In the present invention, the conjugated antisense compound contains at least one phosphodiester bond.

[0028] In certain embodiments, conjugates of the antisense compounds herein are directed to hepatocytes. This results in increased delivery, uptake, and activity in the is delivered to liver tissue. However, in certain embodiments, such delivery An increase in activity alone does not manifest as an overall increase in activity. In certain embodiments, such hepatocytes Even increased uptake does not manifest as increased overall activity. , the productive uptake of the conjugate compound is increased. For example, as shown in Example 102, Certain embodiments of GalNAc-containing conjugates exhibit increased activity in hepatocytes compared to non-parenchymal cells. This concentration increases the concentration of antisense oligonucleotides expressed in hepatocytes. It is beneficial to target oligonucleotides to genes that are expressed.

[0029] In certain embodiments, the conjugated antisense compounds herein are administered to mice exposed to kidney disease. For example, as shown in Example 20, some GalNAc-containing conjugates The concentration of antisense oligonucleotides, including certain embodiments thereof, in the kidney is This is lower than the concentration of the antisense oligonucleotide lacking the lNAc-containing conjugate. It has several beneficial therapeutic implications. In this case, kidney exposure carries the risk of nephrotoxicity without corresponding benefit. High concentrations in the urine typically result in loss of the compound in the urine and more rapid clearance. Therefore, in the case of non-renal targets, accumulation in the kidney is undesirable.

[0030] In certain embodiments, the present disclosure provides an antisense conjugate represented by the formula: providing a compound, [ka] During the ceremony, A is an antisense oligonucleotide, B is a cleavable moiety, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0031] In the figures above and similar figures herein, the branching group "D" is designated by "q". The branching is repeated as many times as necessary to accommodate the number of (E to F) groups. In this case, the formula is: [ka] For q=2, the formula is: [ka] For q=3, the formula is: [ka] For q=4, the formula is: [ka] For q=5, the formula is: [ka]

[0032] In certain embodiments, conjugated antisense compounds are provided having the structure: do. [ka]

[0033] In certain embodiments, conjugated antisense compounds are provided having the structure: do. [ka]

[0034] In certain embodiments, conjugated antisense compounds are provided having the structure: do. [ka]

[0035] In certain embodiments, conjugated antisense compounds are provided having the structure: do. [ka]

[0036] The present disclosure provides the following non-limiting numbered embodiments:

[0037] Implementations with more than one of a particular variable (e.g., more than one "m" or "n") In the embodiments, unless otherwise indicated, each such specific variable is independently selected. Thus, for structures with two or more n's, each n is independently selected and therefore mutually They may or may not be identical.

[0038] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compound comprises a 5'-X and a modified oligonucleotide ISIS 494372 having the formula: c. In certain embodiments, the antisense compound is a 5'-X wherein X is Gal It is a conjugated group containing NAc. [ka]

[0039] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are conjugated modified antisense compounds. In certain embodiments, the antibody comprises the oligonucleotide ISIS 681251. The sense compound consists of the conjugated modified oligonucleotide ISIS 681251. [ka]

[0040] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are conjugate modified In certain embodiments, the oligonucleotide comprises the oligonucleotide ISIS 681257. The chisense compound consists of the conjugated modified oligonucleotide ISIS 681257. [ka]

[0041] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are Modified oligonucleotides having SEQ ID NO: 58 with altered sugar modifications, 5'-GalNAc In certain embodiments, the antisense compounds comprise wing sugar modifications. From modified oligonucleotides having SEQ ID NO: 58 with varying 5'-GalNAc And [ka]

[0042] In the formula, R 1 is -OCH2CH2OCH3(MOE), and R 2 Is it H or or R 1 and R 2 together to form a bridge, where R 1 but, -O- and R 2 is -CH2-, -CH(CH3)-, or -CH2CH2- The resulting bridges are -O-CH2-, -O-CH(CH3)-, and -OC R is selected from H2CH2- 1 and R 2 are directly connected, On the same ring, independently, R on each ring 3 and R 4 For each pair of R 3 H and -OCH 2CH2OCH3, and R 4 is H or R 3 and R 4 together either form a bridge, where R 3 is -O- and R 4 But -CH 2-, -CH(CH3)-, or -CH2CH2-, and the resulting bridge is - -O-CH2-, -O-CH(CH3)-, and -O-CH2CH2- Sea urchin, R 3 and R 4 are directly connected, R 5 is selected from H and -CH3; Z is S - and O- is selected from. The present disclosure provides the following non-limiting numbered embodiments: DETAILED DESCRIPTION OF THE INVENTION

[0043] Both the foregoing general description and the following detailed description are exemplary and explanatory only. It should be understood that this is not a limitation of the present disclosure. The use includes the plural unless expressly stated otherwise. The use of "or" means "and / or" unless otherwise stated. Furthermore, the terms "including" and "i The use of other forms such as "include" and "included" is intended to be limiting. Furthermore, terms such as "element" or "component" are not intended to be limiting unless expressly stated otherwise. Multiple elements containing one unit and multiple components and multiple elements containing two or more subunits The term encompasses both elements and components of the compound.

[0044] The section headings used herein are for organizational purposes only and do not limit the subject matter described. This document includes patents, patent applications, articles, books, and papers. All documents or portions of documents cited in this application, including but not limited to: No. 6,279,629, filed Dec. 1, 2004, which are expressly incorporated herein by reference in their entirety for all purposes. A.Definition

[0045] Unless specific definitions are provided, analytical chemistry, synthetic organic chemistry, and The scientific names used in connection with medicinal and pharmaceutical chemistry, as well as the procedures and techniques involved, are Standard techniques are well known and commonly used in the art. Certain such techniques and procedures can be used in chemical analysis. Arbohydrate Modifications in Antisense R esearch”Edited by Sangvi and Cook,America a Chemical Society,Washington DC,1994 , “Remington's Pharmaceutical Sciences,” M ack Publishing Co.,Easton,Pa.,21 st editi on,2005, and “Antisense Drug Technology,Pr principles, Strategies, and Applications”Edi ted by Stanley T. Crooke, CRC Press, Boca R aton, Florida, and Sambrook et al., “Molecu lar Cloning, A laboratory manual,”2 nd Edi tion,Cold Spring Harbor Laboratory Press , 1989, which are incorporated herein by reference for all purposes. Where permitted, all patents, applications, and related documents referenced throughout this disclosure are incorporated herein by reference. Published applications and other publications and other data are incorporated by reference in their entirety. incorporated herein.

[0046] Unless otherwise indicated, the following terms have the following meanings. As used herein, a "nucleoside" includes a nucleobase moiety and a sugar moiety. Nucleosides refer to compounds that are naturally occurring nucleosides (DNA and RNA). A) as well as modified nucleosides. The cleoside may be linked to a phosphate moiety.

[0047] As used herein, a "chemical modification" refers to a modification that, when compared to its naturally occurring counterpart, The chemical modification of oligonucleotides refers to the chemical difference between the two compounds. Modifications of the sugar moiety and nucleobase are included) and internucleoside linkage modifications. With respect to nucleotides, chemical modifications do not involve differences only in the nucleobase sequence.

[0048] As used herein, "furanosyl" refers to a group of four carbon atoms and one oxygen atom. means a structure containing a five-membered ring containing

[0049] As used herein, a "naturally occurring sugar moiety" refers to a sugar moiety found in naturally occurring RNA. Ribofuranosyl found in naturally occurring DNA or deoxyribofuranosyl found in naturally occurring DNA means.

[0050] As used herein, a "sugar moiety" refers to the naturally occurring sugar moiety of a nucleoside or or modified sugar moiety.

[0051] As used herein, "modified sugar moiety" means a substituted sugar moiety or sugar surrogate. do.

[0052] As used herein, a "substituted sugar moiety" refers to a sugar moiety that is not a naturally occurring sugar moiety. The substituted sugar moiety may have 2', 3', 5', and / or 4' positions. Certain substituted sugar moieties include, but are not limited to, furanosyl containing substituents. , a bicyclic sugar moiety.

[0053] As used herein, a "2'-substituted sugar moiety" refers to a sugar moiety having a 2'-substituted sugar moiety other than H or OH. Unless otherwise indicated, the 2'-substituted sugar moiety is a bicyclic not the sugar moiety (i.e., the 2'-substituent of the 2'-substituted sugar moiety is another atom of the furanosyl ring) does not form a bridge to the child).

[0054] As used herein, "MOE" means -OCH2CH2OCH3.

[0055] As used herein, a "2'-F nucleoside" refers to a nucleoside containing a sugar containing a fluorine at the 2' position. Unless otherwise indicated, the fluorine in a 2'-F nucleoside is , at the ribo position (replacing the OH of natural ribose).

[0056] As used herein, the term "sugar surrogate" refers to the resulting nucleosides. The nucleotide subunits bind together and / or to other nucleosides to form complementary oligonucleotides. and forming oligomeric compounds that can hybridize to oligomeric compounds. The nucleoside is free of furanosyl groups and replaces the naturally occurring sugar moiety of the nucleoside so that it can be Such structures include furanosyl (e.g., 4, 6, or a seven-membered ring), a furanosyl with a different number of atoms than the oxygen and non-oxygen atoms (e.g., carbon, sulfur, or nitrogen), or rings containing both a change in the number of atoms and oxygen substitutions Such structures also include substituted sugar moieties (e.g., six-membered carbocyclic rings optionally containing further substituents). The sugar surrogate may also include substitutions corresponding to those described for the bicyclic sugar surrogate. , as well as more complex sugar substitutes (e.g., the acyclic systems of peptide nucleic acids). cyclohexyl, cyclohexyl, and cyclohexitol. do not have.

[0057] As used herein, a "bicyclic sugar moiety" refers to a sugar moiety that connects two atoms of a 4- to 7-membered ring. A 4- to 7-membered ring (including furanosyl) containing a bridge to form a second ring, resulting in a bicyclic structure. In certain embodiments, 4 In certain embodiments, the 4- to 7-membered ring is a furanosyl. In certain such embodiments, the bridge is between the 2'-carbon and the 4'-carbon of the furanosyl. Connect with the elements.

[0058] As used herein, "nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and single-stranded nucleic acid (ssDNA). ), double-stranded nucleic acid (dsDNA), small interfering ribonucleic acid (siRNA), and microRNA Nucleic acids contain any combination of these elements in a single molecule. It may also include.

[0059] As used herein, a "nucleotide" further comprises a phosphate linking group. As used herein, "linked nucleosides" refers to nucleosides. The nucleotides may or may not be linked by a phosphate bond, and are therefore referred to as "linked nucleosides." As used herein, "linked nucleotides" includes, but is not limited to, "linked nucleotides." "Nucleosides" are nucleosides that are linked in a contiguous sequence (i.e., additional nucleosides). No nucleotides are present between the linked sequences).

[0060] As used herein, a "nucleobase" refers to a base that is linked to a sugar moiety in an oligonucleotide. means a group of atoms that can be incorporated into a nucleoside to form a nucleoside, The molecule binds to a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. The nucleobases can be naturally occurring or modified. As used herein, "nucleobase sequence" refers to a sequence of nucleotides, regardless of any sugar, linkage, or nucleobase modifications. It refers to the order of consecutive nucleic acid bases.

[0061] As used herein, an "unmodified nucleobase" or a "naturally occurring nucleobase" is The term refers to the naturally occurring heterocyclic nucleobases of RNA or DNA, and purines are The bases are adenine (A) and guanine (G), and the pyrimidines are thymine (T), cysteine ​​(C), and thiamin (H). Based on tosine (C) (containing 5-methyl C) and uracil (U).

[0062] As used herein, a "modified nucleobase" refers to a base that is not a naturally occurring nucleobase. It means any nucleic acid base.

[0063] As used herein, "modified nucleosides" refers to nucleosides that are naturally occurring in RNA or It refers to a nucleoside that contains at least one chemical modification compared to a DNA nucleoside. Modified nucleosides contain a modified sugar moiety and / or a modified nucleobase.

[0064] As used herein, a "bicyclic nucleoside" or "BNA" refers to a bicyclic sugar means a nucleoside containing the moiety.

[0065] As used herein, a "constrained ethyl nucleoside" or "cEt" refers to a 4' It refers to a nucleoside containing a bicyclic sugar moiety containing a -CH(CH3)-O-2' bridge.

[0066] As used herein, a "locked acid nucleoside" or "LNA" refers to a nucleoside that is 4' It refers to a nucleoside containing a bicyclic sugar moiety containing a -CH2-O-2' bridge.

[0067] As used herein, a "2'-substituted nucleoside" refers to a nucleoside that has a 2'-substituted nucleoside group other than H or OH. Unless otherwise indicated, 2'-substituted nucleosides refer to nucleosides containing a substituent at the 2'-position. The nucleoside is not a bicyclic nucleoside.

[0068] As used herein, "deoxynucleoside" refers to a naturally occurring deoxynucleoside. Nucleosides containing the 2'-H furanosyl sugar moiety found in ribonucleosides (DNA) In certain embodiments, the 2'-deoxynucleoside is a modified nucleobase or may comprise RNA nucleobases (e.g., uracil).

[0069] As used herein, an "oligonucleotide" refers to a plurality of linked nucleotides. In certain embodiments, the oligonucleotide is a compound comprising 1 one or more unmodified ribonucleosides (RNA) and / or unmodified deoxyribonucleosides nucleotides (DNA) and / or one or more modified nucleosides.

[0070] As used herein, an "oligonucleoside" refers to a nucleoside having an internucleoside bond. As used herein, "oligonucleotide" refers to an oligonucleotide in which none of the following groups contains a phosphorus atom. When, the oligonucleotide comprises an oligonucleoside.

[0071] As used herein, a "modified oligonucleotide" refers to an oligonucleotide containing at least one modification Nucleosides and / or oligonucleotides containing at least one modified internucleoside linkage It means leotide.

[0072] As used herein, a "bond" or "linking group" refers to a group that connects two or more other groups of atoms. It means a group of atoms bonded together.

[0073] As used herein, an "internucleoside linkage" refers to a linkage between adjacent nucleoside residues in an oligonucleotide. It refers to the covalent bond between adjacent nucleosides.

[0074] As used herein, a "naturally occurring internucleoside linkage" refers to a 3' to 5' internucleoside linkage. ' means a phosphodiester bond to the

[0075] As used herein, a "modified internucleoside linkage" refers to a naturally occurring nucleoside It refers to any internucleoside bond other than an internucleoside bond.

[0076] As used herein, a "terminal internucleoside linkage" refers to a terminal internucleoside linkage in an oligonucleotide or or the bond between the last two nucleosides of that defined region.

[0077] As used herein, "phosphorus linking group" means a linking group that includes a phosphorus atom. Phosphorus binding groups include, but are not limited to, groups having the formula: [ka] During the ceremony, R a and R d are each independently O, S, CH2, NH, or NJ1, and J1 is C1-C6 alkyl or substituted C1-C6 alkyl, R b is O or S, R c is OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy alkoxy, substituted C1-C6 alkoxy, amino, or substituted amino; J1 is R b is O or S.

[0078] Phosphorus linking groups include phosphodiester, phosphorothioate, phosphorodithioate, and phosphatidylcholine. Sulfonates, phosphoramidates, phosphorothioamidates, thionoalkylphosphonates , phosphotriesters, thionoalkylphosphotriesters, and boranophosphates These include, but are not limited to:

[0079] As used herein, an "internucleoside phosphorus linking group" refers to a group that connects two nucleosides. means a phosphorus-binding group that directly bonds

[0080] As used herein, a "non-internucleoside phosphorus linking group" refers to a group that links two nucleosides. In certain embodiments, the phosphorus linking group is a group that does not directly link the A non-internucleoside phosphorus linking group links a nucleoside to a moiety other than a nucleoside.

[0081] In certain embodiments, A non-internucleoside phosphorus linking group connects two groups, both of which are nucleosides. Not Do.

[0082] As used herein, "neutral binding group" means a binding group that is not charged. Neutral linking groups include phosphotriesters, methylphosphonates, MMI(-CH2-N( CH3)-O-), amide-3 (-CH2-C(=O)-N(H)-), amide-4 (- CH2-N(H)-C(=O)-), formacetal (-O-CH2-O-), and Examples include, but are not limited to, thioform acetal (-S-CH2-O-). In addition, neutral bonding groups include siloxane (dialkylsiloxane), carboxylic acid ester, Contains nonionic bonds including benzoxamides, sulfides, sulfonate esters, and amides. (e.g., Carbohydrate Modifications in Ant isense Research;YS Sanghvi and PDCook Eds.ACS Symposium Series 580;Chapters 3 and 4 (pp. 40-65). Furthermore, the neutral bonding groups are mixed. It contains non-ionic bonds containing N, O, S, and CH2 moieties.

[0083] As used herein, a "neutral internucleoside linking group" refers to a linking group between two nucleosides. means a neutral bonding group that directly bonds

[0084] As used herein, a "non-internucleoside neutral linking group" refers to a linking group between two nucleosides. In certain embodiments, a non-nucleoside is a neutral linking group that does not directly link a non-nucleoside. An internucleoside neutral linking group links a nucleoside to a non-nucleoside group.

[0085] In certain embodiments, the non-internucleoside neutral linking group connects two groups , none of which are nucleosides.

[0086] As used herein, an "oligomeric compound" refers to a polymeric compound containing two or more substructures. In certain embodiments, the oligomeric compound refers to an oligonucleotide. In certain embodiments, the oligomeric compound comprises one or more conjugated groups and and / or terminal groups. In certain embodiments, the oligomeric compound comprises an oligomer. Oligomeric compounds are composed of nucleotides. Oligomeric compounds also include naturally occurring nucleic acids. In one embodiment, the oligomeric compound comprises a skeleton of one or more linked monomeric subunits. each linked monomeric subunit is directly or indirectly attached to a heterocyclic base moiety In certain embodiments, the oligomeric compound also contains a heterocyclic base moiety. It may also contain monomeric subunits that are not linked to the base, thereby providing an abasic site. In certain embodiments, the monomeric subunits, the sugar moiety or surrogate, and the heterocyclic salt The bonds connecting the radical moieties can be independently modified. The linked sugar units, which may or may not contain a cyclic base, are also useful as monomers in peptide nucleic acids. may be substituted with a mimic of

[0087] As used herein, "terminal group" refers to the 3' or 5' end of an oligonucleotide. It refers to one or more atoms attached to either or both of the 5' ends. In certain embodiments, the terminal group is a conjugated group. contains one or more terminal nucleosides.

[0088] As used herein, a "conjugate" or "conjugate group" refers to an oligonucleotide or Conjugated groups generally refer to atoms or groups of atoms that are bonded to a drug or oligomeric compound. Mechanical properties, pharmacokinetic properties, binding properties, absorption properties, cellular distribution properties, cellular uptake properties These include, but are not limited to, the molecular weight, charge characteristics, and / or clearance characteristics. modifies one or more properties of the compound to which it binds.

[0089] As used herein, a "conjugated linker" or "linker" in reference to a conjugated group means a portion of a conjugated group containing any atom or group of atoms, (1) an oligonucleotide (2) covalently bond two or more portions of the conjugated group to one another; Combine.

[0090] Conjugate groups are shown herein as radicals and are used in antisense oligonucleotides. and the like. In this embodiment, the point of attachment in the oligomeric compound is at the 3' terminal nucleoside of the oligomeric compound. In certain embodiments, the 3'-oxygen atom of the 3'-hydroxyl group of the ... The point of attachment in the oligomeric compound is the 5'-hydroxyl group of the 5'-terminal nucleoside of the oligomeric compound. In certain embodiments, the oligomeric compound is The bond to form the bond to is a severable bond. In some embodiments, such cleavable bonds may constitute all or part of the cleavable moiety. do.

[0091] In certain embodiments, the conjugate group may be a cleavable moiety (e.g., a cleavable bond or or cleavable nucleosides) and carbohydrate clusters such as GalNAc cluster moieties Such carbohydrate cluster moieties include a targeting moiety and, optionally, a conjugated linker. In certain embodiments, the carbohydrate cluster portion comprises a number of ligands and For example, in certain embodiments, carbohydrate clusters are identified by their identity. A GalNAc moiety contains three GalNAc groups and is designated "GalNAc3." In an embodiment, the carbohydrate cluster moiety contains four GalNAc groups and is designated "Gal The specific carbohydrate cluster moieties (specific tethers, branches, and The conjugated linker groups are described herein as being represented by a Roman numeral followed by the subscript "a " Therefore, "GalNac3-1 a " has three GalNac groups, and specific carbohydrates of conjugated groups with specifically defined tethers, branches, and linking groups. Such carbohydrate cluster fragments refer to portions of the carbohydrate cluster that are cleavable or fragmentable. It is attached to the oligomeric compound via a cleavable moiety, such as a cleavable nucleoside.

[0092] As used herein, a "cleavable moiety" refers to a moiety that can be cleaved under physiological conditions. In certain embodiments, the cleavable moiety is a lysosomal bond or group. In certain embodiments, the protein is cleaved within a cell or subcellular compartment, such as: The cleavable portion is cleaved by an endogenous enzyme, such as a nuclease. In this embodiment, the cleavable moiety may be one, two, three, four, or more than four cleavable moieties. Includes atomic groups having bonds. As used herein, "cleavable bond" means any chemical bond that can be split. In certain embodiments, the cleavable bond is an amide, a polyamide, an ester, or a copolymer. esters of one or both of esters of alcohols, ethers, phosphodiesters, phosphate esters, The hydroxyl group is selected from among bamates, disulfides, or peptides.

[0093] As used herein, a "carbohydrate cluster" refers to a carbohydrate cluster attached to a scaffold or linker group. "Carbohydrate conjugates" refers to compounds having one or more carbohydrate residues attached to them (e.g., carbohydrate conjugates). Examples of stars include those described by Maier et al., which are incorporated herein by reference in their entirety. al.,“Synthesis of Antisense Oligonucleot ides Conjugated to a Multivalent Carbohy drate Cluster for Cellular Targeting,”Bi conjugate Chemistry,2003,(14):18-29, or Rensen et al., “Design and Synthesis of N ovel N-Acetylgalactosamine-Terminated Gl ycolipids for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein Receptor ,” J. Med. Chem. 2004, (47): 5798-5808).

[0094] As used herein, a "modified carbohydrate" refers to a carbohydrate that is modified in a manner that is different from naturally occurring carbohydrates. By "carbohydrate" is meant any carbohydrate having one or more chemical modifications.

[0095] As used herein, a "carbohydrate derivative" refers to a compound that is produced using carbohydrates as a starting material or intermediate. It means any compound that can be synthesized using hydrates.

[0096] As used herein, "carbohydrate" refers to any carbohydrate, including naturally occurring carbohydrates, modified carbohydrates, and the like. It refers to a carbohydrate or carbohydrate derivative.

[0097] As used herein, a "protecting group" refers to any compound or protecting group known to those skilled in the art. Non-limiting examples of protecting groups include "Protective Groups in Organic Chemistry”,TWGreene,PGMWut s,ISBN 0-471-62301-6,John Wiley & Sons,I nc, New York, which is incorporated herein by reference in its entirety. can be.

[0098] As used herein, a "single strand" is one that is not hybridized to its complement and means an oligomeric compound that lacks sufficient self-complementarity to form a stable self-duplex. do.

[0099] As used herein, a "duplex" refers to oligomers that are hybridized to one another. It refers to a pair of compounds or a single self-complementary oligomeric compound that forms a hairpin structure. In certain embodiments, the double-stranded oligomeric compound comprises a first and a second oligomer. Includes mer compounds.

[0100] As used herein, "antisense compounds" include oligonucleotides. means a compound consisting of or consisting of a nucleotide, at least a portion of which is a nucleotide sequence to which it hybridizes and a target nucleic acid that is complementary to the target nucleic acid and that provides at least one antisense activity. vinegar.

[0101] As used herein, "antisense activity" refers to the ability of an antisense compound to Any detectable and / or measurable activity resulting from hybridization to a target nucleic acid. In certain embodiments, antisense activity refers to the alteration of a target nucleic acid transcript ( For example, modulation of the amount or activity of an anti- Sense activity includes regulation of pre-mRNA splicing.

[0102] As used herein, an "RNase H-based antisense compound" refers to an At least part of the antisense activity of an antisense compound is due to the activity of the target nucleus of the antisense compound. This occurs due to hybridization to the target nucleic acid and subsequent cleavage of the target nucleic acid by RNase H. The term "antisense compounds" refers to compounds that induce

[0103] As used herein, a "RISC-based antisense compound" refers to an antisense At least part of the antisense activity of the silencing compounds is due to their ability to bind to the RNA-induced silencing complex ( This refers to an antisense compound that originates from RISC.

[0104] As used herein, "detection" or "measurement" refers to the act of detecting or measuring a sample. Such detection and / or measurement means that a test or assay is performed. Therefore, a test for detecting or measuring no activity (zero) may result in a value of zero. If the step of detecting or measuring activity provides knowledge of the activity of the target molecule, the step of detecting or measuring activity may still be performed. It is being carried out.

[0105] As used herein, "detectable and / or measurable activity" means any activity that is greater than or equal to zero. indicates no statistically significant activity.

[0106] As used herein, "essentially invariant" refers to a parameter that is substantially invariant to another parameter that varies significantly. It means that there is little or no change in a particular parameter, especially compared to In certain embodiments, when a parameter changes by less than 5%, the parameter is In certain embodiments, a parameter may vary by less than two-fold. If a parameter is specified, that parameter is essentially invariant, while another parameter is at least For example, in certain embodiments, antisense activity is measured by a factor of 10 or more of the target nucleic acid. In certain such embodiments, the change in the amount of the non-target nucleic acid is the change in the amount of the target nucleic acid. If the change in the amount of target nucleic acid is much smaller than the change in the amount of target nucleic acid, it is essentially unchanged, but if the change is zero, It doesn't have to be.

[0107] As used herein, "expression" refers to the process by which a gene ultimately results in a protein. Expression includes transcription, post-transcriptional modifications (e.g., splicing, polyadenylation) , addition of a 5'-cap), and translation.

[0108] As used herein, a "target nucleic acid" refers to a nucleic acid to which an antisense compound hybridizes. Antisense refers to a nucleic acid molecule that is intended to produce a desired antisense activity. The oligonucleotides are sufficiently long to allow hybridization under physiological conditions. They have sufficient complementarity to their target nucleic acid.

[0109] As used herein, the term "nucleobase complementarity" or "complementarity" with respect to nucleobases refers to refers to a nucleobase that can base pair with another nucleobase. For example, in DNA, In RNA, adenine (A) is complementary to thymine (T). Aminine (A) is complementary to uracil (U). In certain embodiments, the complementary nucleoside Acid-base refers to the base pairing of an antisense compound with the nucleobase of its target nucleic acid. For example, a nucleobase at a specific position in an antisense compound may be a target If it can hydrogen bond with the nucleobase at a specific position in the nucleic acid, it can be used as an oligonucleotide. The hydrogen bond positions between the target nucleic acid and the nucleic acid are considered to be complementary in the nucleic acid base pair. Nucleobases containing certain modifications may retain the ability to pair with corresponding nucleobases, and Therefore, it is possible to still have nucleobase complementarity.

[0110] As used herein, "non-complementary" with respect to nucleobases means that they do not form hydrogen bonds with each other. It refers to a pair of nucleic acid bases that do not form a nucleotide.

[0111] As used herein, an oligomeric compound (e.g., linked nucleosides, oligonucleotides, "Complementary" with respect to oligomeric compounds (nucleotides, or nucleic acids) refers to the degree to which such oligomeric compounds or those regions can be linked to another oligomeric compound or those regions through nucleobase complementarity. Complementary oligomeric compounds have the ability to hybridize to each nucleoside. Nucleobase complementarity is not required; rather, some mismatches are permitted. In certain embodiments, complementary oligomeric compounds or regions have 70% of the nucleobases In certain embodiments, the complementary oligomers In certain embodiments, the complementary compounds or regions are 80% complementary. The ligomeric compounds or regions are 90% complementary. In certain embodiments, the complementary oligomeric compounds or regions are 95% complementary. , complementary oligomeric compounds or regions are 100% complementary.

[0112] As used herein, "mismatch" refers to a mismatch between a first and a second oligomeric compound. When aligned, they can pair with nucleobases at corresponding positions of a second oligomeric compound. The first and second oligomerizations refer to the nucleobases of the first oligomeric compound that are incapable of Either or both of the constructs may be oligonucleotides.

[0113] As used herein, "hybridization" refers to the formation of complementary oligomers. The term "antisense compound" refers to the pairing of a compound (e.g., an antisense compound and its target nucleic acid) by a specific mechanism. The most common pairing mechanism includes, but is not limited to, hydrogen bonding, which is the mechanism by which complementary nucleic acids bind to one another. Watson-Crick hydrogen bonds, Hoogsteen hydrogen bonds, or reverse Hoogsteen hydrogen bonds between groups It may be a hydrogen bond.

[0114] As used herein, "specifically hybridizes" refers to an oligomeric compound hybridizes to one nucleic acid site with higher affinity than it hybridizes to another nucleic acid site. This means the ability to

[0115] As used herein, "fully complementary" refers to an oligonucleotide or portion thereof. "Suitable" means that each nucleobase of an oligonucleotide or portion thereof is complementary to a complementary nucleic acid or Therefore, it means that the nucleic acid can be paired with the nucleic acid bases of the contiguous portion of the The complementary regions do not contain mismatched or non-hybridizing nucleobases on either strand. .

[0116] As used herein, "percent complementarity" refers to a sequence that is complementary to an equal length portion of a target nucleic acid. Percent complementarity refers to the proportion of nucleobases in an oligomeric compound that are complementary to the corresponding nucleotides in a target nucleic acid. The number of nucleic acid bases in the oligomeric compound that are complementary to the nucleic acid base at the position where the nucleic acid base is located is expressed as the total number of nucleic acid bases in the oligomeric compound. It is calculated by dividing by the length.

[0117] As used herein, "percent identity" refers to the percentage of the total number of nucleobases in a first nucleic acid. the same type (independent of chemical modification) of the nucleobase at the corresponding position of the second nucleic acid, divided by means the number of nucleic acid bases of the first nucleic acid.

[0118] As used herein, "modulation" refers to the amount or activity of a molecule, function, or activity prior to modulation. A change in the quantity or quality of a molecule, function, or activity compared to the original quantity or quality. For example, Modulation can be an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression. As a further example, modulation of expression can include a change in the amount of a gene that is higher than the amount in the absence of modulation. Pre-mRNAs that result in changes in the absolute or relative amounts of specific splice variants compared The process may involve alterations in splice site selection.

[0119] As used herein, a "chemical motif" refers to an oligonucleotide or a region thereof. A motif refers to a pattern of chemical modifications in a specific region of an oligonucleotide. The nucleotides may be defined by modifications at the nucleosides and / or at certain linking groups.

[0120] As used herein, a "nucleoside motif" refers to an oligonucleotide or refers to the pattern of nucleoside modifications in that region. The bonds of the nucleotides may be modified or unmodified. A motif that describes only a nucleoside is intended to be a nucleoside motif. Therefore, in such cases, the bond is not limited.

[0121] As used herein, a "sugar motif" refers to an oligonucleotide or a region thereof. This refers to the sugar modification pattern in

[0122] As used herein, a "binding motif" refers to an oligonucleotide or a region thereof. The term refers to the pattern of bond modifications in the nucleosides of such oligonucleotides. The bonds may be modified or unmodified. Unless otherwise indicated, only bonds are referred to herein. The motifs described are intended to be binding motifs. In the above, the nucleoside is not limited.

[0123] As used herein, a "nucleobase modification motif" refers to a nucleic acid sequence along an oligonucleotide. Unless otherwise indicated, the nucleobase modification motif refers to the pattern of modifications to the nucleobase. The function is independent of the nucleic acid base sequence.

[0124] As used herein, a "sequence motif" refers to an oligonucleotide or portion thereof. Unless otherwise indicated, a sequence motif refers to a pattern of nucleobases arranged along a molecule. is independent of chemical modification and therefore can be used with any combination of chemical modifications, including no chemical modification. It may have a combination.

[0125] As used herein, a nucleoside or a "class" of nucleosides "Type of modification" refers to the chemical modification of a nucleoside, including modified and unmodified nucleosides. Thus, unless otherwise indicated, "nucleosides having a first type of modification" may be an unmodified nucleoside.

[0126] As used herein, "differently modified" refers to compounds that are different from each other, including the absence of a modification. Thus, for example, MOE nucleosides and and unmodified DNA nucleosides are "separately" related to the unmodified DNA nucleosides. Similarly, DNA and RNA are both naturally occurring unmodified. Even nucleosides are "differently modified." Nucleosides that are identical but contain different nucleobases are The nucleosides are not separately modified. For example, a 2'-OMe modified sugar and an unmodified adenine Nucleosides containing nucleobases and nucleosides containing 2'-OMe modified sugars and unmodified thymine nucleobases The cleosides are not separately modified.

[0127] As used herein, "the same type of modification" refers to modifications that are identical to each other, including the absence of the modification. Thus, for example, two unmodified DNA nucleosides are referred to as a DNA nucleoside. Even if the amino acid is not modified, it has the same type of modification. Such nucleosides may contain different nucleobases.

[0128] As used herein, "distinct region" means a portion of an oligonucleotide Any adjacent chemical modifications or chemical modification motifs may be used to distinguish distinct regions from one another. The method includes at least one difference that allows the method to be implemented.

[0129] As used herein, "a pharmaceutically acceptable carrier or diluent" refers to a substance that is suitable for administration to an animal. In certain embodiments, pharmaceutical An acceptable carrier or diluent for the preparation of the pharmaceutical composition is sterile saline. , such sterile saline is pharmaceutical grade saline.

[0130] As used herein, the term "metabolic disorder" refers to a disorder that primarily affects metabolism (breaking down food). A disease characterized by the dysregulation of the complex series of chemical reactions involved in generating energy It means a disease or condition.

[0131] As used herein, the term "cardiovascular disorder" refers to a disorder primarily affecting the functioning of the heart or blood vessels. "Disease" means a disease or condition characterized by a disorder.

[0132] As used herein, the term "monocyclic or polycyclic ring system" refers to a monocyclic or Polycyclic radical ring systems are intended to include all ring systems selected from the group consisting of: Fused or linked, aliphatic, alicyclic, aryl, heteroaryl, aralkyl, aryl heteroalkyl, heterocyclic, heteroaryl, heteroaromatic, and heteroarylalkyl It is intended to include single and mixed ring systems individually selected from: and polycyclic structures each having the same level of saturation or each independently being completely Contains rings with varying degrees of saturation, including fully saturated, partially saturated, or fully unsaturated. Each ring may be present in heterocyclic rings and mixed motifs such as benzimidazole. selected from C, N, O, and S to give rise to a ring containing only C ring atoms that may be present. The ring may contain ring atoms of one carbon ring only, and the fused ring may contain two nitrogen atoms. A monocyclic or polycyclic ring system may, for example, have two =O atoms bonded to one of the rings. The monocyclic or polycyclic ring system may be further substituted with a substituent such as phthalimide having a group. Direct bonds through ring atoms, fused bonds through multiple ring atoms, bonds through substituents, or bonds between two groups The nucleotides can be attached to the parent molecule using a variety of strategies, such as attachment via a functional binding moiety.

[0133] As used herein, a "prodrug" refers to a compound that, when administered to a subject, is metabolized to an active compound. an inactive form of a compound or compound that forms a more active compound (e.g., a drug) It means a less active form.

[0134] As used herein, the terms "substituent" and "substituent ( "Substituent group" refers to an atom or group of a named parent compound. For example, the substituents of a modified nucleoside are atoms or groups that are naturally occurring. Any atom or group that is different from the atoms or groups found in a nucleoside (e.g., modified The 2'-substituted group may be any atom at the 2' position of the nucleoside other than H or OH. The substituents may be protected or unprotected. In certain embodiments, Thus, the compounds of the present disclosure have substituents at one position or at more than one position on the parent compound. The substituents may be further substituted with other substituents and may be directly attached to the parent compound or may be attached to an aryl group. It may be attached via a linking group such as an alkyl or hydrocarbyl group.

[0135] Similarly, as used herein, a "substituent" with respect to a chemical functional group refers to a designated It means an atom or group of atoms that is different from the atom or group of atoms normally present in a functional group. In certain embodiments, a substituent replaces a hydrogen atom of a functional group (e.g., in certain embodiments, In embodiments, the substituent of the substituted methyl group replaces one of the hydrogen atoms of the unsubstituted methyl group. (An atom or group other than hydrogen that substitutes for the substituted aryl group) Unless otherwise indicated, following its use as a substituent, Suitable groups include halogen, hydroxyl, alkyl, alkenyl, alkynyl, acyl (- C(O)R aa ), carboxyl (-C(O)OR aa ), aliphatic groups, alicyclic groups, alkane Oxy, substituted oxy (-OR aa ), aryl, aralkyl, heterocyclic radicals, heterocyclic radicals Aryl, heteroaryl alkyl, amino (-N(R bb )(R cc )), Imino( =NR bb ), amide (-C(O)N(R bb )(R cc ) or -N(R bb )C(O )R aa ), azide (-N3), nitro (-NO2), cyano (-CN), carbamide ( -OC(O)N(R bb )(R cc ) or -N(R bb )C(O)OR aa ), Uray Do(-N(R bb )C(O)N(R bb )(R cc )), thioureido (-N(R bb ) C(S)N(R bb )(R cc)), guanidinyl (-N(R bb )C(=NR bb )N (R bb )(R cc )), amidinyl (-C(=NR bb )N(R bb )(R cc )Also -N(R bb )C(=NR bb )(R aa )), thiol (-SR bb ), Sulfini Lu(-S(O)R bb ), sulfonyl (-S(O)R bb ), and sulfonamidyl (-S(O)2N(R bb )(R cc ) or -N(R bb )S(O)2R bb ) included In the formula, each R aa , R bb , and R cc is, independently, H, optionally linked chemical functional groups, or alkyl, alkenyl, alkynyl, aliphatic, Alkoxy, acyl, aryl, aralkyl, heteroaryl, alicyclic, heterocyclic, and Further, a preferred list includes, but is not limited to, arylalkyl and heteroarylalkyl. Selected substituents within the compounds described herein may exist to a recursive degree. There is.

[0136] As used herein, "alkyl" refers to an alkyl group having up to 24 carbon atoms. The term "alkyl" refers to a saturated straight or branched chain hydrocarbon radical containing hydrogen atoms. Examples of alkyl groups are: and methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, dextran. Examples of alkyl groups include, but are not limited to, cyclohexyl ... 1 to about 24 carbon atoms, more typically 1 to about 12 carbon atoms (C1 to C 12 Al More preferably, it contains 1 to about 6 carbon atoms.

[0137] As used herein, "alkenyl" refers to alkyl groups containing up to 24 carbon atoms; a straight or branched hydrocarbon chain radical having at least one carbon-carbon double bond; Examples of alkenyl groups include ethenyl, propenyl, butenyl, 1-methyl-2 Examples of suitable olefins include, but are not limited to, dienes such as 1,3-buten-1-yl and 1,3-butadiene. Alkenyl groups typically contain 2 to about 24 carbon atoms, more typically 2 to 4 carbon atoms. It contains about 12 carbon atoms, more preferably 2 to about 6 carbon atoms. The alkenyl group may optionally include one or more further substituents.

[0138] As used herein, "alkynyl" refers to alkyl groups containing up to 24 carbon atoms and and a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, 1-propynyl, and 1-butynyl. Alkynyl groups typically contain from 2 to about 24 carbon atoms. More typically, it contains from 2 to about 12 carbon atoms, with from 2 to about 6 carbon atoms being more preferred. As used herein, alkynyl groups may optionally include one or more further substituents. .

[0139] As used herein, "acyl" refers to a compound formed by removal of the hydroxyl group from an organic acid. and has the general formula -C(O)-X, where X is typically is aliphatic, alicyclic, or aromatic. Examples include aliphatic carbonyl, aromatic carbonyl, sulphonyl, aliphatic sulphonyl, aromatic sulphinyl, aliphatic sulphinyl, aromatic phosphat As used herein, an acyl group includes an alkyl group, an aliphatic phosphate, an aliphatic phosphate, and the like. It may optionally contain substituents.

[0140] As used herein, "alicyclic" means a cyclic ring system, wherein the ring is aliphatic. The ring system may contain one or more rings, at least one of which is aliphatic. Preferred alicyclic groups include rings having from about 5 to about 9 carbon atoms in the ring. The alicyclic groups may optionally include further substituents.

[0141] As used herein, "aliphatic" refers to straight or loose chain fatty acids containing up to 24 carbon atoms. or branched chain hydrocarbon radicals, and the saturation between any two carbon atoms can be single, double, or The aliphatic group preferably has 1 to about 24 carbon atoms, more typically Preferably, the fat contains 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms. The straight or branched chain of the aromatic group may contain one or more heteroatoms, including nitrogen, oxygen, sulfur, and phosphorus. Such aliphatic groups interrupted by heteroatoms include polyalkoxy groups. Examples of suitable polyalkylene glycols include polyamines and polyimines. As used herein, aliphatic groups may optionally include further substituents. obtain.

[0142] As used herein, "alkoxy" refers to a group formed between an alkyl group and an oxygen atom. The oxygen atom is used to attach the alkoxy group to the parent molecule. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and methyl. oxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n- As used herein, alkoxy includes, but is not limited to, hexoxy, and the like. The group may optionally include further substituents.

[0143] As used herein, "aminoalkyl" refers to an amino-substituted C1-C 12 means an alkyl radical, the alkyl portion of which forms a covalent bond with the parent molecule. The amino group can be located at any position, and the aminoalkyl group can be alkyl and / or may be substituted with further substituents on the amino moiety.

[0144] As used herein, "aralkyl" and "arylalkyl" refer to C1- C 12 means an aromatic group covalently bonded to an alkyl radical. The alkyl radical portion of the alkyl (or arylalkyl) group forms a covalent bond with the parent molecule. Examples include, but are not limited to, benzyl, phenethyl, etc. As used herein, an aralkyl group refers to an alkyl, aryl, or aryl group that forms a radical group. Both of these groups may optionally contain further substituents attached thereto.

[0145] As used herein, "aryl" and "aromatic" refer to one or more aromatic rings. Examples of aryl groups include: Examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, etc. Preferred aryl ring systems include those containing from about 5 to about 20 carbon atoms in one or more rings. As used herein, aryl groups may optionally include further substituents. .

[0146] As used herein, "halo" and "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0147] As used herein, "heteroaryl" and "heteroaromatic" refer to monocyclic or a radical containing a polycyclic aromatic ring, ring system, or fused ring system, among said rings At least one of is aromatic and contains one or more heteroatoms. Heteroaryl is It is also intended to include fused ring systems, including systems in which one or more of the fused rings does not contain a heteroatom. Heteroaryl groups typically contain one or more carbon atoms selected from sulfur, nitrogen, or oxygen. Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, and the like. , pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl , thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquino linyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, etc. The heteroaryl radical can be directly attached to the parent molecule or may be attached via a linking moiety such as an aliphatic group or a heteroatom. The heteroaryl group may optionally include further substituents.

[0148] As used herein, a "conjugated compound" refers to any compound suitable for use as a conjugated group. In certain embodiments, a conjugated compound The pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, and cellular uptake including, but not limited to, binding characteristics, charge characteristics, and / or clearance characteristics1 It may have or be endowed with one or more properties.

[0149] As used herein, unless otherwise indicated or modified, "double-stranded" The term refers to two distinct oligomeric compounds that are hybridized to one another. Such double-stranded compounds may contain one or both of the strands (overhangs). may have one or more terminal nucleosides or unhybridized nucleosides, and / or have one or more unhybridized internal nucleosides (mismatches). may be used, provided that the hybridization is sufficient to maintain hybridization under physiologically relevant conditions. This is subject to the existence of complementarity.

[0150] As used herein, a "5' target site" refers to the most Refers to the nucleotide of the target nucleic acid that is complementary to the 5' nucleotide.

[0151] As used herein, "about" means within ±10% of a value. If it says "the number of markers can increase by about 50%, then the number of markers will increase by 45% to 55%." It includes the meaning of obtaining.

[0152] As used herein, "administered simultaneously" means that the pharmacological effects of the two agents are Co-administration refers to the co-administration of two drugs in any manner that results in the drugs appearing to the patient at the same time. In some cases, both drugs may be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration. The effects of both drugs do not have to occur simultaneously. They only need to overlap for some period of time, and do not need to be extensive together.

[0153] As used herein, "administer" or "administration" refers to providing a pharmaceutical agent to an individual. This means administration by a healthcare professional and self-administration, including, but not limited to, Administration of a pharmaceutical agent to an individual can be continuous, chronic, short-term, or intermittent. Administration can be parenteral or non-parenteral. .

[0154] As used herein, a "drug" is a substance that provides a therapeutic benefit when administered to an animal. "First agent" means a therapeutic compound of the present invention. For example, the first agent may be an antisense oligonucleotide that targets apo(a). A "second agent" refers to a second therapeutic compound of the present invention (e.g., apo(a)). a second antisense oligonucleotide targeting apo(a) It refers to a therapeutic compound.

[0155] As used herein, "improvement" or "ameliorate" or "Ameliorating" means to improve or reduce the severity of an associated disease, disorder, or condition. The severity of an indicator may be measured by a method known to those skilled in the art. It may be determined by subjective or objective measures.

[0156] As used herein, "animal" refers to a human, or a mouse, rat, rabbit, or mouse. Nutrients of animals include, but are not limited to, guinea pigs, cats, pigs, and non-human primates (including, but not limited to, monkeys and chimpanzees). "Non-human animals" refers to non-human animals, including, but not limited to, animals not living in the wild.

[0157] As used herein, "apo(a)" refers to any gene encoding apo(a). It refers to a nucleic acid or protein sequence. For example, in certain embodiments, apo( a) is a DNA sequence encoding apo(a), a DNA sequence encoding apo(a), Transcribed RNA sequences (including genomic DNA containing introns and exons), apo( The present invention includes an mRNA sequence encoding apo(a), or a peptide sequence encoding apo(a).

[0158] As used herein, "apo(a) nucleic acid" refers to any nucleic acid encoding apo(a). For example, in certain embodiments, apo(a) nucleic acids refer to nucleic acids of any type. DNA sequence encoding o(a), RNA transcribed from DNA encoding apo(a) A sequence (including genomic DNA containing introns and exons), and apo(a) It contains the encoding mRNA sequence.

[0159] As used herein, "apo(a) mRNA" refers to a gene encoding the apo(a) protein. It means the mRNA encoding

[0160] As used herein, "apo(a) protein" refers to a protein encoding Apo(a). By "protein" is meant any protein sequence that

[0161] As used herein, an "apo(a)-specific inhibitor" refers to an apo(a) nucleic acid and Any agent capable of specifically inhibiting the expression of apo(a) and / or apo(a) protein For example, apo(a)-specific inhibitors include nucleic acids (including antisense compounds), peptides, and the like. peptides, antibodies, small molecules, and apo(a) nucleic acids and / or apo(a) proteins In certain embodiments, apoE, apoE, and other agents capable of inhibiting expression of apoE. (a) by specifically modulating nucleic acid expression and / or apo(a) protein expression Therefore, apo(a)-specific inhibitors may affect other components of the lipid transport system, including downstream components. Similarly, in certain embodiments, apo(a)-specific inhibitors are It may affect other molecular processes.

[0162] As used herein, "atherosclerosis" refers to the development of arterial wall disease in large and medium-sized arteries. It refers to the hardening of the arteries that affect the blood vessels and is characterized by the presence of fatty deposits. These are called "terror plaques" or "plaques" and are made up of primarily cholesterol and other fats, calcium, and It consists of blood vessels, plaque, and scar tissue that damage the lining of the artery.

[0163] As used herein, "coronary heart disease (CHD)" refers to a condition in which blood and oxygen are lost to the bloodstream. This refers to narrowing of the small blood vessels that supply the heart, often caused by atherosclerosis This is the result.

[0164] As used herein, "diabetes mellitus" or "diabetes" refers to an inadequate level of insulin. metabolic disorders and abnormally high blood sugar (hyperglycemia) due to decreased insulin or insulin sensitivity It is a syndrome characterized by excessive urine production ( Polyuria), excessive thirst and increased fluid intake to compensate for increased urination (polydipsia), blurred vision These include blurred vision, unexplained weight loss, and lethargy due to the effects of high blood sugar on the blood sugar levels.

[0165] As used herein, "diabetic dyslipidemia" or "type 2 diabetes with dyslipidemia" refers to "Diabetic diseases" are characterized by type 2 diabetes, decreased HDL-C, increased triglycerides (TG), and It refers to a condition characterized by an increase in dense LDL particles.

[0166] As used herein, a "diluent" is a substance that lacks pharmacological activity but is not pharmaceutically necessary. It refers to a component in a composition that is present or desired, e.g., a dilution in an infused composition. The agent may be a liquid, for example, saline.

[0167] As used herein, "dyslipidemia" refers to a condition in which the lipid and / or lipoprotein Refers to disorders of lipid and / or lipoprotein metabolism, including overproduction or deficiency of lipids. The lipid disorders include chylomicrons, cholesterol, and triglycerides, as well as This is evident in the increase of lipoproteins, such as low-density lipoprotein (LDL) cholesterol. It could be something like that.

[0168] As used herein, a "dosage unit" refers to the form in which a pharmaceutical agent is provided, e.g., a pill. In certain embodiments, the term "dosage unit" refers to a tablet, tablet, or other dosage unit known in the art. In this case, the dosage unit is a vial containing lyophilized antisense oligonucleotide. In certain embodiments, the dosage unit comprises a reconstituted antisense oligonucleotide. A vial containing nucleotides.

[0169] As used herein, a "dose" refers to a dose provided in a single administration or administered over a specific period. In certain embodiments, a dose refers to a specific amount of a pharmaceutical agent provided during a period of time. The dose may be administered in two or more boluses, tablets, or infusions. In this embodiment, when subcutaneous administration is desired, the desired dose can be easily provided in a single injection. requires a volume not provided and therefore may require more than one injection to achieve the desired dose. In certain embodiments, the pharmaceutical agent can be administered by infusion over an extended period of time or Administered continuously. Dose is the amount of medication given per hour, day, week, or month. Doses may also be presented in mg / kg or g / kg.

[0170] As used herein, an "effective amount" or a "therapeutically effective amount" refers to an amount of an active pharmaceutical ingredient and administering to an individual in need thereof an amount of active pharmaceutical agent sufficient to produce a desired physiological result. It means that an effective amount is determined based on the health and physical condition of the individual being treated, the taxonomic group of the individual being treated, , which may vary between individuals depending on the formulation of the composition, assessment of the individual's medical condition, and other relevant factors. .

[0171] As used herein, "fully complementary" or "100% complementary" refers to a sequence that is complementary to the first sequence. Each nucleobase of the nucleobase sequence of one nucleic acid is complementary to a second nucleobase sequence of a second nucleic acid. In certain embodiments, the first nucleic acid has an antisense base. The first nucleic acid is a target nucleic acid.

[0172] As used herein, "glucose" refers to a source of energy and an inflammatory intermediate. "Plasma glucose" refers to the glucose present in plasma. Refers to the course.

[0173] As used herein, "high density lipoprotein-C" or "HDL-C" means , meaning cholesterol associated with high-density lipoprotein particles. The concentration of HDL- in the blood is typically quantified in mg / dL or nmol / L. "Serum HDL-C" and "plasma HDL-C" refer to the HDL levels in serum and plasma, respectively. It means LC.

[0174] As used herein, "HMG-CoA reductase inhibitor" refers to atorvastatin, statin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and synthase refers to drugs that act by inhibiting the enzyme HMG-CoA reductase, such as Vastatin .

[0175] As used herein, "hypercholesterolemia" refers to high cholesterol in adults. The National Cholesterol Education Program (NCEP) The guidelines of the expert committee report show that elevated cholesterol or circulating (plasma ) cholesterol, LDL-cholesterol, and VLDL-cholesterol (See Arch. Int. Med. (1988) 148, 36-39) (This refers to lighting.)

[0176] As used herein, "hyperlipidemia" or "Hyperlipemia" refers to the abnormality of serum lipids or circulating (plasma) lipids. This condition is characterized by an abnormally high concentration of lipids in the circulating blood. The fractions are cholesterol, low density lipoprotein, very low density lipoprotein, and chylomic The Fredrickson classification of dyslipidemia is based on electrophoresis or of TG and cholesterol-rich lipoprotein particles measured by ultracentrifugation Based on the pattern, characterize the primary cause of dyslipidemia, such as hypertriglyceridemia in general (Fredrickson and Lee, Circulation, 1 965,31:321-327,Fredrickson et al.,New En g J Med,1967,276(1):34-42).

[0177] As used herein, "hypertriglyceridemia" refers to a decrease in triglyceride levels Its etiology includes transient factors (i.e., genetic causes) ) and secondary factors (diabetes, metabolic syndrome / insulin resistance, obesity, physical inactivity, smoking, excessive alcohol consumption and other underlying causes such as a diet very high in carbohydrates), or or in many cases, a combination of these (Yuan et al. CMAJ, 2007,176:1113-1120).

[0178] As used herein, "identifying" or "identifying a metabolic or cardiovascular disease" refers to "Selecting animals with hypercholesterolemia, hyperglycemia, dyslipidemia, hypertriglyceridemia, Hyperlipidemia, hypertension, increased insulin resistance, decreased insulin sensitivity, above normal body weight, and / or above normal body fat content, or any combination thereof Developing metabolic disorders, cardiovascular diseases, or metabolic syndrome, including but not limited to: Identify subjects who are susceptible to or diagnosed with metabolic disease, cardiovascular disease, or metabolic syndrome. determining or selecting a metabolic disease, cardiovascular disease, or metabolic syndrome; Such identification may be achieved by measuring serum or is the measurement of circulating (plasma) cholesterol, serum or circulating (plasma) blood glucose, serum or Measurement of circulating (plasma) triglycerides, blood pressure, body fat content, and weight This may be accomplished by any method, including, but not limited to, clinical trials or evaluations of do.

[0179] As used herein, "improved cardiovascular outcomes" refers to the reduction in adverse cardiovascular events. Examples of adverse cardiovascular events include death, recurrence, and These include infarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest, and atrial dysrhythmia. Not limited to these.

[0180] As used herein, "immediately adjacent" means that there is a gap between immediately adjacent elements, e.g., Absence of intervening elements between regions, segments, nucleotides, and / or nucleosides means.

[0181] As used herein, "increasing HDL" or "elevating HDL" refers to any the HDL levels of animals administered at least one compound of the present invention compared to the HDL levels of animals not administered the compound. This means an increase in the levels of HDL in animals after administration of the compound.

[0182] As used herein, an "individual" or "subject" or "animal" refers to a person who is By "subject" is meant a human or non-human animal selected for therapy.

[0183] As used herein, an "individual in need thereof" refers to an individual in need of treatment or therapy. "Treatment" refers to a human or non-human animal selected for such treatment or therapy.

[0184] As used herein, "induce," "inhibit," "enhance," "elevate," "Increase," "Decrease," "Reduce," etc. indicate the quantitative difference between two states. For example, "an amount effective to inhibit the activity or expression of apo(a)" refers to an amount of apo(a) that is The level of apo(a) activity or expression in the treated sample was compared to that of the untreated sample. (i.e., the level of activity or expression of a gene or protein) is different from that of the gene or protein. This applies to current and active levels.

[0185] As used herein, an "inflammatory condition" refers to a disease, condition, syndrome, or condition that results in inflammation. or other conditions. For example, rheumatoid arthritis and liver fibrosis are inflammatory conditions. Other examples of inflammatory conditions include sepsis, myocardial ischemia / reperfusion injury, adult respiratory distress syndrome, nephritis, and migration. Graft rejection, inflammatory bowel disease, multiple sclerosis, arteriosclerosis, atherosclerosis, and Vasculitis is one example.

[0186] As used herein, "inhibiting the expression or activity" refers to inhibiting the expression or activity of an RNA or protein. refers to the reduction or inhibition of protein expression or activity, not necessarily the complete elimination of expression or activity. It does not show.

[0187] As used herein, "insulin resistance" refers to the inability of normal amounts of insulin to penetrate the bloodstream. It is defined as a state in which there is insufficient insulin to produce a normal insulin response from fat, muscle, and liver cells. Insulin resistance in adipocytes increases the free fatty acid stores in the plasma. This leads to the hydrolysis of the adsorbed triglycerides. Insulin resistance in the lungs reduces glucose storage, while insulin uptake decreases Both of these effects act to raise blood sugar. High plasma levels of insulin and glucose often contribute to metabolic syndrome and type 2 diabetes leads to illness.

[0188] As used herein, "insulin sensitivity" refers to how effectively an individual can regulate glucose levels. Individuals with high insulin sensitivity are able to process glucose efficiently. whereas individuals with low insulin sensitivity do not process glucose as effectively. stomach.

[0189] As used herein, "lipid-lowering" refers to the reduction of one or more lipids (e.g., "Lipid elevation" refers to a reduction in lipids (e.g., LDL, VLDL) in a subject. Lipid lowering or lipid elevation may occur over time with one or more doses. You can.

[0190] As used herein, "lipid-lowering therapy" or "lipid-lowering agent" refers to a method for reducing the risk of heart disease in a subject. It refers to a therapeutic regimen provided to a subject to reduce one or more lipids associated with certain conditions. In certain embodiments, lipid-lowering therapy involves reducing apo(a), CETP, apo(b) in a subject. B, total cholesterol, LDL-C, VLDL-C, IDL-C, non-HDL-C, triglycerides Decreases one or more of: lipids, small, dense LDL particles, and Lp(a) Examples of lipid-lowering therapies include apoB inhibitors, statins, fibrates, and MTP inhibitors.

[0191] As used herein, "lipoproteins" such as VLDL, LDL, and HDL refers to a group of proteins found in serum, plasma, and lymph that are important in lipid transport. The chemical composition of each lipoprotein varies, for example, HDL contains a higher proportion of proteins than lipids. VLDL has a lower proportion of protein than lipids, whereas VLDL has a lower proportion of protein than lipids. differs.

[0192] As used herein, "Lp(a)" refers to a protein containing apo(a) and apoB. apo(a) is linked to apoB by a disulfide bond. do.

[0193] As used herein, "low-density lipoprotein-cholesterol (LDL-C) " means cholesterol carried in low-density lipoprotein particles. The concentration of LDL-C in blood (or plasma) is typically measured in mg / dL or nmol / L. "Serum LDL-C" and "plasma LDL-C" are the serum and plasma LDL-C, respectively. It refers to LDL-C in plasma.

[0194] As used herein, a "major risk factor" refers to a high risk factor for a particular disease or condition. In certain embodiments, the major risk factors for coronary heart disease are Risk factors include smoking, high blood pressure, high LDL, low HDL-C, family history of coronary heart disease, and These factors include, but are not limited to, age, and other factors disclosed herein.

[0195] As used herein, a "metabolic disorder" or "metabolic disease" refers to an alteration in metabolic function. "Metabolic" and "metabolism" refer to a condition characterized by a metabolic disorder or disorder. is a term that generally includes any kind of biochemical process that occurs within a living organism. Metabolic disorders include hyperglycemia, prediabetes, diabetes (type 1 and type 2), obesity, and insulin resistance. These include dyslipidemia due to insulin resistance, metabolic syndrome, and type 2 diabetes. Not limited to.

[0196] As used herein, "metabolic syndrome" refers to a combination of lipid and non-lipid cardiovascular disorders of metabolic origin. In certain embodiments, metabolic The syndrome is characterized by the following factors: height greater than 102 cm in men and greater than 88 cm in women waist circumference; serum triglycerides of at least 150 mg / dL; 40 mg in men g / dL, HDL-C less than 50 mg / dL in women; at least 130 / 85 blood pressure of at least 110 mg / dL; and fasting glucose of at least 110 mg / dL These determinants can be easily measured in clinical practice. (JAMA, 2001, 285:2486-2497).

[0197] "Parenteral administration" means administration via injection or infusion. Parenteral administration includes subcutaneous administration. administration, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial, e.g. Administration may be continuous, chronic, short-term, or intrathecal. The administration may be intermittent.

[0198] As used herein, a "peptide" is a molecule that is joined by at least two amino acids via an amide bond. A peptide is a molecule formed by linking amino acids. and proteins.

[0199] As used herein, a "pharmaceutical product" refers to a substance that provides a therapeutic benefit when administered to an individual. For example, in certain embodiments, apo(a)-targeting agents are used. Such antisense oligonucleotides are pharmaceuticals.

[0200] As used herein, a "pharmaceutical composition" or "composition" refers to a pharmaceutical composition suitable for administration to an individual. For example, a pharmaceutical composition refers to a mixture of one or more active agents and a pharmaceutical carrier, e.g. For example, it may comprise a sterile aqueous solution.

[0201] As used herein, "pharmaceutically acceptable derivatives" includes solvates, hydrates, esters, and the like. Stereos, prodrugs, polymorphs, isomers, isotopically labeled variants, pharmaceutically acceptable salts and other derivatives known in the art. .

[0202] As used herein, "pharmaceutically acceptable salts" refers to the synthesis of antisense compounds. Physically and pharmaceutically acceptable salts, i.e., salts that retain the desired biological activity of the parent compound. "Pharmaceutically acceptable" means a salt that is compatible with the intended compound and does not have any undesirable toxicological effects thereon. The term "salt" or "salts" refers to the synthesis of pharmaceutically acceptable non-toxic acids or bases (inorganic or organic). The term "pharmaceutically acceptable salts" as used herein includes salts prepared from organic acids and bases. Pharmaceutically acceptable salts can be prepared by methods well known in the art. For a general review of salt, see Stahl and Wermuth, Handbook of Pharmaceutical Salts:Properties,Selectio n and Use(Wiley-VCH,Weinheim,Germany,200 2). Sodium salts of antisense oligonucleotides are useful. It is widely accepted for therapeutic administration to humans. The compounds described herein are in the form of sodium salts.

[0203] As used herein, a "portion" refers to a contiguous (i.e., linked) portion of a nucleic acid. In certain embodiments, a portion of a target nucleic acid is a defined number of nucleobases. In certain embodiments, the moiety is an anti- It is a defined number of consecutive nucleobases of a sense compound.

[0204] As used herein, "prevent" or "prevention" refers to a period of time ranging from a few minutes to an indefinite period of time. Delaying or preventing the onset or development of a disease, disorder, or condition Prevention can also mean reducing the risk of developing a disease, disorder, or condition.

[0205] As used herein, "elevated" means an increase in the amount, e.g., plasma HDL By increasing the levels is meant increasing the amount of HDL in the plasma.

[0206] As used herein, "reduce" means to a lesser extent, a smaller magnitude, a smaller amount, For example, lowering plasma triglyceride levels By this we mean reducing the amount of triglycerides in the plasma.

[0207] As used herein, a "region" or "target region" refers to at least one identifiable region. A target region is defined as a portion of a target nucleic acid that has a structure, function, or property that can be used to identify the target nucleic acid. For example, a target region is , 3'UTR, 5'UTR, exon, intron, exon / intron junction, The nucleic acid sequence may include a nucleic acid sequence including ... The structurally defined regions of apo(a) are identified by accession numbers in sequence databases such as NCBI. and such information is incorporated herein by reference. In certain embodiments, the target region is a 5' target portion of a target segment within the target region. The target region may include a sequence from the 3' target site of another target segment within the target region.

[0208] As used herein, a "second agent" or "second therapeutic agent" refers to an agent that is an agent that is more effective than a "first agent." The second therapeutic agent refers to an agent that can be used in combination with apo(a) or The antibody may include, but is not limited to, an antisense oligonucleotide that targets apoB. Secondary drugs include anti-apo(a) antibodies, apo(a) peptide inhibitors, and cholesterol inhibitors. Lactose-lowering agents, lipid-lowering agents, glucose-lowering agents, and anti-inflammatory agents may also be included.

[0209] As used herein, a "segment" refers to a smaller subportion of a region within a nucleic acid. For example, a "target segment" is a segment that is targeted by one or more antisense compounds. "5' target site" refers to the nucleotide sequence of a target nucleic acid that is "3' target site" refers to the 3'-most nucleotide of a target segment. Alternatively, "start site" refers to the 5'-most nucleotide of a target segment. "Stop site" refers to the 3'-most nucleotide of the target segment. A target segment begins at a "start site" in one sequence and ends at a "stop site" in another sequence. It is possible.

[0210] As used herein, "statins" refers to drugs that inhibit the activity of HMG-CoA reductase. It means an agent that inhibits

[0211] As used herein, "subcutaneous administration" means administration just below the skin.

[0212] As used herein, a "subject" refers to a human or non-human subject selected for treatment or therapy. It means a human animal.

[0213] As used herein, "symptoms of a cardiovascular disease or disorder" refers to a condition that is associated with a cardiovascular disease or disorder. It refers to and serves as an indicator of phenomena that result from and accompany a disorder or injury. Na, chest pain, shortness of breath, palpitations, weakness, dizziness, nausea, sweating, tachycardia, bradycardia, arrhythmia, atrial fibrillation, Swelling of the legs, cyanosis, fatigue, fainting, facial numbness, numbness of the legs, claudication or muscle cramps Swelling, abdominal swelling, or fever are symptoms of cardiovascular disease or disorders.

[0214] As used herein, "target" or "targeting" refers to a specific target nucleic acid. Design and manufacture of antisense compounds that hybridize specifically and produce the desired effect. It means a process of selection.

[0215] As used herein, a "therapeutically effective amount" refers to an amount that provides a therapeutic benefit to an individual. It means the amount of medicine.

[0216] As used herein, "therapeutic lifestyle changes" refers to changes in fat / fat (adipose) intended to reduce tissue mass and / or cholesterol This means making changes to your diet and lifestyle. Such changes can lower your risk of developing heart disease. It can reduce the risk of heart disease and help lower your daily total calories, total fat, saturated fat, polyunsaturated fat, and cholesterol. Recommended dietary intakes of monounsaturated fats, carbohydrates, protein, cholesterol, and insoluble fiber , as well as physical activity recommendations.

[0217] As used herein, "treating" or "treatment" refers to administering a compound described herein to a patient. Refers to the administration of a substance to bring about an alteration or improvement of a disease, disorder, or condition.

[0218] As used herein, "triglyceride" or "TG" refers to a triglyceride consisting of three fatty acid components. It refers to lipids or neutral fats consisting of glycerol bound to a carbohydrate.

[0219] As used herein, "type 2 diabetes mellitus," "diabetes mellitus type 2," "insulin "Non-Independent Diabetes Mellitus," "NIDDM," "Obesity-Related Diabetes Mellitus," or "Adult-Onset Diabetes Mellitus" Type 2 diabetes, as it is known, is primarily caused by insulin resistance, relative insulin deficiency, and It is a metabolic disorder characterized by hyperglycemia. Certain embodiments

[0220] In certain embodiments, the compound is an apolipoprotein (a ) (apo(a)), and an siRNA or antisense oligonucleotide targeting apo(a) and a conjugation group as described herein. Examples of oligonucleotides include those listed in the National Institute of Standards and Technology, which are incorporated herein by reference in their entirety. International Publication No. WO2013 / 177468, U.S. Patent No. US8,673,632, U.S. Patent No. S7,259,150, and U.S. Patent Application Publication No. US2004 / 0242516 In certain embodiments, the present invention includes, but is not limited to, those disclosed. The compounds are SEQ ID NOs: 12-13 as disclosed in International Publication No. WO2013 / 177468. Antisense oligonucleotides having any of the nucleic acid base sequences of 0, 133, and 134 In certain embodiments, the compound comprises: SEQ ID NOS: 11-45 and 85-9 as disclosed in US Pat. No. 8,673,632 and an antisense oligonucleotide having any one of the nucleic acid base sequences of the present invention. and a conjugate group as described in U.S. Pat. Any of the nucleic acid base sequences of SEQ ID NOs: 11 to 45 disclosed in US Pat. No. 2,259,150. and a conjugate group as described herein. In certain embodiments, the compound is a compound according to U.S. Patent Application Publication No. US2004 / 0242516. an antisense having any one of the nucleic acid base sequences of SEQ ID NOs: 7 to 41, The oligonucleotides include the oligonucleotides and the conjugate groups described herein. All of the nucleic acid sequences are incorporated herein by reference.

[0221] Certain embodiments provide for the reduction of apo(a) mRNA and protein expression. In certain embodiments, the compound is apo(a) and apo(a)-specific inhibitors for treating, preventing, or ameliorating associated diseases. In certain embodiments, the compound is an antisense oligonucleotide that targets apo(a). In certain embodiments, the compound is an enzyme that targets apo(a). a transsense oligonucleotide and a conjugate group.

[0222] Certain embodiments provide compounds and methods for reducing Lp(a) levels. In certain embodiments, the compounds are useful for treating, preventing, or treating Lp(a)-associated diseases. In certain embodiments, the compound is an apo(a)-specific inhibitor for improving The product is an antisense oligonucleotide that targets apo(a). In embodiments, the compound is an antisense oligonucleotide targeted to apo(a). and conjugated groups.

[0223] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. In certain embodiments, the modified oligonucleotide having a conjugate group comprises , 15-30, 18-24, 19-22, 13-25, 14-25, 15-25 connections In certain embodiments, the modified oligonucleotide comprises a nucleoside having a conjugate group. Nucleotides are at least 12, at least 13, at least 14, at least 15, At least 16, at least 17, at least 18, at least 19, at least 20, At least 21, at least 22, at least 23, at least 24, at least 25, at least At least 26, at least 27, at least 28, at least 29, or 30 connections In certain embodiments, modified oligonucleotides having a conjugate group include nucleosides. A nucleotide consists of 20 linked nucleosides.

[0224] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide is provided as a compound comprising a group, At least 8, at least 9, at least 10, at least 11 complementary to an equal length portion of , at least 12, at least 13, at least 14, at least 15, at least 16 , at least 17, at least 18, at least 19, or 20 consecutive nucleobases Includes.

[0225] Certain embodiments include modified oligonucleotides that target the apo(a) segment. and a conjugate group, and the modified oligonucleotide is described, for example, in Examples 114 and 115. and 117, at least one of which is complementary to an equal length portion of any of the target segments shown in 8, at least 9, at least 10, at least 11, at least 12, at least 13 , at least 14, at least 15, at least 16, at least 17, at least 18 , or at least 19, or 20 consecutive nucleobases. "Stop site" refers to the 5'-most nucleotide of a target segment, and "stop site" refers to the 5'-most nucleotide of a target segment. The target segment refers to the 3'-most nucleotide of each sequence listed in the table. Alternatively, the target segment may extend from the start site to the end site of a sequence. and may end at the termination site of another sequence. For example, The target segment is from 3901 to 3920 (start to end of SEQ ID NO: 58) In another example, as shown in Table 125, the target segment can range from 3900 to 3923 (starting site of SEQ ID NO: 57 to ending site of SEQ ID NO: 61).

[0226] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide has a nucleobase sequence selected from the group consisting of SEQ ID NOs: 1 to 4. At least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary. Certain embodiments target apo(a). and a compound comprising a modified oligonucleotide and a conjugate group, The nucleobase sequences of the target segments shown in Examples 114 and 117 are At least 80%, at least 85%, at least 90%, at least 95% , or 100% complementary.

[0227] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. a small number of bases complementary to the isometric portion of nucleobases 3901 to 3920 of SEQ ID NO: 1; at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least a nucleic acid sequence containing at least 18, at least 19, or at least 20 consecutive nucleic acid bases the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO:1. is.

[0228] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. A small number of bases consisting of nucleotides complementary to the isometric portion of nucleobases 3900 to 3923 of SEQ ID NO: 1. at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least At least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least a nucleobase sequence comprising at least 28, at least 29, or at least 30 contiguous nucleobases, The nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. .

[0229] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and any one of the nucleic acid base sequences of SEQ ID NOs: 12 to 130, 133, and 134. At least 8, at least 9, at least 10, at least 11, at least 12 of any , at least 13, at least 14, at least 15, at least 16, at least 17 , at least 18, at least 19, or 20 consecutive nucleobases. In certain embodiments, the modified oligonucleotide has a sequence of SEQ ID NO: 12 to At least 8 consecutive sequences of any one of the nucleic acid base sequences 130, 133, and 134 In certain embodiments, the compound has a nucleobase sequence comprising nucleobases of the sequence It consists of one of the numbers 12 to 130, 133, and 134 and a conjugated group.

[0230] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and SEQ ID NOs: 12 to 20, 22 to 33, 35 to 44, 47 to 50, 51, 53, 57-62, 65-66, 68, 70-79, 81, 85-86, 89-90, 9 Nucleic acid base sequences 2-94, 97, 105-110, 103-104, 133-134 At least 8, at least 9, at least 10, at least 11, or at least At least 12, at least 13, at least 14, at least 15, at least 16, at least Nucleotides containing at least 17, at least 18, at least 19, or 20 consecutive nucleobases In certain embodiments, the compound has the acid-base sequence of SEQ ID NOs: 12-20, 2 2~33, 35~44, 47~50, 51, 53, 57~62, 65~66, 68, 70 ~79, 81, 85~86, 89~90, 92~94, 97, 105~110, 103~ It consists of any one of the nucleic acid base sequences 104, 133 to 134 and a conjugated group.

[0231] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and SEQ ID NOs: 12 to 19, 26 to 30, 32, 35, 38 to 44, 46 to 47, 50, 57-58, 61, 64-66, 68, 72-74, 76-77, 92-9 4, at least 8, at least 9, or at least a few of any of the nucleic acid sequences of 103 to 110 at least 10, at least 11, at least 12, at least 13, at least 14, at least at least 15, at least 16, at least 17, at least 18, at least 19, or or 20 consecutive nucleobases. In certain embodiments, The compounds are SEQ ID NOs: 12 to 19, 26 to 30, 32, 35, 38 to 44, and 46 to 47. , 50, 57-58, 61, 64-66, 68, 72-74, 76-77, 92-94, It consists of any one of 103 to 110 nucleic acid base sequences and a conjugated group.

[0232] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and the nucleic acid base sequences of SEQ ID NOs: 111, 114 to 121, and 123 to 129. At least 8, at least 9, at least 10, at least 11, or at least at least 12, at least 13, at least 14, at least 15, at least 16, at least Contains at least 17, at least 18, at least 19, or 20 consecutive nucleobases In certain embodiments, the compound has the nucleobase sequence SEQ ID NO: 111, 11 It consists of either a nucleic acid base sequence of 4 to 121 or 123 to 129 and a conjugated group.

[0233] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and SEQ ID NOs: 14, 17, 18, 26-28, 39, 71, 106-10 At least 8, at least 9, at least 10, or at least 12 of any of the seven nucleic acid base sequences At least 11, at least 12, at least 13, at least 14, at least 15, at least At least 16, at least 17, at least 18, at least 19, or 20 consecutive In certain embodiments, the compound has a nucleobase sequence comprising nucleobases of the same structure. Nucleic acid base sequences of columns 14, 17, 18, 26-28, 39, 71, and 106-107 It consists of a conjugated group with one of these.

[0234] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and the nucleic acid base sequences of SEQ ID NOs: 14, 26-29, 39-40, and 82 At least 8, at least 9, at least 10, at least 11, or at least At least 12, at least 13, at least 14, at least 15, at least 16, at least a nucleic acid containing at least 17, at least 18, at least 19, or 20 consecutive nucleobases In certain embodiments, the compound has the base sequence of SEQ ID NO: 14, 26-29. , 39-40, or 82 nucleic acid base sequences and a conjugated group.

[0235] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and at least one of the nucleic acid base sequences of SEQ ID NOs: 14, 16 to 18. At least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least It has a nucleobase sequence comprising 18, at least 19, or 20 consecutive nucleobases. In certain embodiments, the compound has the nucleobase sequence of SEQ ID NOs: 14, 16-18. It consists of a conjugated group with one of these.

[0236] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and at least one of the nucleic acid base sequences of SEQ ID NOs: 26 to 27 and 107. at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least have a nucleobase sequence containing at least 18, at least 19, or at least 20 consecutive nucleobases In certain embodiments, the compound comprises the nucleobase sequence of SEQ ID NOs: 26-27, 107. and a conjugated group.

[0237] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and any one of the nucleic acid base sequences of SEQ ID NOs: 28 to 29, 39 to 40, and 47. At least 8, at least 9, at least 10, at least 11, at least 12 of any , at least 13, at least 14, at least 15, at least 16, at least 17 , at least 18, at least 19, or 20 consecutive nucleobases. In certain embodiments, the compound has the sequence of SEQ ID NOs: 28-29, 39-40. , consisting of any of 47 nucleic acid base sequences and a conjugated group.

[0238] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and any one of the nucleic acid base sequences of SEQ ID NOs: 28, 93, 104, and 134. or at least 8, at least 9, at least 10, at least 11, at least 12, At least 13, at least 14, at least 15, at least 16, at least 17, a nucleobase sequence containing at least 18, at least 19, or 20 consecutive nucleobases In certain embodiments, the compound has SEQ ID NOs: 28, 93, 104, 13 It consists of one of four nucleobase sequences and a conjugated group.

[0239] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. and comprising at least 8, at least 9, or at least 10 of the nucleobase sequence of SEQ ID NO: 58. At least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or In certain embodiments, the nucleic acid sequence comprises 20 consecutive nucleic acid bases. The modified oligonucleotide having a conjugate group comprises at least 8 of the nucleobase sequence of SEQ ID NO:58. In certain embodiments, the compound has a nucleobase sequence comprising 10 contiguous nucleobases. The product consists of SEQ ID NO: 58 and a conjugate group.

[0240] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compound comprises a 5'-X and a modified oligonucleotide ISIS 494372 having the formula: c. In certain embodiments, the antisense compound is a 5'-X wherein X is Gal It is a conjugated group containing NAc. [ka]

[0241] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are conjugated modified antisense compounds. In certain embodiments, the antibody comprises the oligonucleotide ISIS 681251. The sense compound consists of the conjugated modified oligonucleotide ISIS 681251. [ka]

[0242] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are conjugate modified In certain embodiments, the oligonucleotide comprises the oligonucleotide ISIS 681257. The chisense compound consists of the conjugated modified oligonucleotide ISIS 681257. [ka]

[0243] In certain embodiments, the present disclosure provides conjugated antisense oligonucleotides represented by the following structure: In certain embodiments, the antisense compounds are Modifications having the nucleobase sequence of SEQ ID NO: 58 with 5'-GalNAc, which alters the sugar modification In certain embodiments, the antisense compound comprises a virus. The nucleic acid sequence of SEQ ID NO: 58 has a 5'-GalNAc sugar modification in the amino acid sequence. a modified oligonucleotide comprising [ka]

[0244] In the formula, R 1 is -OCH2CH2OCH3(MOE), and R 2 Is it H or or R 1 and R 2 together to form a bridge, where R 1 but, -O- and R 2 is -CH2-, -CH(CH3)-, or -CH2CH2- The resulting bridges are -O-CH2-, -O-CH(CH3)-, and -OC R is selected from H2CH2- 1 and R 2 are directly connected, On the same ring, independently, R on each ring 3 and R 4 For each pair of R 3 H and -OCH 2CH2OCH3, and R 4 is H or R 3 and R 4 together either form a bridge, where R 3 is -O- and R 4 But -CH 2-, -CH(CH3)-, or -CH2CH2-, and the resulting bridge is - -O-CH2-, -O-CH(CH3)-, and -O-CH2CH2- Sea urchin, R 3 and R 4 are directly connected, R 5 is selected from H and -CH3; Z is S - and O - is selected from.

[0245] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The compound is provided comprising a group, and the modified oligonucleotide is single-stranded.

[0246] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). and wherein at least one internucleoside linkage is a modified internucleoside group. In certain embodiments, the modified internucleoside linkage is a phosphorothioate linkage. In certain embodiments, the modified oligonucleoside linkage is At least 1, at least 2, at least 3, at least 4, at least 5, At least 6, at least 7, at least 8, at least 9, or at least 10 The internucleoside linkage is a phosphorothioate internucleoside linkage. In the formula (I), each internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified oligonucleotide comprises at least 1, at least 2, At least 3, at least 4, at least 5, at least 6, at least 7, at least containing 8, at least 9, or at least 10 phosphodiester internucleoside linkages In certain embodiments, each internucleoside linkage of a modified oligonucleotide is From phosphodiester and phosphorothioate internucleoside linkages be selected.

[0247] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The present invention provides compounds comprising a group wherein at least one nucleoside comprises a modified nucleobase. In certain embodiments, the modified nucleobase is 5-methylcytosine.

[0248] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The compounds are provided comprising a group, wherein the modified oligonucleotide comprises at least one modified sugar. In certain embodiments, the modified sugar is a bicyclic sugar. The modified sugars may be 2'-O-methoxyethyl, constrained ethyl, 3'-fluoro-HNA, or 4'- '-(CH2) n It contains an -O-2' bridge, where n is 1 or 2.

[0249] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 12 to 30 linked nucleotides. (a) a gap segment consisting of linked deoxynucleosides; (b) a 5' wing segment consisting of linked nucleosides; (c) a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of a nucleotide sequence, and a gap segment between the 5' wing segment and the 3' wing segment. and 3' wing segments, each nucleotide of each wing segment. The leioside comprises a modified sugar.

[0250] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 20 linked nucleosides. and (a) a gap segment consisting of 10 linked deoxynucleosides. (b) a 5' wing segment consisting of five linked nucleosides; (c) a 5' wing segment consisting of five linked nucleosides; the gap segment comprises 5′ wing segments consisting of 5′ nucleotides linked together; Located between the 'wing segment and the 3' wing segment, each wing segment Each nucleoside of the methyl group contains a 2'-O-methoxyethyl sugar and at least one nucleoside The internucleotide linkages are phosphorothioate, and each cytosine residue is 5-methylcytosine. It's Shin.

[0251] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 20 linked nucleosides. and at least eight of SEQ ID NOs: 12 to 130, 133, and 134 and the modified oligonucleotide has a nucleobase sequence comprising 10 consecutive nucleobases. (b) a gap segment consisting of five linked deoxynucleosides; (c) a 5' wing segment consisting of five linked nucleosides a 3' wing segment comprising a gap segment and a 5' wing segment; Each nucleoside of each wing segment is located between the 3' wing segment and the 3' wing segment. contains a 2'-O-methoxyethyl sugar and at least one internucleoside linkage is The linkages are holothioate and each cytosine residue is a 5-methylcytosine.

[0252] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). The modified oligonucleotide comprises 20 linked nucleosides. and having a nucleobase sequence comprising at least 8 consecutive nucleobases of SEQ ID NO: 58. and the modified oligonucleotide consists of (a) 10 linked deoxynucleosides. (b) a gap segment, (c) a 5' wing segment consisting of five linked nucleosides (c) a 3' wing segment consisting of five linked nucleosides, The wing segment is located between the 5' and 3' wing segments. Each nucleoside in each wing segment contains a 2'-O-methoxyethyl sugar and At least one internucleoside linkage is a phosphorothioate linkage, and each cytosine residue is 5-methylcytosine.

[0253] Certain embodiments provide modified oligonucleotides and conjugates that target apo(a). and the modified oligonucleotide comprises 20 nucleobases having the nucleobase sequence of SEQ ID NO:58. The modified oligonucleotide consists of (a) 10 linked nucleosides. (b) a gap segment consisting of five linked nucleosides; (c) a 5' wing segment consisting of five linked nucleosides; The gap segment is between the 5' wing segment and the 3' wing segment. Each nucleoside in each wing segment is located between the 2'-O- Contains a methoxyethyl sugar and at least one internucleoside linkage is phosphorothioate bond, and each cytosine residue is a 5-methylcytosine.

[0254] In certain embodiments, the conjugate group is at the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is linked to the oligonucleotide. The nucleotide is linked at its 3' end to a modified oligonucleotide.

[0255] In certain embodiments, the conjugate group comprises one or more ligands. In certain embodiments, the conjugate group comprises two or more ligands. The conjugate group comprises three or more ligands. In certain embodiments, the conjugate group comprises three ligands. In certain embodiments, each ligand comprises a polysaccharide, a modified polysaccharide, a sugar, a modified Polysaccharides, mannose, galactose, mannose derivatives, galactose derivatives, D-mannose Pyranose, L-mannopyranose, D-arabinose, L-galactose, D-xylo Furanose, L-xylofuranose, D-glucose, L-glucose, D-galactose L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D -Mannopyranose, β-D-Mannopyranose, α-D-Glucopyranose, β-D- Glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-furanose fructopyranose, α-D-fructopyranose, α-D-galactopyranose, β-D -galactopyranose, α-D-galactofuranose, β-D-galactofuranose, Glucosamine, sialic acid, α-D-galactosamine, N-acetylgalactosamine, 2-acetyl Amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyramine 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy -4-Formamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy- 2-Sulfoamino-D-glucopyranose, N-glycoloyl-α-neuraminic acid, 5- Thio-β-D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio- 6-O-Trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose , ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α- D-gluco-heptopyranoside, 2,5-anhydro-D-allonitrile, ribose, Select from D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose. In certain embodiments, each ligand is selected from N-acetylgalactosamine. be.

[0256] In certain embodiments, each ligand is N-acetylgalactosamine.

[0257] In certain embodiments, the conjugate group comprises: [ka]

[0258] In certain embodiments, the conjugate group comprises: [ka]

[0259] In certain embodiments, the conjugate group comprises: [ka]

[0260] In certain embodiments, the conjugate group comprises: [ka]

[0261] In certain embodiments, the conjugate group comprises: [ka]

[0262] In certain embodiments, the conjugated group comprises at least one phosphorus linking group or a neutral linking group. Contains a group.

[0263] In certain embodiments, the conjugate group comprises a structure selected from the following: [ka] In the formula, n is 1 to 12, m is 1 to 12.

[0264] In certain embodiments, the conjugated group is a tether having a structure selected from the following: and [ka] wherein L is either a phosphorus linking group or a neutral linking 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 0 to 20, and at least one m1 is 0 for each tether. Exceeds.

[0265] In certain embodiments, the conjugated group is a tether having a structure selected from the following: and [ka] wherein Z2 is H or CH3; Each m1 is independently 0 to 20, and at least one m1 is 0 for each tether. Exceeds.

[0266] In certain embodiments, the conjugated group is a tether having a structure selected from the following: and [ka] In the formula, n is 1 to 12, m is 1 to 12.

[0267] In certain embodiments, the conjugate group is covalently attached to the modified oligonucleotide.

[0268] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, B is a cleavable moiety, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0269] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, B is a cleavable moiety, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; each n is independently 0 or 1; q is an integer of 1 to 5. In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, B is a cleavable moiety, C is a conjugated linker; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0270] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0271] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, C is a conjugated linker; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0272] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, B is a cleavable moiety, D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0273] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, B is a cleavable moiety, Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0274] In certain embodiments, the compound has a structure represented by the following formula: [ka] During the ceremony, A is a modified oligonucleotide, D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0275] In certain embodiments, the conjugated linker has a structure selected from the following: [ka] wherein each L is independently a phosphorus linking group or a neutral linking group; Each n is independently 1 to 20.

[0276] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0277] In certain embodiments, the conjugated linker has the following structure: [ka]

[0278] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0279] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0280] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0281] In certain embodiments, the conjugated linker comprises pyrrolidine. In certain embodiments, the conjugate linker does not contain pyrrolidine. In certain embodiments, the conjugated linker comprises an amide. In certain embodiments, the conjugated linker comprises at least two amides. In certain embodiments, the conjugated linker does not comprise an amide. In certain embodiments, the conjugated linker comprises a polyamide. In certain embodiments, the conjugated linker comprises one or more disulfides. In certain embodiments, the conjugated linker comprises a protein binding moiety. In certain embodiments, the protein-binding moiety comprises a lipid.

[0282] In certain embodiments, the protein-binding moiety is selected from the group consisting of cholesterol, cholic acid, and acetylcholine. Damantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexa Decyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol ol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, stearic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenoic acid, dimethicone xytrityl, or phenoxazine), vitamins (e.g., folate, vitamin A, vitamin Vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides) , tetrasaccharides, oligosaccharides, polysaccharides), endosomolytic components, steroids (e.g., uvaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsaparilla nin, friedelin, epifriedelanol-derivatized lithocholic acid), or cationic The lipids are selected from the group consisting of:

[0283] In certain embodiments, the protein-binding moiety is a C16 to C22 long chain saturated or Contains unsaturated fatty acids, cholesterol, cholic acid, vitamin E, adamantane, or 1-petroleum The compound is selected from among tetrafluoropropyl.

[0284] In certain embodiments, the conjugated linker has a structure selected from the following: [ka] wherein each n is independently 1 to 20, and p is 1 to 6.

[0285] In certain embodiments, the conjugated linker has a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0286] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0287] In certain embodiments, the conjugated linker has a structure selected from the following: [ka] In the formula, n is 1 to 20.

[0288] In certain embodiments, the conjugated linker has a structure selected from the following: . [ka]

[0289] In certain embodiments, the conjugated linker has a structure selected from the following: [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0290] In certain embodiments, the conjugated linker has the following structure: [ka]

[0291] In certain embodiments, the branching group has one of the following structures: [ka] wherein each A1 is independently O, S, C=O, or NH; Each n is independently 1 to 20.

[0292] In certain embodiments, the branching group has one of the following structures: [ka] wherein each A1 is independently O, S, C=O, or NH; Each n is independently 1 to 20.

[0293] In certain embodiments, the branching group has the following structure: [ka]

[0294] In certain embodiments, the branching group has the following structure: [ka]

[0295] In certain embodiments, the branching group has the following structure: [ka]

[0296] In certain embodiments, the branching group has the following structure: [ka]

[0297] In certain embodiments, the branching group comprises an ether.

[0298] In certain embodiments, the branching group has the structure: [ka] wherein each n is independently 1 to 20; m is 2 to 6.

[0299] In certain embodiments, the branching group has the following structure: [ka]

[0300] In certain embodiments, the branching group has the following structure: [ka]

[0301] In certain embodiments, the branching group has: [ka] wherein each j is an integer from 1 to 3; Each n is an integer from 1 to 20.

[0302] In certain embodiments, the branching group has the following: [ka]

[0303] In certain embodiments, each tether is selected from the following: [ka] wherein L is selected from phosphorus linking groups and neutral linking 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 0 to 20, and at least one m1 is 0 for each tether. Exceeds.

[0304] In certain embodiments, each tether is selected from the following: [ka] wherein Z2 is H or CH3; Each m2 is independently 0 to 20, and at least one m2 is 0 for each tether. Exceeds.

[0305] In certain embodiments, each tether is selected from the following: [ka] In the formula, n is 1 to 12, m is 1 to 12.

[0306] In certain embodiments, at least one tether comprises ethylene glycol In certain embodiments, at least one tether comprises an amide. In embodiments, at least one tether comprises polyamide. In certain embodiments, at least one tether comprises an amine. At least two of the tethers are different from each other. In certain embodiments, all of the tethers are In certain embodiments, each tether is selected from the following: [ka] wherein each n is independently 1 to 20; Each p is from 1 to about 6.

[0307] In certain embodiments, each tether is selected from the following: [ka]

[0308] In certain embodiments, each tether has the following structure: [ka] wherein each n is independently 1 to 20.

[0309] In certain embodiments, each tether has the following structure: [ka]

[0310] In certain embodiments, the tether is [ka] and having a structure selected from wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0311] In certain embodiments, the tether has a structure selected from the following: [ka]

[0312] In certain embodiments, the ligand is galactose. In the above, the ligand is mannose-6-phosphate.

[0313] In certain embodiments, each ligand is selected from: [ka] wherein each R1 is selected from OH and NHCOOH.

[0314] In certain embodiments, each ligand is selected from the following: [ka]

[0315] In certain embodiments, each ligand has the following structure: [ka]

[0316] In certain embodiments, each ligand has the following structure: [ka]

[0317] In certain embodiments, the conjugate group comprises a cell targeting moiety.

[0318] In certain embodiments, the conjugate group comprises a cell targeting moiety having the structure: [ka] wherein each n is independently 1 to 20.

[0319] In certain embodiments, the cell targeting moiety has the structure: [ka]

[0320] In certain embodiments, the cell targeting moiety has the structure: [ka] wherein each n is independently 1 to 20.

[0321] In certain embodiments, the cell targeting moiety has the structure: [ka]

[0322] In certain embodiments, the cell targeting moiety comprises: [ka]

[0323] In certain embodiments, the cell targeting moiety comprises: [ka]

[0324] In certain embodiments, the cell targeting moiety comprises: [ka]

[0325] In certain embodiments, the cell targeting moiety comprises: [ka]

[0326] In certain embodiments, the cell targeting moiety comprises: [ka]

[0327] In certain embodiments, the cell targeting moiety comprises: [ka]

[0328] In certain embodiments, the cell targeting moiety comprises: [ka]

[0329] In certain embodiments, the cell targeting moiety comprises: [ka]

[0330] In certain embodiments, the cell targeting moiety comprises: [ka]

[0331] In certain embodiments, the cell targeting moiety comprises: [ka]

[0332] In certain embodiments, the cell targeting moiety comprises: [ka]

[0333] In certain embodiments, the cell targeting moiety comprises: [ka]

[0334] In certain embodiments, the cell targeting moiety comprises: [ka]

[0335] In certain embodiments, the cell targeting moiety comprises: [ka]

[0336] In certain embodiments, the cell targeting moiety comprises: [ka]

[0337] In certain embodiments, the cell targeting moiety comprises: [ka]

[0338] In certain embodiments, the cell targeting moiety comprises: [ka]

[0339] In certain embodiments, the cell targeting moiety comprises: [ka]

[0340] In certain embodiments, the cell targeting moiety comprises: [ka]

[0341] In certain embodiments, the cell targeting moiety comprises: [ka]

[0342] In certain embodiments, the cell targeting moiety comprises: [ka]

[0343] In certain embodiments, the cell targeting moiety comprises: [ka] In the formula, each Y is O, S, substituted or unsubstituted C1-C10 alkyl, amino, substituted amino The alkyl group is selected from aryl, aryl, aryl azide, aryl, aryl alkynyl, aryl cycloalkyl ... cycloalkyl.

[0344] In certain embodiments, the conjugate group comprises: [ka] In the formula, each Y is O, S, substituted or unsubstituted C1-C10 alkyl, amino, substituted amino The alkyl group is selected from aryl, aryl, aryl azide, aryl, aryl alkynyl, aryl cycloalkyl ... cycloalkyl.

[0345] In certain embodiments, the conjugate group comprises: [ka] In the formula, each Y is O, S, substituted or unsubstituted C1-C10 alkyl, amino, substituted amino The alkyl group is selected from aryl, aryl, aryl azide, aryl, aryl alkynyl, aryl cycloalkyl ... cycloalkyl.

[0346] In certain embodiments, the conjugate group comprises: [ka]

[0347] In certain embodiments, the conjugate group comprises: [ka]

[0348] In certain embodiments, the conjugate group comprises: [ka]

[0349] In certain embodiments, the conjugate group comprises: [ka]

[0350] In certain embodiments, the conjugate group is a phosphodiester, an amide, or an ester. The cleavable moiety is selected from:

[0351] In certain embodiments, the conjugate group comprises a phosphodiester cleavable moiety.

[0352] In certain embodiments, the conjugate group does not include a cleavable moiety; and the oligonucleotide. wherein the conjugate group comprises an amide cleavable moiety. In certain embodiments, the conjugate group is , containing an ester cleavable moiety.

[0353] In certain embodiments, the compound has the structure: [ka] wherein each n is independently 1 to 20; Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0354] In certain embodiments, the compound has the structure: [ka] wherein each n is independently 1 to 20; Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0355] In certain embodiments, the compound has the structure: [ka] wherein each n is independently 1 to 20; Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Z is H or a bound solid support; Bx is a heterocyclic base moiety.

[0356] In certain embodiments, the compound has the structure: [ka] wherein each n is independently 1 to 20; Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Z is H or a bound solid support; Bx is a heterocyclic base moiety.

[0357] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0358] In certain embodiments, the compound has the structure: [ka] wherein Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0359] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0360] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0361] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0362] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0363] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0364] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0365] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0366] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0367] In certain embodiments, the compound has the structure: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0368] In certain embodiments, the conjugate group comprises: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0369] In certain embodiments, the conjugate group comprises: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0370] In certain embodiments, the conjugate group comprises: [ka] In the formula, Q13 is H or O(CH2)2-OCH3; A is a modified oligonucleotide, Bx is a heterocyclic base moiety.

[0371] In certain embodiments, Bx is adenine, guanine, thymine, uracil, or is selected from cytosine, or 5-methylcytosine. In certain embodiments, Bx is adenine. In certain embodiments, Bx is thymine. In certain embodiments, Q13 is O(CH2)2-OCH3. In an embodiment, Q13 is H.

[0372] In certain embodiments, the compound is in a salt form. The compound further comprises a pharmaceutically acceptable carrier or diluent. In this case, the compound comprises a modified oligonucleotide and a conjugate group that targets apo(a), and includes salts thereof, as well as pharmaceutically acceptable carriers or diluents.

[0373] Certain embodiments provide compositions comprising the conjugated antisense compounds described herein. and the viscosity level of the compound is less than 40 centipoise (cP). In the present invention, the conjugate antisense compounds described herein are When measured by a meter, the values ​​were less than 40 cP, less than 35 cP, less than 30 cP, less than 25 cP, and It is effective because it has a viscosity of less than 0 cP or less than 15 cP.

[0374] Certain embodiments involve administering to an animal a composition and a conjugate antisense compound disclosed herein. In certain embodiments, the method includes administering a compound or composition to a subject. Administration of the antisense compounds prevents cardiovascular, metabolic, and / or inflammatory diseases. To treat, cure, ameliorate, or slow the progression of.

[0375] Certain embodiments provide therapeutic agents for treating an apo(a)-related disease, disorder, or condition. Certain embodiments provide compositions and methods for use in the method of treating Lp(a ) compositions for use in therapy to treat related diseases, disorders, or conditions; and In certain embodiments, apo(a) and / or Lp(a) are provided. In certain embodiments, the composition comprises apo(a)-1, apo(a)-2, and apo(a)-3. In certain embodiments, compounds comprising apo(a)-specific inhibitors The inhibitor is a nucleic acid. In certain embodiments, the nucleic acid is an antisense compound. In certain embodiments, the antisense compound targets apo(a). In certain embodiments, the antisense compound is a po(a) is a modified oligonucleotide targeted to po(a) and a conjugate group. In this embodiment, modified oligonucleotides targeting apo(a) with conjugated groups are Treating, preventing, or slowing the progression of vascular and / or metabolic diseases, disorders, or conditions In certain embodiments, therapeutic compositions and methods are used in preventing and improving involves administering an apo(a)-specific inhibitor to an individual in need thereof.

[0376] Certain embodiments provide compositions and methods for reducing apo(a) levels. Certain embodiments provide compositions and methods for reducing Lp(a) levels. In certain embodiments, apo(a) in a tissue, organ, or subject is provided. ) levels improves the LDL:HDL or TG:HDL ratio. The formulations are intended to reduce apo(a) mRNA or protein expression in animals. Compositions and methods are provided for administering to animals the conjugated antisense compounds or compositions disclosed herein. administering a composition to reduce apo(a) mRNA or protein expression in animals Certain embodiments include a method for reducing Lp(a) levels in an animal. Compositions and methods are provided to administer to an animal the conjugated antisense compounds or The composition is administered to reduce apo(a) mRNA or protein expression in the animal. This includes:

[0377] Certain embodiments of the composition include the use of apo(a)-related diseases, disorders, or the like in a subject in need thereof. , and preventing, treating, delaying, slowing the progression of, and / or ameliorating conditions. Certain embodiments provide compositions and methods for treating a patient in need thereof. Prevent, treat, delay, and eradicate Lp(a)-related diseases, disorders, and conditions in elephants. The present invention provides compositions and methods for slowing and / or ameliorating the progression of certain In embodiments, such diseases, disorders, and conditions include inflammatory, cardiovascular, and and / or metabolic diseases, disorders, and conditions. Certain such cardiovascular diseases , disorders, or conditions include chylomyasis, hypertriglyceridemia, aortic stenosis, aneurysms ( For example, abdominal aortic aneurysm, angina, arrhythmia, atherosclerosis, cerebrovascular disease, coronary artery disease Arterial disease, coronary heart disease, dyslipidemia, hypercholesterolemia, dyslipidemia, hypertension Hypertriglyceridemia, myocardial infarction, peripheral vascular disease (e.g., peripheral arterial disease, peripheral arterial hyperplasia) These include, but are not limited to, retinal vascular occlusion, retinal vascular occlusion, or stroke. Such metabolic diseases, disorders, or conditions include hyperglycemia, prediabetes, diabetes (type 1 and These include types I and II), obesity, insulin resistance, metabolic syndrome, and diabetic dyslipidemia. Certain such inflammatory diseases, disorders, or conditions include, but are not limited to: is aortic stenosis, coronary artery disease (CAD), Alzheimer's disease, and thromboembolic disease. Certain thromboembolic diseases, disorders, or conditions include, but are not limited to: The disorders, disorders, or conditions include stroke, thrombosis (e.g., venous thromboembolism), myocardial infarction, and In certain embodiments, the present invention is directed to treating aortic valve stenosis, including, but not limited to, peripheral vascular disease. Compositions and methods for preventing, treating, retarding, slowing the progression of, and / or ameliorating vascular disease and methods are provided.

[0378] Certain embodiments provide a method for alleviating at least one symptom of a cardiovascular disease, disorder, or condition. In certain embodiments, these symptoms include angina, Chest pain, shortness of breath, palpitations, weakness, dizziness, nausea, sweating, tachycardia, bradycardia, arrhythmia, atrial fibrillation, lower limb swelling of the face, cyanosis, fatigue, fainting, numbness in the face, numbness in the limbs, claudication or muscle cramps, abdominal pain Symptoms include, but are not limited to, swelling of the abdomen, and fever. A method for alleviating at least one symptom of valvular stenosis is provided.

[0379] In certain embodiments, modulation of apo(a) or Lp(a) expression is achieved in cells, tissues, or the like. In certain embodiments, the modulation occurs within a cell, tissue, or organ in an animal. In certain embodiments, the modulation occurs within a tissue or organ. In certain embodiments, the modulation is a decrease in apo(a) protein levels. In certain embodiments, apo(a) mRNA levels and apo(a) mRNA levels are decreased. In certain embodiments, the modulation is , a decrease in Lp(a) levels. Such a decrease occurs in a time-dependent or dose-dependent manner. This can occur.

[0380] In certain embodiments, the subject or animal is a human.

[0381] In certain embodiments, the conjugated antisense compound is administered parenterally. In an embodiment, the parenteral administration is subcutaneous administration.

[0382] In certain embodiments, the conjugated antisense compound or composition may be administered in combination with a second agent or In certain embodiments, the conjugated antisense compound or The composition and the second agent are administered simultaneously.

[0383] In certain embodiments, the second agent is a glucose-lowering agent. In embodiments, the second agent is an LDL, TG, or cholesterol lowering agent. In certain embodiments, the second agent is an anti-inflammatory agent. In certain embodiments, the second drug is an Alzheimer's drug. Agents include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin), niacin (e.g., Niaspan), nicotinic acid, apoB inhibitors (e.g., Mipomersen) , CETP inhibitors (e.g., Anacetrapib), apo(a) inhibitors, thyroid hormone irumone analogues (e.g., Eprotiromes), HMG-CoA reductase inhibitors ( statins), fibrates (e.g., Gemfibrozil), and microsteroids and a steroid hormone receptor inhibitor (e.g., lomitapide). The therapy can be, but is not limited to, Lp(a) apheresis. Not limited. Agents or therapies may be co-administered or administered simultaneously. Alternatively, the therapies may be administered sequentially or sequentially.

[0384] Certain embodiments provide apo(a)-reducing agents for reducing apo(a) levels in an animal. Certain embodiments provide for the use of conjugated antisense compounds targeting a) an animal Targeting apo(a) to reduce Lp(a) levels in humans. Certain embodiments provide for the use of compounds of the present invention in treating apo(a)-associated diseases, disorders, Conjugate agonists targeting apo(a) to treat, prevent, or ameliorate a disease or condition Certain embodiments provide for the use of Tisens compounds in treating Lp(a)-associated diseases, Apo(a)-targeted conjugates for treating, preventing, or ameliorating disorders or conditions. Uses of antisense compounds are provided.

[0385] Certain embodiments include the use of a medicament for reducing apo(a) levels in an animal. The present invention provides the use of conjugated antisense compounds that target apo(a) in certain embodiments. Embodiments include the use of apo(a) in the preparation of a medicament for reducing Lp(a) levels in an animal. In certain embodiments, conjugated antisense compounds are provided that target apo (a) for the preparation of a medicament for treating, preventing, or ameliorating a disease, disorder, or condition associated with Certain embodiments provide for the use of conjugated antisense compounds for the treatment of Lp(a). Conjugates for the preparation of medicaments for treating, preventing, or ameliorating associated diseases, disorders, or conditions. Uses of antisense compounds are provided.

[0386] Certain embodiments are directed to diseases associated with apo(a) and / or Lp(a). In the manufacture of a medicament to treat, ameliorate, delay, or prevent one or more of Uses of the conjugated antisense compounds described herein are provided.

[0387] Certain embodiments include a method for treating, preventing, or treating a disease, disorder, or condition described herein. provides a kit for improving the expression of apo(a) as described herein, the kit comprising: (i) apo(a) as described herein; a specific inhibitor and, optionally, (ii) a second agent or therapy as described herein.

[0388] The kits of the present invention can be used to treat the diseases, disorders, or instructions for using the kit to treat, prevent, or ameliorate a condition. It may be included in. B. A specific compound

[0389] In certain embodiments, the present invention provides antisense oligonucleotides and conjugates. Conjugated antisense compounds comprising the moiety are provided. a. Certain antisense oligonucleotides

[0390] In certain embodiments, the present invention provides antisense oligonucleotides Such antisense oligonucleotides comprise linked nucleosides, with each nucleoside The oligonucleotide comprises a sugar moiety and a nucleobase. The structure of a nucleic acid molecule can be determined by its chemical characteristics (e.g., modifications and modification patterns) and nucleic acid base sequence (e.g., (e.g., the sequence, identity, and sequence of the target nucleic acid of the antisense oligonucleotide) It can be considered. i. a particular chemical characteristic

[0391] In certain embodiments, the antisense oligonucleotides contain one or more modifications. In certain such embodiments, the antisense oligonucleotide comprises: Contains one or more modified nucleosides and / or modified internucleoside linkages. In embodiments, the modified nucleoside comprises a modified sugar moiety and / or a modified nucleobase. 1. Certain sugar moieties

[0392] In certain embodiments, compounds of the present disclosure comprise one or more modified nucleic acids containing a modified sugar moiety. Such compounds containing one or more sugar-modified nucleosides are naturally occurring. compared to oligonucleotides containing only nucleosides with the sugar moiety present. These may have desirable properties such as enhanced enzyme stability or increased binding affinity to the target nucleic acid. In certain embodiments, the modified sugar moiety is a substituted sugar moiety. Thus, the modified sugar moiety is a sugar surrogate. Such a sugar surrogate corresponds to the substitution of the substituted sugar moiety. The amino acid sequence may include one or more substitutions.

[0393] In certain embodiments, the modified sugar moiety comprises a substituent at the 2' and / or 5' position. A substituted sugar moiety containing one or more non-bridging sugar substituents, including, but not limited to, 2 Examples of suitable sugar substituents at the 2'-position include 2'-F, 2'-OCH3 ("OMe" or "O- methyl), and 2'-O(CH2)2OCH3 ("MOE"). In certain embodiments, the sugar substituent at the 2' position is selected from the group consisting of allyl, amino, , azido, thio, O-allyl, O-C1~C 10 Alkyl, O-C1-C 10 Substituted Alkynes OCF3, O(CH2)2SCH3, O(CH2)2-ON(Rm)(Rn), and and O—CH—C(═O)—N(Rm)(Rn), wherein each Rm and R n is independently H or substituted or unsubstituted C1-C 10 Alkyl. Sugar at 5' position Examples of substituents include 5'-methyl (R or S), 5'-vinyl, and 5'-methoxy. In certain embodiments, the substituted sugar may include, but is not limited to, two or more The above non-bridging sugar substituents include, for example, 2'-F-5'-methyl sugar moieties (additional 5',2 For '-bis-substituted sugar moieties and nucleosides, see, e.g., PCT International Application No. WO20 (See issue 08 / 101157).

[0394] Nucleosides containing a 2'-substituted sugar moiety are referred to as 2'-substituted nucleosides. In certain embodiments, the 2'-substituted nucleoside is selected from halo, allyl, amino, azido, S H, CN, OCN, CF3, OCF3, O, S, or N(R m )-Alkyl; O, S, or N(R m )-alkenyl; O, S, or N(R m )-Alkynyl;O-Alkyne Nyl-O-alkyl, alkynyl, aralkyl, O-alkaryl, O-ara Rukyru, O(CH2)2SCH3, O-(CH2)2-ON(R m )(R n );or O-CH2-C(=O)-N(R m )(R n ), wherein , each R m and R n are independently H, an amino protecting group, or a substituted or unsubstituted C ~C 10 These 2'-substituents are hydroxyl, amino, alkoxy, and , carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S -alkyl), independent of halogen, alkyl, aryl, alkenyl, and alkynyl It may be further substituted with one or more substituents selected from the following:

[0395] In certain embodiments, the 2'-substituted nucleoside is selected from the group consisting of F, NH, N, OCF 3、 O-CH3, O(CH2)3NH2, CH2-CH=CH2, O-CH2-CH=C H2, OCH2CH2OCH3, O(CH2)2SCH3, O-(CH2)2-ON( R m )(R n ), O(CH2)2O(CH2)2N(CH3)2, and N-substituted acetonitriles Amide (O-CH2-C(=O)-N(R m )(R n ) containing a 2'-substituent selected from In the formula, each R m and R n are independently H, an amino protecting group, or a substituted or unsubstituted ExchangeC1~C 10 It is alkyl.

[0396] In certain embodiments, the 2'-substituted nucleoside is F, OCF 3、 O-CH3 , OCH2CH2OCH3, O(CH2)2SCH3, O-(CH2)2-ON(CH 3)2, -O(CH2)2O(CH2)2N(CH3)2, and O-CH2-C(=O )-N(H)CH3.

[0397] In certain embodiments, 2'-substituted nucleosides include F, O-CH3, and O The sugar moiety includes a 2'-substituent selected from CH2CH2OCH3.

[0398] Certain modified sugar moieties include a bridging sugar substituent that forms a second ring to provide a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a 4' furanose ring atom and the 2' furanose ring atom. Examples of such 4' to 2' sugar substituents include , -[C(R a )(R b )] n -, -[C(R a )(R b )] n -O-, -C(R a R b )-N(R)-O-, or -C(R a R b )-ON(R)-;4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-(CH2)-O-2'( LNA);4'-(CH2)-S-2';4'-(CH2)2-O-2'(ENA);4 '-CH(CH3)-O-2'(cEt); and 4'-CH(CH2OCH3)-O- 2'; and analogs thereof (see, e.g., U.S. Pat. No. 6,239,999, issued July 15, 2008). See No. 7,399,845; 4'-C(CH3)(CH3)-O-2' and and analogs thereof (e.g., International Publication No. WO2009 / 006, published January 8, 2009). 478); 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., See, for example, International Publication No. WO2008 / 150729, published December 11, 2008. 4'-CH2-ON(CH3)-2' (e.g., published on September 2, 2004) See published US 2004 / 0171570; 4'-CH2-ON(R) -2'; and 4'-CH2-N(R)-O-2'- (wherein each R is independently H, Protecting group, or C1-C 12 alkyl); 4'-CH2-N(R)-O-2' (formula In the middle, R is H, C1~C 12 alkyl, or protecting group) (September 23, 2008 See issued U.S. Patent No. 7,427,672; 4'-CH2-C(H)( CH3)-2' (e.g., Chattopadhyaya, et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH2-C(=CH2 )-2' and analogs thereof (PCT International Application No. WO200802222222, published December 8, 2008) 008 / 154401).

[0399] In certain embodiments, such 4' to 2' bridges are independently -[C(R a )(R b )] n -, -C(R a )=C(R b )-, -C(R a )=N-, -C(=NR a )-, -C(=O)-, -C(=S)-, -O-, -Si(R a )2-, -S(=O) x - and -N(R a )-, and During the ceremony, x is 0, 1, or 2; n is 1, 2, 3, or 4; Each R a and R b are independently H, a protecting group, hydroxyl, C1-C 12 Alkyl, Substitution C1~C 12 Alkyl, C2-C 12 Alkenyl, substituted C2-C 12 Alkenyl, C 2~C 12 Alkynyl, substituted C2-C 12 Alkynyl, C5-C 20 Aryl, substituted C5 ~C 20 Aryl, heterocyclic radical, substituted heterocyclic radical, heteroaryl, substituted heterocyclic radical Heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, COOJ1, acyl (C(=O)-H), substituted acyl CN, sulfonyl (S(=O)2-J1), or sulfoxyl (S(=O)-J1 ) and Each J1 and J2 is independently H, C1 to C 12 Alkyl, substituted C1-C 12 Archi Lu, C2~C 12 Alkenyl, substituted C2-C 12 Alkenyl, C2-C 12 Alkynyl, Substitution C2~C 12 Alkynyl, C5-C 20 Aryl, substituted C5-C 20 Aryl, Arrow acyl (C(=O)-H), substituted acyl, heterocyclic radical, substituted heterocyclic radical, C1- C 12 Aminoalkyl, substituted C1-C 12aminoalkyl, or a protecting group.

[0400] Nucleosides containing a bicyclic sugar moiety are called bicyclic nucleosides or BNAs. Cyclic nucleosides include: (A) α-L-methyleneoxy (4'-CH2 -O-2')BNA, (B) β-D-methyleneoxy(4'-CH2-O-2')BNA (also called locked nucleic acid or LNA), (C) ethyleneoxy(4'-(CH2) 2-O-2')BNA, (D) aminooxy (4'-CH2-ON(R)-2')BN A, (E) oxyamino (4'-CH2-N(R)-O-2') BNA, (F) methyl ( Methyleneoxy)(4'-CH(CH3)-O-2')BNA (Restricted Ethyl or cEt (G) methylene-thio(4'-CH2-S-2')BNA; (H) methylene Benzene-amino(4'-CH2-N(R)-2')BNA, (I) Methyl carbocyclic (4'- CH2-CH(CH3)-2') BNA, and (J) propylene carbocyclic (4'-(C H2)3-2')BNA, including but not limited to: [ka] wherein Bx is a nucleobase moiety and R is independently H, a protecting group, or a C1-C1 2 alkyl.

[0401] Additional bicyclic sugar moieties are known in the art and are described, for example, in Singh et al. .,Chem.Commun.,1998,4,455-456,Koshkin et. al., Tetrahedron, 1998, 54, 3607-3630, Wahle stedt et al.,Proc.Natl.Acad.Sci.USA,2 000,97,5633-5638, Kumar et al.,Bioorg.Med .Chem.Lett.,1998,8,2219-2222,Singh et al. .,J.Org.Chem.,1998,63,10035-10039,Srivas tava et al., J. Am. Chem. Soc., 129(26)8362-8 379(Jul.4,2007), Elayadi et al.,Curr.Opin ion Invens.Drugs,2001,2,558-561, Braasch et al.,Chem.Biol.,2001,8,1-7,Orum et al. ,Curr.Opinion Mol.Ther.,2001,3,239-243, National Patent Nos. 7,053,207, 6,268,490, and 6,770,748 , No. 6,794,499, No. 7,034,133, No. 6,525,191, Nos. 6,670,461 and 7,399,845, International Publication No. WO2004 / 106356, WO1994 / 14226, WO2005 / 021570 No. WO2007 / 134181, U.S. Patent Publication No. US2004 / 0171 570, US2007 / 0287831, and US2008 / 00396 No. 18, U.S. Patent No. 12 / 129,154, U.S. Patent No. 60 / 989,574, U.S. Patent No. 61 / No. 026,995, No. 61 / 026,998, No. 61 / 056,564, No. 6 Nos. 1 / 086,231, 61 / 097,787, and 61 / 099,844 No., and PCT International Application Nos. PCT / US2008 / 064591 and PCT / U S2008 / 066154, and PCT / US2008 / 068922. .

[0402] In certain embodiments, bicyclic sugar moieties and compounds incorporating such bicyclic sugar moieties Nucleosides are further defined by isomeric configurations, e.g., 4'-2'methylene- Nucleosides containing an oxy bridge may be in the α-L or β-D configuration. L-methyleneoxy (4'-CH2-O-2') bicyclic nucleosides have antisense activity. It has been incorporated into antisense oligonucleotides that exhibit cytotoxicity (Frieden et al. al.,Nucleic Acids Research,2003,21,6365- 6372).

[0403] In certain embodiments, the substituted sugar moiety comprises one or more non-bridging sugar substituents and one or more The above bridging sugar substituents (e.g., 5'-substituted and 4'-2' bridging sugars) are included (2007). PCT International Application No. WO2007 / 134181 published on January 22nd (for example, LNA) For example, substituted with 5'-methyl or 5'-vinyl groups).

[0404] In certain embodiments, the modified sugar moiety is a sugar surrogate. In embodiments, the oxygen atoms of naturally occurring sugars are replaced with, for example, sulfur, carbon, or nitrogen atoms. In certain such embodiments, such modified sugar moieties are substituted with These bridging and / or non-bridging substituents may also be present. For example, certain sugar surrogates may contain 4'-sulfur groups. The yellow atom and the 2'-position (see, for example, U.S. Patent Application No. US 2005 / 0129999, published June 16, 2005) 2005 / 0130923) and / or substitutions at the 5' position. As further examples, carbocyclic bicyclic nucleosides with a 4'-2' bridge have been described (e.g., For example, Freier et al., Nucleic Acids Research, 1997,25(22),4429-4443, and Albaek et al.,J .Org.Chem.,2006,71,7731-7740).

[0405] In certain embodiments, the sugar surrogate contains a ring with more than 5 atoms. For example, In certain embodiments, the sugar surrogate comprises a morpholino. and their use in oligomeric compounds are described in numerous patents and published articles (e.g., Braasch et al.,Biochemistry,2002,41,4503 -4510, and U.S. Patent Nos. 5,698,685, 5,166,315, and (See US Pat. Nos. 5,185,444 and 5,034,506) As used herein, the term "morpholino" has the following structure: It means sugar surrogate. [ka]

[0406] In certain embodiments, the morpholino is, for example, derived from the morpholino structure described above. Such sugar surrogates can be modified by adding or changing various substituents. , referred to herein as "modified morpholinos."

[0407] As another example, in certain embodiments, the sugar surrogate may be a 6-membered tetrahydropyran. Such tetrahydropyrans may be further modified or substituted. Nucleosides containing tetrahydropyran-modified nucleosides include hexitol nucleic acids (HNA), aniitol nucleic acids (ANs), and tetrahydropyran-modified nucleosides. Leumann nucleic acid (ANA), mannitol nucleic acid (MNA) (Leumann, CJ. Bioorg. & Med. Chem. (2002) 10:841-854), Fluoro H NA (F-HNA), and compounds having the following formula VI: Unable to [ka] wherein independently, said at least one tetrahydropyran nucleoside analog of Formula VI For each of the body, Bx is a nucleobase moiety; T3 and T4 each independently convert a tetrahydropyran nucleoside analog into an antisense the internucleoside linking group that connects the nucleoside to the nucleoside compound, or One is a nucleoside analogue that links a tetrahydropyran nucleoside analog to an antisense compound. The other of T3 and T4 is H, a hydroxyl protecting group, a bonding a conjugated group, or a 5'- or 3'-terminal group, q1, q2, q3, q4, q5, q6, and q7 are each independently H, C1 to C6 Alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl , C2-C6 alkynyl, or substituted C2-C6 alkynyl; Each of R1 and R2 is hydrogen, halogen, substituted or unsubstituted alkoxy, NJ1J2 , SJ1, N3, OC(=X)J1, OC(=X)NJ1J2, NJ3C(=X)NJ1 J2, and CN, wherein X is O, S, or NJ1; , each J1, J2, and J3 is independently H or C1-C6 alkyl.

[0408] In certain embodiments, modified THP nucleosides of formula VI are provided, wherein q 1, q2, q3, q4, q5, q6, and q7 are each H. Certain embodiments In this case, at least one of q1, q2, q3, q4, q5, q6, and q7 is , H. In certain embodiments, q1, q2, q3, q4, q5, q6, and at least one of q7 is methyl. In certain embodiments, THP nucleosides of formula VI are provided, wherein one of R1 and R2 is F. In certain embodiments, R1 is fluoro, R2 is H, and R1 is methoxy. and R2 is H, R1 is methoxyethoxy, and R2 is H.

[0409] can be used to modify nucleosides for incorporation into antisense compounds Many other bicyclo and tricyclo sugar surrogate ring systems are known in the art (e.g., Review: Leumann, JC, Bioorganic & Medicinal Ch. (See emistry, 2002, 10, 841-854).

[0410] 2'-F-5'-methyl substituted nucleosides (other disclosed 5',2'-bis substituted nucleosides) Regarding leioside, see PCT International Application No. WO2008, published on August 21, 2008. / 101157), and substitution of the ribosyl ring oxygen atom with S and 2' Further substitutions at positions (see U.S. Patent Application No. US2005-002005, published June 16, 2005) 0130923), or alternatively 5'-substituted (4'-CH 2-O-2' bicyclic nucleosides further substituted with a 5'-methyl or 5'-vinyl group at the 5' position Replaced PCT International Application No. WO2007 / 13 published November 22, 2007 Combinations of modifications are also provided, including, but not limited to, the following: In addition to the oligomerization and biochemical studies of carbocyclic and bicyclic nucleosides, The synthesis and preparation of has also been described (e.g., Srivastava et al., J See Am.Chem.Soc.2007,129(26),8362-8379 and).

[0411] In certain embodiments, the present disclosure provides oligonucleotides comprising modified nucleosides. These modified nucleotides may comprise a modified sugar, a modified nucleobase, and / or a modified The specific modifications may include linkages, which may provide the resulting oligonucleotide with desirable characteristics. In certain embodiments, the oligonucleotide is selected to have one or more In certain embodiments, the oligonucleotide comprises an RNA-like nucleoside. , containing one or more DNA-like nucleotides. 2. Certain nucleic acid base modifications

[0412] In certain embodiments, nucleosides of the present disclosure contain one or more unmodified nucleobases. In certain embodiments, the nucleosides of the present disclosure include one or more modified nucleobases. Includes.

[0413] In certain embodiments, the modified nucleobase is a universal salt as defined herein. groups, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. -substituted pyrimidines, 6-azapyrimidines, and N-2, N-6, and O-6 substituted pyrimidines Phosphorus includes 2-aminopropyladenine, 5-propynyluracil, as defined herein. 5-propynylcytosine; 5-hydroxymethylcytosine, xanthine, hypoxane thiazolinone, 2-aminoadenine, 6-methyl and other alkyl groups of adenine and guanine derivatives, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thio Uracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-Propynyl (-CoC-CH3) uracil and cytosine and pyrimidine bases Other alkynyl derivatives, 6-azouracil, cytosine and thymine, 5-uracil (sh 4-Thiouracil, 4-Thiouracil, 8-Halo, 8-Amino, 8-Thioyl, 8-Thioa alkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo, especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines , 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenosine 8-Azaguanine and 8-Azaadenine, 7-Deazaguanine and 7-Deaza Adenine, 3-deazaguanine and 3-deazaadenine, universal bases, hydrophobic salts These include bases, promiscuous bases, size-expanded bases, and fluorinated bases. Groups include tricyclic pyrimidines, such as phenoxazine cytidine ([5,4-b][1,4 ]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[ 5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps, e.g. Substituted phenoxazine cytidine (e.g., 9-(2-aminoethoxy)-H-pyrimido[5 ,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine ( 2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H -pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-2-one) Modified nucleobases include those in which the purine or pyrimidine base is replaced with another heterocycle, e.g., a 7-death substituted with 7-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone Additionally, nucleobases may include bases such as those disclosed in U.S. Pat. No. 3,687,808. The base shown, The Concise Encyclopedia of Polym er Science and Engineering,Kroschwitz,J. I., Ed., John Wiley & Sons, 1990, pp. 858-859 The bases used, Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613 Sanghvi, YS, Chapter 15, Antisens e Research and Applications,Crooke,STa nd Lebleu, B., Eds., CRC Press, 1993, 273-288 These include bases disclosed by:

[0414] Representative examples of modified nucleobases that teach certain preparations of the above-described modified nucleobases as well as other modified nucleobases are provided. National patents include U.S. Patent Nos. 3,687,808, 4,845,205, and 5,1 No. 30,302, No. 5,134,066, No. 5,175,273, No. 5,36 No. 7,066, No. 5,432,272, No. 5,457,187, No. 5,459 , No. 255, No. 5,484,908, No. 5,502,177, No. 5,525, No. 711, No. 5,552,540, No. 5,587,469, No. 5,594,1 No. 21, No. 5,596,091, No. 5,614,617, No. 5,645,98 No. 5, No. 5,681,941, No. 5,750,692, No. 5,763,588 Nos. 5,830,653, and 6,005,096, including, but not limited to, those Certain of these patents, including but not limited to, are commonly owned with this application and each of them is incorporated herein by reference in its entirety. 3. Certain internucleoside linkages

[0415] In certain embodiments, the present disclosure provides oligonucleosides comprising linked nucleosides. In such embodiments, the nucleosides may be any internucleoside. The two main classes of internucleoside linking groups are phosphorus The typical phosphorus-containing internucleoside linkage is the phospho Phosphodiester (PO), phosphotriester, methylphosphonate, phosphoramidate, Representative non-phosphorus-containing thiol groups include, but are not limited to, thiol groups (PS) and phosphorothioates (PS). The internucleoside linking group is methylenemethylimino (-CH2-N(CH3)-O-CH 2-), thiodiester (-OC(O)-S-), thionocarbamate (-OC(O )(NH)-S-), siloxane (-O-Si(H)2-O-), and N,N'-dimethyl including, but not limited to, methylhydrazine (-CH2-N(CH3)-N(CH3)-). The modified linkages improve the nucleotide sequence of the oligonucleotide compared to the natural phosphodiester linkage. It can be used to alter, typically increase, enzyme resistance. In embodiments, internucleoside linkages having chiral atoms are available as racemic mixtures and can be prepared as separate enantiomers. A representative chiral bond is alkylphosphonate and phosphorothioates. Phosphorus-containing and non-phosphorus-containing Methods for preparing internucleoside linkages are well known to those skilled in the art.

[0416] The oligonucleotides described herein contain one or more asymmetric centers and therefore are isomeric. In terms of allochemical configuration, (R) or (S), α or β in the case of sugar anomers, etc., In the case of amino acids, etc., enantiomers, diastereomers, which may be defined as (D) or (L) and other stereoisomeric configurations. includes all such possible isomers, as well as their racemic and optically active forms. contains the pure form.

[0417] Neutral internucleoside linkages include phosphotriesters, methylphosphonates, and MMI(3 '-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N( Amide-4 ((3'-CH2-N(H)-C(=O)-5'), Formaldehyde acetal (3'-O-CH2-O-5'), and thioform acetal (3'-SC H2-O-5'). In addition, neutral internucleoside bonds In this case, siloxane (dialkylsiloxane), carboxylic acid ester, carboxamide, Nonionic bonds including sulfides, sulfonate esters, and amides are included (e.g., Carbohydrate Modifications in Antisense Research;YS Sanghvi and PDCook,Eds.,A CS Symposium Series 580;Chapters 3 and 4 ,40-65). In addition, the neutral internucleoside linkages can contain mixed N, O, S, and non-ionic bonds containing CH2 moieties. 4. A specific motif

[0418] a. In certain embodiments, the antisense oligonucleotide contains one or more modifications Modified nucleosides (e.g., nucleosides containing modified sugars and / or modified nucleobases) and / or one or more modified internucleoside linkages. Such a pattern of modifications is referred to herein as a motif. In the nucleotide sequence, the sugar, the nucleobase, and the binding motif are independent of each other. a. A specific sugar motif

[0419] In certain embodiments, the oligonucleotides have a defined pattern or sugar modifications. one or more modified sugars arranged along the oligonucleotide or region thereof in a decorative motif Such motifs include the amino acid sequences discussed herein, and / or naturally occurring sugar moieties. The sugar modifications may include any of the sugar modifications described above and / or other known sugar modifications.

[0420] In certain embodiments, the oligonucleotides comprise two outer regions or "winners." and a gapmer glycosyl motif containing a central or internal region or "gap." It comprises or consists of a region that contains three regions of gapmer sugar motifs (5'- wing, gap, and 3'-wing) form a continuous sequence of nucleosides At least a portion of the sugar moieties of each nucleoside in the wings are It is different from at least a part of the sugar moiety of the nucleoside. the 3'-most nucleoside of the 5'-wing and the 5'-most nucleoside of the 3'-wing. The sugar moiety of each wing nucleoside is attached to the adjacent gap nucleoside. It is different from the sugar portion of the side chain and therefore defines the boundary between the wings and the gap. In certain embodiments, the sugar moieties within the gap are identical to each other. In this embodiment, the gap may have a sugar moiety that is different from the sugar moiety of one or more other nucleosides in the gap. In certain embodiments, the nucleoside moiety is one or more nucleosides having two cyclization groups. The sugar motifs of the gapmers are identical to each other (symmetric sugar gapmers). In this case, the sugar motif in the 5'-wing is different from that in the 3'-wing (unclear). asymmetric sugar gapmer). i. A specific 5'-wing

[0421] In certain embodiments, the 5'-wing of a gapmer comprises 1 to 8 linked amino acids. In certain embodiments, the 5'-wing of the gapmer is In certain embodiments, the gap matrices are composed of 1 to 7 linked nucleosides. The 5'-wing of each of the nucleotides consists of 1 to 6 linked nucleosides. In the 5'-wing of a gapmer, the 5'-wing consists of 1 to 5 linked nucleosides In certain embodiments, the 5'-wing of a gapmer comprises 2 to 5 linked amino acids. In certain embodiments, the 5'-wing of the gapmer is In certain embodiments, the gap matrix is ​​composed of 3 to 5 linked nucleosides. The 5'-wing of each nucleotide is composed of 4 or 5 linked nucleosides. In this configuration, the 5'-wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises 1 to 3 linkages. In certain embodiments, the 5'-win of the gapmer is A group consists of one or two linked nucleosides. The 5'-wing of a champer consists of two to four linked nucleosides. In an embodiment, the 5'-wing of a gapmer comprises two or three linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 3 or consists of four linked nucleosides. In certain embodiments, a gapmer The 5'-wing consists of one nucleoside. The 5'-wing of the polymer consists of two linked nucleosides. In the present invention, the 5'-wing of a gapmer consists of three linked nucleosides. In certain embodiments, the 5'-wing of a gapmer is comprised of four linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of five In certain embodiments, the 5'-unit of a gapmer is The ring consists of six linked nucleosides.

[0422] In certain embodiments, the 5'-wing of a gapmer comprises at least one double bond. In certain embodiments, the 5'-wing of a gapmer comprises a cyclic nucleoside. In certain embodiments, the gap The 5'-wing of the polymer contains at least three bicyclic nucleosides. In embodiments, the 5'-wing of the gapmer comprises at least four bicyclic nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises at least In certain embodiments, the 5′ position of the gapmer contains one constrained ethyl nucleoside. The '-wing comprises at least one LNA nucleoside. wherein each nucleoside in the 5'-wing of the gapmer is a bicyclic nucleoside. In certain embodiments, each nucleoside in the 5'-wing of a gapmer is In certain embodiments, the 5'-win of the gapmer is an ethyl nucleoside. Each nucleoside of the amino acid sequence is an LNA nucleoside.

[0423] In certain embodiments, the 5'-wing of the gapmer comprises at least one non- In certain embodiments, the 5'-nucleoside of the gapmer comprises a bicyclic modified nucleoside. The ring comprises at least one 2'-substituted nucleoside. Therefore, the 5'-wing of a gapmer contains at least one 2'-MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one In certain embodiments, the 5'- of the gapmer comprises a 2'-OMe nucleoside. Each nucleoside in the wing is a non-bicyclic modified nucleoside. In this case, each nucleoside in the 5'-wing of the gapmer is a 2'-substituted nucleoside. In certain embodiments, each nucleoside in the 5'-wing of a gapmer is , 2'-MOE nucleosides. In certain embodiments, the 5' Each nucleoside in the -wing is a 2'-OMe nucleoside.

[0424] In certain embodiments, the 5'-wing of a gapmer comprises at least one 2 In certain embodiments, the gapmer comprises a 5'-deoxynucleoside. Each nucleoside of the wing is a 2'-deoxynucleoside. wherein the 5'-wing of the gapmer contains at least one ribonucleoside In certain embodiments, each nucleoside in the 5'-wing of a gapmer is In certain embodiments, the 5'-wing nucleoside is a 5'-wing nucleoside. One, more than one, or each of them is an RNA-like nucleoside.

[0425] In certain embodiments, the 5'-wing of a gapmer comprises at least one double bond. It includes cyclic nucleosides and at least one non-bicyclic modified nucleoside. In an embodiment, the 5'-wing of the gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the nucleoside comprises at least one 2'-substituted nucleoside. Therefore, the 5'-wing of a gapmer contains at least one bicyclic nucleoside and at least one In certain embodiments, the gap The 5'-wing of the mer comprises at least one bicyclic nucleoside and at least one In certain embodiments, the 5'- of the gapmer comprises a 2'-OMe nucleoside. The wings comprise at least one bicyclic nucleoside and at least one 2'-deoxyribonucleotide. Contains synucleosides.

[0426] In certain embodiments, the 5'-wing of the gapmer contains at least one restriction The nucleoside may be a substituted or unsubstituted nucleoside, and may be a substituted or unsubstituted nucleoside. In certain embodiments, the 5'-wing of the gapmer contains at least one constrained ethyl group. nucleoside and at least one 2'-substituted nucleoside. In some embodiments, the 5'-wing of the gapmer comprises at least one constrained ethyl nucleoside. and at least one 2'-MOE nucleoside. The 5'-wing of the gapmer contains at least one constrained ethyl nucleoside and In certain embodiments, the galactose-containing nucleoside comprises at least one 2'-OMe nucleoside. The 5'-wing of the primer contains at least one constrained ethyl nucleoside and at least also contains one 2'-deoxynucleoside. ii. Certain 3'-wings

[0427] In certain embodiments, the 3'-wing of a gapmer comprises 1 to 8 linked amino acids. In certain embodiments, the 3'-wing of the gapmer is In certain embodiments, the gap matrices are composed of 1 to 7 linked nucleosides. The 3'-wing of each of the nucleotides consists of 1 to 6 linked nucleosides. wherein the 3'-wing of the gapmer consists of 1 to 5 linked nucleosides In certain embodiments, the 3'-wing of a gapmer comprises 2 to 5 linked amino acids. In certain embodiments, the 3'-wing of the gapmer is In certain embodiments, the gap matrix is ​​composed of 3 to 5 linked nucleosides. The 3'-wing of each nucleotide is composed of 4 or 5 linked nucleosides. In some configurations, the 3'-wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises 1 to 3 linkages. In certain embodiments, the 3'-win of the gapmer is A group consists of one or two linked nucleosides. The 3'-wing of a champer consists of 2 to 4 linked nucleosides. In embodiments, the 3'-wing of a gapmer comprises two or three linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 3 or consists of four linked nucleosides.

[0428] In certain embodiments, the 3'-wing of a gapmer is one nucleoside In certain embodiments, the 3'-wing of the gapmer consists of two linked In certain embodiments, the 3'-win of the gapmer is A gap matrix consists of three linked nucleosides. The 3'-wing of each nucleotide is comprised of four linked nucleosides. In some cases, the 3'-wing of a gapmer consists of five linked nucleosides. In certain embodiments, the 3'-wing of a gapmer is 6 linked nucleosides. It consists of:

[0429] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. In certain embodiments, the 3'-wing of a gapmer comprises a cyclic nucleoside. In certain embodiments, the nucleoside comprises at least one constrained ethyl nucleoside. The 3'-wing of the chamfer contains at least one LNA nucleoside. In this embodiment, each nucleoside in the 3'-wing of the gapmer is a bicyclic nucleoside. In certain embodiments, each nucleotide of the 3'-wing of a gapmer is a nucleotide. A gapmer is a constrained ethyl nucleoside. Each nucleoside in the 3'-wing of is an LNA nucleoside.

[0430] In certain embodiments, the 3'-wing of the gapmer comprises at least one non- In certain embodiments, the 3'-cyclic modified nucleoside of a gapmer comprises a bicyclic modified nucleoside. The ring comprises at least two non-bicyclic modified nucleosides. In this case, the 3'-wing of the gapmer contains at least three non-bicyclic modified nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises at least four In certain embodiments, the 3' of the gapmer comprises a non-bicyclic modified nucleoside. The -wing comprises at least one 2'-substituted nucleoside. In the present invention, the 3'-wing of the gapmer contains at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of the gapmer comprises at least one In certain embodiments, the gapmer comprises 3 2'-OMe nucleosides. Each nucleoside in the '-wing is a non-bicyclic modified nucleoside. In this embodiment, each nucleoside in the 3'-wing of the gapmer is a 2'-substituted nucleoside. In certain embodiments, each nucleoside in the 3'-wing of a gapmer In certain embodiments, the gapmer nucleoside is a 2'-MOE nucleoside. Each nucleoside in the 3'-wing is a 2'-OMe nucleoside.

[0431] In certain embodiments, the 3'-wing of a gapmer comprises at least one 2 In certain embodiments, the gapmer comprises a 3'-deoxynucleoside. Each nucleoside of the wing is a 2'-deoxynucleoside. wherein the 3'-wing of the gapmer contains at least one ribonucleoside In certain embodiments, each nucleoside in the 3'-wing of a gapmer is In certain embodiments, the 5'-wing nucleoside is a 5'-wing nucleoside. One, more than one, or each of them is an RNA-like nucleoside.

[0432] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. It includes cyclic nucleosides and at least one non-bicyclic modified nucleoside. In embodiments, the 3'-wing of the gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the nucleoside comprises at least one 2'-substituted nucleoside. Therefore, the 3'-wing of a gapmer contains at least one bicyclic nucleoside and at least one In certain embodiments, the gap The 3'-wing of the mer comprises at least one bicyclic nucleoside and at least one In certain embodiments, the 3'- of the gapmer comprises a 2'-OMe nucleoside. The wings comprise at least one bicyclic nucleoside and at least one 2'-deoxyribonucleotide. Contains synucleosides.

[0433] In certain embodiments, the 3'-wing of the gapmer contains at least one restriction The nucleoside may be a substituted or unsubstituted nucleoside, and may be a substituted or unsubstituted nucleoside. In certain embodiments, the 3'-wing of the gapmer contains at least one constrained ethyl group. nucleoside and at least one 2'-substituted nucleoside. In some embodiments, the 3'-wing of the gapmer comprises at least one constrained ethyl nucleoside. and at least one 2'-MOE nucleoside. The 3'-wing of the gapmer contains at least one constrained ethyl nucleoside and In certain embodiments, the galactose-containing nucleoside comprises at least one 2'-OMe nucleoside. The 3'-wing of the primer contains at least one constrained ethyl nucleoside and at least also contains one 2'-deoxynucleoside.

[0434] In certain embodiments, the 3'-wing of a gapmer comprises at least one L NA nucleosides and at least one non-bicyclic modified nucleoside. In an embodiment, the 3'-wing of the gapmer comprises at least one LNA nucleotide. In certain embodiments, the nucleoside comprises at least one 2'-substituted nucleoside. Therefore, the 3'-wing of the gapmer contains at least one LNA nucleoside and at least one In certain embodiments, the gap The 3'-wing of the mer comprises at least one LNA nucleoside and at least one In certain embodiments, the 3'- of the gapmer comprises a 2'-OMe nucleoside. The wings comprise at least one LNA nucleoside and at least one 2'-deoxyribonucleic acid nucleotide. Contains synucleosides.

[0435] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. a cyclic nucleoside, at least one non-bicyclic modified nucleoside, and at least one In certain embodiments, the gapmer comprises 3 2'-deoxynucleosides. The '-wing is a nucleoside selected from at least one constrained ethyl nucleoside, at least one non-bicyclic modified nucleosides, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of the gapmer comprises at least one LNA nucleotide. a nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'- Contains deoxynucleosides.

[0436] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. a cyclic nucleoside, at least one 2'-substituted nucleoside, and at least one In certain embodiments, the 3' of the gapmer comprises a 2'-deoxynucleoside. -wings comprise at least one constrained ethyl nucleoside, at least one 2'-substituted nucleosides, and at least one 2'-deoxynucleoside. In an embodiment, the 3'-wing of the gapmer comprises at least one LNA nucleotide. at least one 2'-substituted nucleoside, and at least one 2'-deoxy Contains synucleosides.

[0437] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. a cyclic nucleoside, at least one 2'-MOE nucleoside, and at least one In certain embodiments, the gapmer comprises 3 2'-deoxynucleosides. The '-wing is comprised of at least one constrained ethyl nucleoside, at least one 2'-M OE nucleosides and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of the gapmer comprises at least one LNA nucleotide. nucleoside, at least one 2'-MOE nucleoside, and at least one 2'- Contains deoxynucleosides.

[0438] In certain embodiments, the 3'-wing of a gapmer comprises at least one double bond. a cyclic nucleoside, at least one 2'-OMe nucleoside, and at least one In certain embodiments, the gapmer comprises 3 2'-deoxynucleosides. The '-wing is a nucleotide sequence consisting of at least one constrained ethyl nucleoside, at least one 2'-O Me nucleosides, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of the gapmer comprises at least one LNA nucleotide. nucleoside, at least one 2'-OMe nucleoside, and at least one 2'- Contains deoxynucleosides. iii. A specific central region (gap)

[0439] In certain embodiments, the gap of a gapmer is between 6 and 20 linked nucleotides. In certain embodiments, the gap of a gapmer is comprised of 6 to 15 amino acids. In certain embodiments, the gapmer consists of linked nucleosides. The gap consists of 6 to 12 linked nucleosides. The gap of a chamfer consists of 6 to 10 linked nucleosides. In structure, the gap of a gapmer consists of 6 to 9 linked nucleosides. In certain embodiments, the gap of a gapmer is between 6 and 8 linked nucleosides. In certain embodiments, the gap of the gapmer consists of 6 or 7 amino acids. In certain embodiments, the gap of a gapmer is A group consists of 7 to 10 linked nucleosides. The gap of the primer consists of 7 to 9 linked nucleosides. In the gapmer, the gap consists of 7 or 8 linked nucleosides. In certain embodiments, the gap of a gapmer is 8-10 linked nucleotides. In certain embodiments, the gap of a gapmer consists of 8 or 9 amino acids. In certain embodiments, the gapmer consists of linked nucleosides. A gap consists of 6 linked nucleosides. The gap of the mer consists of 7 linked nucleosides. The gap of a gapmer consists of 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 10 linked nucleosides. In certain embodiments, the gap of a gapmer is 11 linked nucleotides. In certain embodiments, the gap of a gapmer consists of 12 amino acids. It consists of linked nucleosides.

[0440] In certain embodiments, each nucleoside of the gap of a gapmer is a 2'-deoxyribonucleotide. In certain embodiments, the gap is formed by one or more modifications In certain embodiments, each nucleoside in the gap of a gapmer Nucleosides are either 2'-deoxynucleosides or "DNA-like" modified nucleosides. In such embodiments, "DNA-like" refers to gapmers and RNA Nucleosides are attached to DNA so that the double strand containing the molecule can activate RNase H. A has the same characteristics as A. For example, under certain conditions, 2'-(ara )-F has been shown to support the activation of RNase H and therefore DNA-like In certain embodiments, one or more nucleosides of the gap of a gapmer It is not a 2'-deoxynucleoside and is not DNA-like. In embodiments, gapmers still support RNase H activation. (e.g., by virtue of the number or placement of non-DNA nucleosides).

[0441] In certain embodiments, the gap is interrupted by one or more modified nucleosides. It contains a stretch of unmodified 2'-deoxynucleosides, and therefore has three subregions ( Two stretches of one or more 2'-deoxynucleosides and a stretch of one or more interruptions In certain embodiments, any stretch of unmodified nucleosides 2'-deoxynucleosides are also shorter than 5, 6, or 7 nucleosides. In this embodiment, such short runs are achieved by using short gap regions. In certain embodiments, the short stretches interrupt longer gap regions. This is achieved by:

[0442] In certain embodiments, the gap comprises one or more modified nucleosides. In certain embodiments, the gap is selected from cEt, FHNA, LNA, and 2-thio-thio. In certain embodiments, the modified nucleoside is selected from the group consisting of methylamine, methylamino ... In certain embodiments, the gap comprises one modified nucleoside. The fragment contains a 5'-substituted sugar moiety selected from 5'-Me and 5'-(R)-Me. In certain embodiments, the gap comprises two modified nucleosides. In certain embodiments, the gap comprises three modified nucleosides. In certain embodiments, the gap comprises four modified nucleosides. , the gap comprises two or more modified nucleosides, each modified nucleoside being identical. In certain embodiments, the gap comprises two or more modified nucleosides, each modified Nucleosides are different.

[0443] In certain embodiments, the gap comprises one or more modified bonds. In embodiments, the gap comprises one or more methylphosphonate bonds. In embodiments, the gap comprises two or more modified bonds. , the gap contains one or more modified bonds and one or more modified nucleosides. In one embodiment, the gap comprises one modified bond and one modified nucleoside. In certain embodiments, the gap comprises two modified bonds and two or more modified nucleotides. Contains leioside. b. A specific internucleoside linkage motif

[0444] In certain embodiments, the oligonucleotides have a defined pattern or modification. Modifications placed along the oligonucleotide or region at the internucleoside linkage motif In certain embodiments, the oligonucleotide comprises a modified internucleoside linkage. In certain embodiments, the present invention comprises a region having a reciprocal internucleoside linkage motif. The disclosed oligonucleotides contain regions of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a phosphorothioate nucleotide. In certain embodiments, the oligonucleotide comprises a region homogeneously linked by interosidic bonds. The dinucleotides are uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, each internucleoside linkage of an oligonucleotide is a phosphodiester. esters and phosphorothioates. The internucleoside bonds of nucleotides are phosphodiester and phosphorothioate. and at least one internucleoside linkage is phosphorothioate.

[0445] In certain embodiments, the oligonucleotide comprises at least six phosphorothioates. In certain embodiments, the oligonucleotide comprises an etheno-nucleoside linkage. , and at least 7 phosphorothioate internucleoside linkages. In the present invention, the oligonucleotide has at least eight phosphorothioate internucleoside residues. In certain embodiments, the oligonucleotide comprises at least 9 nucleotides. In certain embodiments, the oligonucleotide comprises a phosphorothioate internucleoside linkage. The nucleic acid comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide contains at least 11 phosphorothioate residues. In certain embodiments, the oligonucleotide comprises at least one internucleoside linkage. In certain embodiments, the nucleic acid sequence contains at least 12 phosphorothioate internucleoside linkages. In this case, the oligonucleotide contains at least 13 phosphorothioate internucleoside bonds. In certain embodiments, the oligonucleotide comprises at least 14 nucleotides. Contains phosphorothioate internucleoside linkages.

[0446] In certain embodiments, the oligonucleotide comprises at least six consecutive phosphonates. At least one block of holothioate internucleoside linkages is included. In the form, the oligonucleotide comprises at least seven consecutive phosphorothioate nucleotides. In certain embodiments, the nucleotides include at least one block of internucleotide linkages. A oligonucleotide is a nucleotide consisting of at least eight consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least one of at least nine consecutive phosphorothioate internucleoside linkages In certain embodiments, the oligonucleotide comprises at least one Contains at least one block of 0 consecutive phosphorothioate internucleoside linkages In certain embodiments, the oligonucleotide comprises at least one 12-stranded oligonucleotide. It contains at least one block of consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is an oligonucleotide. In certain such embodiments, at least one One such block is located within the three nucleosides at the 3' end of the oligonucleotide. In certain embodiments, the oligonucleotide contains fewer than 15 phosphoro In certain embodiments, the oligonucleotide contains a thioate internucleoside linkage. The nucleotides contain fewer than 14 phosphorothioate internucleoside linkages. In the present invention, the oligonucleotide has less than 13 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 12 phosphorothioates. In certain embodiments, the oligonucleotide comprises an oate internucleoside linkage. contains fewer than 11 phosphorothioate internucleoside linkages. In the present invention, the oligonucleotide contains less than 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 9 phosphorothioates. In certain embodiments, the oligonucleotide comprises: In certain embodiments, the nucleoside linkages are less than 8. The oligonucleotide contains fewer than seven phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide contains less than 6 phosphorothioate nucleotides. In certain embodiments, the oligonucleotide comprises less than 5 interside linkages. containing phosphorothioate internucleoside linkages of C. a specific nucleobase modification motif

[0447] In certain embodiments, the oligonucleotides are arranged in a defined pattern or nucleic acid. Base modification motifs are used to target nucleobases arranged along the oligonucleotide or its region. In certain such embodiments, the nucleobase modification includes a chemical modification that In certain embodiments, the nucleobase modifications are arranged in an alternating motif. In certain embodiments, each nucleobase is modified. In embodiments, none of the nucleobases are chemically modified.

[0448] In certain embodiments, the oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is present at the 3' end of the oligonucleotide. In certain such embodiments, the block is present at the 5' end of the oligonucleotide. is located within three nucleotides of the 5' end of the oligonucleotide.

[0449] In certain embodiments, the nucleobase modifications are at specific positions in the oligonucleotide. For example, in certain embodiments, the oligonucleotide In certain embodiments, each purine or each pyrimidine of is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each cytosine is modified. In certain embodiments, each uracil is modified.

[0450] In certain embodiments, some of the cytosine moieties of the oligonucleotide or all are 5-methylcytosine moieties, or none are 5-methylcytosine moieties As used herein, 5-methylcytosine is not a "modified nucleobase." Thus, unless otherwise indicated, unmodified nucleobases include cytosine residues with a 5-methyl and In certain embodiments, all cytosine residues are cytosine residues that lack a 5-methyl. Alternatively, the methylation state of some cytosine nucleobases is identified.

[0451] In certain embodiments, the chemical modification to the nucleobase is the addition of certain conjugate groups to the nucleic acid. In certain embodiments, each purine or base of an oligonucleotide Each pyrimidine may optionally be modified to include a conjugated group. d. a certain total length

[0452] In certain embodiments, the present disclosure provides oligonucleotides of any of a range of lengths. In certain embodiments, the oligonucleotide is a nucleotide sequence of X to Y linked nucleosides, where X is the minimum number of nucleosides in the range. and Y represents the maximum number of nucleosides in that range. In this case, X and Y are 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17, respectively. , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 4 4, 45, 46, 47, 48, 49, and 50, with the proviso that X is Y. For example, in certain embodiments, the oligonucleotide Chid is 8~9, 8~10, 8~11, 8~12, 8~13, 8~14, 8~15, 8~ 16, 8~17, 8~18, 8~19, 8~20, 8~21, 8~22, 8~23, 8~ 24, 8~25, 8~26, 8~27, 8~28, 8~29, 8~30, 9~10, 9~ 11, 9~12, 9~13, 9~14, 9~15, 9~16, 9~17, 9~18, 9~ 19, 9~20, 9~21, 9~22, 9~23, 9~24, 9~25, 9~26, 9~ 27, 9-28, 9-29, 9-30, 10-11, 10-12, 10-13, 10-1 4, 10-15, 10-16, 10-17, 10-18, 10-19, 10-20, 10 ~21, 10~22, 10~23, 10~24, 10~25, 10~26, 10~27, 10-28, 10-29, 10-30, 11-12, 11-13, 11-14, 11-1 5, 11-16, 11-17, 11-18, 11-19, 11-20, 11-21, 11 ~22, 11~23, 11~24, 11~25, 11~26, 11~27, 11~28, 11~29、11~30、12~13、12~14、12~15、12~16、12~1 7、12~18、12~19、12~20、12~21、12~22、12~23、12 ~24、12~25、12~26、12~27、12~28、12~29、12~30、 13~14、13~15、13~16、13~17、13~18、13~19、13~2 0、13~21、13~22、13~23、13~24、13~25、13~26、13 ~27、13~28、13~29、13~30、14~15、14~16、14~17、 14~18、14~19、14~20、14~21、14~22、14~23、14~2 4、14~25、14~26、14~27、14~28、14~29、14~30、15 ~16、15~17、15~18、15~19、15~20、15~21、15~22、 15~23、15~24、15~25、15~26、15~27、15~28、15~2 9、15~30、16~17、16~18、16~19、16~20、16~21、16 ~22、16~23、16~24、16~25、16~26、16~27、16~28、 16~29、16~30、17~18、17~19、17~20、17~21、17~2 2、17~23、17~24、17~25、17~26、17~27、17~28、17 ~29、17~30、18~19、18~20、18~21、18~22、18~23、 18~24、18~25、18~26、18~27、18~28、18~29、18~3 0、19~20、19~21、19~22、19~23、19~24、19~25、19 ~26、19~29、19~28、19~29、19~30、20~21、20~22、 20~23、20~24、20~25、20~26、20~27、20~28、20~2 9, 20-30, 21-22, 21-23, 21-24, 21-25, 21-26, 21 ~27, 21~28, 21~29, 21~30, 22~23, 22~24, 22~25, 22~26, 22~27, 22~28, 22~29, 22~30, 23~24, 23~2 5, 23-26, 23-27, 23-28, 23-29, 23-30, 24-25, 24 ~26, 24~27, 24~28, 24~29, 24~30, 25~26, 25~27, 25-28, 25-29, 25-30, 26-27, 26-28, 26-29, 26-3 0, 27-28, 27-29, 27-30, 28-29, 28-30, or 29-30 Whether in a range or a specific number, the compound may consist of 10 linked nucleosides. In embodiments where the number of nucleosides in the compound oligonucleotide is limited, the compound The compound may nevertheless further comprise further other substituents. For example, 8 to 30 nucleophiles. The oligonucleotide containing 31 nucleosides is an oligonucleotide having 31 nucleosides. Unless otherwise indicated, such oligonucleotides include, for example, 1 It may further include one or more conjugated groups, terminal groups, or other substituents.

[0453] Additionally, oligonucleotides may be described by overall length ranges and regions having specific lengths. and the sum of the specific lengths of those regions is less than the upper limit of the total length range, A nucleotide may have additional nucleosides beyond the length of a particular region, provided that the nucleotide Provided that the total number of leiosides does not exceed the upper limit of the total length range. 5. Chemical motifs of certain antisense oligonucleotides

[0454] In certain embodiments, the chemical structural features of the antisense oligonucleotide are: their sugar motifs, internucleoside linkage motifs, nucleobase modification motifs, and total length In certain embodiments, each such parameter is characterized by: Therefore, oligonucleotides with gapmer sugar motifs Each internucleoside bond may be modified or unmodified, and the sugar-modified gapmer The wing regions of the sugar gapmer may or may not follow a modification pattern. The internucleoside linkages within the gap region may be identical or different from each other, and the internucleoside linkages within the gap region may be different from each other. The inter-sugar linkages may be the same or different. The oligonucleotide may contain one or more modified nucleic acids, independent of the gapmer pattern of sugar modifications. Those skilled in the art will appreciate that such motifs can be combined to produce various oligonucleotides. It is recognized that nucleotides can be made.

[0455] In certain embodiments, the selection of internucleoside linkages and nucleoside modifications is determined by: are not independent of each other. i. A specific sequence and target

[0456] In certain embodiments, the present invention provides an antisense oligonucleotide having a sequence complementary to a target nucleic acid. Such antisense compounds hybridize to target nucleic acids. The specific implementation can be modified to produce at least one antisense activity. In embodiments, antisense compounds specifically hybridize to one or more target nucleic acids. In certain embodiments, the specifically hybridizing antisense compound is The target nucleic acid is hybridized to the target nucleic acid and has antisense activity. The desired target is a target with sufficient complementarity to achieve specific hybridization to any non-target. under physiological conditions for in vivo or therapeutic use, and in vitro assays. In the case of an assay, non-specific hybridization to non-target nucleic acid sequences occurs under the conditions in which the assay is performed. and regions with insufficient complementarity to avoid or reduce cleavage. and a nucleobase sequence. In certain embodiments, both the target and non-target Although the oligonucleotide contains the target sequence, it is selective between the target and non-target. In such embodiments, selectivity is achieved by selectively targeting one nucleic acid molecule relative to another nucleic acid molecule. This may be due to the relative proximity of the regions.

[0457] In certain embodiments, the present disclosure provides a method for targeting nucleic acids over the entire length of an oligonucleotide. The present invention provides antisense compounds comprising oligonucleotides perfectly complementary to certain In certain embodiments, the oligonucleotide is 99% complementary to the target nucleic acid. In certain embodiments, the oligonucleotide is 95% complementary to the target nucleic acid. In some embodiments, such oligonucleotides are 90% complementary to the target nucleic acid. .

[0458] In certain embodiments, such oligonucleotides have a sequence that is 85% identical to the target nucleic acid. In certain embodiments, such oligonucleotides are complementary to the target nucleic acid. In certain embodiments, the antisense compound is 80% complementary to the target nucleic acid. and is at least In certain such embodiments, the region of perfect complementarity is 80%. The region is 6 to 14 nucleobases in length.

[0459] In certain embodiments, the oligonucleotide comprises a hybridizing region and a terminal end. In certain such embodiments, the hybridizing region comprises 12 to 3 0 linked nucleosides and is perfectly complementary to the target nucleic acid. In some embodiments, the hybridizing region contains one mismatch compared to the target nucleic acid. In certain embodiments, the hybridizing region has two mismatches compared to the target nucleic acid. In certain embodiments, a hybridizing region comprises a match compared to the target nucleic acid. In certain embodiments, the terminal region contains 1 to 4 terminal mismatches. In certain embodiments, the terminal nucleoside is the 3'-terminal In certain embodiments, one or more of the terminal nucleosides is present in the target It is not complementary to nucleic acids.

[0460] The antisense mechanism involves hybridization of an oligonucleotide with a target nucleic acid. This includes any mechanism by which hybridization results in a biological effect. In certain embodiments, such hybridization occurs during, for example, translation of the target nucleic acid. targeting by simultaneous inhibition or stimulation of cellular machinery involving transcription or splicing This results in either nucleic acid degradation or occupation.

[0461] One type of antisense mechanism that involves degradation of target RNA is RNase H-mediated antisense. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. "DNA-like" single-stranded antisense compounds promote RNA synthesis in mammalian cells. It is known in the art that RNase H activity is induced. Activation of the ATP leads to cleavage of the RNA target, thereby inhibiting the DNA-like oligonucleotide regulation of gene expression. Significantly improves the efficiency of leutide-mediated inhibition.

[0462] In certain embodiments, the conjugate group comprises a cleavable moiety. In certain embodiments, the conjugate group comprises one or more cleavable bonds. The conjugate group comprises a linker. In certain embodiments, the linker is a protein bond. In certain embodiments, the conjugate group comprises a cell-targeting moiety (also referred to as a cell-targeting group). In certain embodiments, the cell targeting moiety comprises a branched group. In certain embodiments, the cell targeting moiety comprises one or more tethers. In the present invention, the cell targeting moiety comprises a carbohydrate or carbohydrate cluster. ii. Certain cleavable parts

[0463] In certain embodiments, the cleavable moiety is a cleavable bond. In embodiments, the cleavable moiety comprises a cleavable bond. In certain such embodiments, the conjugate group comprises a cleavable moiety. The functional moiety is attached to the antisense oligonucleotide. In certain such configurations, the cleavable moiety binds directly to the cell targeting moiety. In embodiments, the cleavable moiety is attached to a conjugated linker. In certain embodiments, the cleavable moiety comprises a phosphate or a phosphodiester. In embodiments, the cleavable moiety is a cleavable nucleoside or nucleoside analog. In certain embodiments, the nucleoside or nucleoside analog is an optionally protected compound selected from a substituted purine, a pyrimidine, or a substituted pyrimidine; In certain embodiments, the cleavable moiety comprises a cyclic base such as uracil, thymine, or the like. , cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl- 5-methylcytosine, adenine, 6-N-benzoyladenine, guanine, and 2-N -isobutyrylguanine, In certain embodiments, the cleavable moiety is a phosphodiester bond. attached to the 3' position of the antisense oligonucleotide and A 2'-deoxynucleoside attached to a linker by a phosphorothioate bond. In certain embodiments, the cleavable moiety is attached by a phosphodiester bond. Attached to the 3' position of the antisense oligonucleotide and containing a phosphodiester or phospho It is a 2'-deoxyadenosine attached to the linker by a dithioate bond. In certain embodiments, the cleavable moiety is linked to the antisense via a phosphodiester bond. The linker is attached to the 3' position of the oligonucleotide via a phosphodiester bond. It is 2'-deoxyadenosine bound to

[0464] In certain embodiments, the cleavable moiety is In certain embodiments, the cleavable moiety is attached at the 3' position of the antisense oligonucleotide. In certain embodiments, the cleavable moiety is attached to the 5' position of the oligonucleotide. is attached to the 2' position of the antisense oligonucleotide. The cleavable moiety is attached to the antisense oligonucleotide by a phosphodiester bond. In certain embodiments, the cleavable moiety is linked to a phosphodiester bond. or phosphorothioate bond to the linker. In embodiments, the cleavable moiety is attached to the linker by a phosphodiester bond. In certain embodiments, the conjugate group does not include a cleavable moiety.

[0465] In certain embodiments, the cleavable moiety is internalized by the target cell. Only after the complex is administered to an animal is the cleavable portion cleaved intracellularly. The oligonucleotide is cleaved, thereby releasing the active antisense oligonucleotide. Although we do not want the cleavable portion to be cleaved by one or more nucleases within the cell, In certain embodiments, one or more nuclei may be cleaved. The enzyme cleaves the phosphodiester bond between the cleavable moiety and the linker. In an embodiment of the present invention, the cleavable moiety has a structure selected from the following: [ka] wherein each of Bx, Bx1, Bx2, and Bx3 is independently a heterocyclic base moiety. In certain embodiments, the cleavable moiety has a structure selected from the following: Has. [ka] iii. Certain linkers

[0466] In certain embodiments, the conjugate group comprises a linker. In certain such embodiments, the linker is covalently attached to the cleavable moiety. In embodiments, the linker is covalently attached to the antisense oligonucleotide. In certain embodiments, the linker is covalently attached to the cell targeting moiety. In certain embodiments, the linker further comprises a covalent bond to a solid support. In certain embodiments, the linker further comprises a covalent bond to the protein binding moiety. In some embodiments, the linker further comprises a covalent bond to the solid support and a protein-binding moiety. In certain embodiments, the linker further comprises a covalent bond to a tethered ligand. In certain embodiments, the linker comprises multiple positions for attachment of tethered In certain embodiments, the hydroxyl group contains multiple positions for attachment of bonds and is not attached to a branching group. In certain embodiments, the linker further comprises one or more cleavable bonds. In this case, the conjugate group does not include the linker.

[0467] In certain embodiments, the linker may be an alkyl, amide, disulfide, or polyethylene. Styrene glycol, ether, thioether (-S-), and hydroxylamino (- The compound includes at least one linear group containing a group selected from the group consisting of an ON(H)- group. In embodiments, the linear group comprises a group selected from alkyl, amide, and ether groups. In certain embodiments, the linear group is selected from alkyl and ether groups. In certain embodiments, the linear group includes at least one phosphorus linking group. In certain embodiments, the linear group comprises at least one phosphodiester group. In certain embodiments, the linear group includes at least one neutral linking group. In certain embodiments, the linear group is covalently attached to the cell targeting moiety and the cleavable moiety. In certain embodiments, the linear group comprises a cell targeting moiety and an antisense oligonucleotide. In certain embodiments, the linear group is covalently attached to a cell targeting moiety, In certain embodiments, the linear cleavable moiety is covalently attached to a solid support. The hydroxyl group is covalently linked to the cell targeting moiety, the cleavable moiety, the solid support, and the protein binding moiety. In certain embodiments, the linear group contains one or more cleavable bonds. .

[0468] In certain embodiments, the linker comprises a linear group that is covalently attached to the scaffold group. In certain embodiments, the scaffold is an alkyl, amide, disulfide, polyethylene glycol, or containing a group selected from alkyl, ether, thioether, and hydroxylamino groups. In certain embodiments, the scaffold comprises alkyl, amide, and branched aliphatic groups. and branched aliphatic groups containing groups selected from ether groups. In certain embodiments, the scaffold comprises at least one monocyclic or polycyclic ring system. In certain embodiments, the scaffold comprises at least two monocyclic or polycyclic ring systems. wherein the linear group is covalently attached to a scaffold group, and the scaffold group is linked to a cleavable moiety and a linker In certain embodiments, the linear group is covalently attached to the scaffold group. The bond is covalently attached to the cleavable moiety, the linker, and the solid support. In embodiments, the linear group is covalently attached to a scaffold group, and the scaffold group is linked to a cleavable moiety, a linker. and covalently attached to a protein-binding moiety. is covalently attached to a scaffold group, which in turn comprises a cleavable moiety, a linker, a protein binding moiety, and covalently attached to a solid support. In certain embodiments, the scaffold group comprises one or more The cleavable bond is as follows:

[0469] In certain embodiments, the linker comprises a protein binding moiety. In embodiments, the protein-binding moiety is, for example, cholesterol, cholic acid, adamantan, Testosterone, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl) ) Glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol , menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristyl Acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenoic acid, dimethoxal ricin, or phenoxazine), vitamins (e.g., folate, vitamin A, vitamin E , biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides , oligosaccharides, polysaccharides), endosomolytic components, steroids (e.g., uvaol, hesige nin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid), or cationic lipids In certain embodiments, protein-binding The binding portion is C16 to C22 long-chain saturated or unsaturated fatty acids, cholesterol, cholic acid, Vitamin E, adamantane, or 1-pentafluoropropyl.

[0470] In certain embodiments, the linker has a structure selected from the following: [ka] wherein each n is independently 1 to 20, and p is 1 to 6.

[0471] In certain embodiments, the linker has a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0472] In certain embodiments, the linker has a structure selected from the following: [ka] In the formula, n is 1 to 20.

[0473] In certain embodiments, the linker has a structure selected from the following: [ka] wherein each L is independently a phosphorus linking group or a neutral linking group; Each n is independently 1 to 20.

[0474] In certain embodiments, the linker has a structure selected from the following: [ka]

[0475] In certain embodiments, the linker has a structure selected from the following: [ka]

[0476] In certain embodiments, the linker has a structure selected from the following: [ka]

[0477] In certain embodiments, the linker has a structure selected from the following: [ka] In the formula, n is 1 to 20.

[0478] In certain embodiments, the linker has a structure selected from the following: [ka]

[0479] In certain embodiments, the linker has a structure selected from the following: [ka]

[0480] In certain embodiments, the linker has a structure selected from the following: [ka]

[0481] In certain embodiments, the conjugated linker has the following structure: [ka]

[0482] In certain embodiments, the conjugated linker has the following structure: [ka]

[0483] In certain embodiments, the linker has a structure selected from the following: [ka]

[0484] In certain embodiments, the linker has a structure selected from the following: [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7. iv. A specific cell-targeting moiety

[0485] In certain embodiments, the conjugate group comprises a cell targeting moiety. The cell-targeting moiety increases cellular uptake of the antisense compound. wherein the cell targeting moiety comprises a branching group, one or more tethers, and one or more ligands. In certain embodiments, the cell targeting moiety may comprise a branching group, one or more tethers, one or more and one or more cleavable bonds. 1. Certain branched groups

[0486] In certain embodiments, the conjugated group comprises a branching group and at least two tethering groups. In certain embodiments, the branching group comprises a targeting moiety that includes a conjugated linker. In certain embodiments, the branching group attaches a cleavable moiety. In embodiments, the branching group attaches the antisense oligonucleotide. In embodiments, the branching group is covalently attached to each of the linker and the tethered ligand. In certain embodiments, the branching group is an alkyl, amide, disulfide, polyethylene a group selected from glycol, ether, thioether and hydroxylamino group; In certain embodiments, the branched group includes alkyl, amide, In certain embodiments, the branching group comprises a group selected from: In certain embodiments, the branched The group includes monocyclic or polycyclic ring systems. In certain embodiments, the branched group may include one or more In certain embodiments, the conjugated group does not include a branched group. .

[0487] In certain embodiments, the branching group has a structure selected from the following: [ka] [ka] wherein each n is independently 1 to 20; j is 1 to 3, m is 2 to 6.

[0488] In certain embodiments, the branching group has a structure selected from the following: [ka] wherein each n is independently 1 to 20; m is 2 to 6.

[0489] In certain embodiments, the branching group has a structure selected from the following: [ka]

[0490] In certain embodiments, the branching group has a structure selected from the following: [ka] wherein each A1 is independently O, S, C=O, or NH; Each n is independently 1 to 20.

[0491] In certain embodiments, the branching group has a structure selected from the following: [ka] wherein each A1 is independently O, S, C=O, or NH; Each n is independently 1 to 20.

[0492] In certain embodiments, the branching group has a structure selected from the following: [ka] wherein A1 is O, S, C=O, or NH; Each n is independently 1 to 20.

[0493] In certain embodiments, the branching group has a structure selected from the following: [ka]

[0494] In certain embodiments, the branching group has a structure selected from the following: [ka]

[0495] In certain embodiments, the branching group has a structure selected from the following: [ka] 2. A specific tether

[0496] In certain embodiments, the conjugated group comprises one or more tethers covalently attached to the branching group. In certain embodiments, the conjugate group comprises one or more tethers covalently bonded to the linking group. In certain embodiments, each tether comprises, in any combination, alkyl, From ether, thioether, disulfide, amide, and polyethylene glycol groups In certain embodiments, each of the groups is a linear aliphatic group containing one or more groups selected from the group consisting of: The ether may be alkyl, substituted alkyl, ether, thioether, disulfide, or methyl ether in any combination. 1 selected from sulfide, amide, phosphodiester and polyethylene glycol groups In certain embodiments, each tether is a linear aliphatic group comprising one or more groups. and a combination of one or more groups selected from alkyl, ether, and amide groups. In certain embodiments, each tether is a linear aliphatic group comprising , alkyl, substituted alkyl, phosphodiester, ether, and amide groups. In certain embodiments, each tether is a linear aliphatic group comprising one or more groups represented by containing one or more groups selected from alkyl and phosphodiester, in any combination. In certain embodiments, each tether is a linear aliphatic group containing at least one linker. It contains a cyclic or neutral linking group.

[0497] In certain embodiments, the tether comprises one or more cleavable bonds. In this embodiment, the tether is attached to the branching group via either an amide group or an ether group. In certain embodiments, the tether is branched via a phosphodiester group. In certain embodiments, the tether is attached to a phosphorus linking group or a neutral linking group. In certain embodiments, the tether is attached to the branching group via an ether group. In certain embodiments, the tether is attached to the branching group via an amide group or an amide group. In certain embodiments, the tether is attached to the ligand via one of the tether groups. is attached to the ligand via an ether group. In certain embodiments, the tether is , and are attached to the ligand via either an amide group or an ether group. In the embodiment, the tether is attached to the ligand via an ether group.

[0498] In certain embodiments, each tether has about 8 to about 20 .mu.m bonds between the ligand and the branching group. In certain embodiments, each tether group comprises a length in atoms between the ligand and the branching group. In certain embodiments, each tether group comprises a chain length of about 10 to about 18 atoms. Contains a chain length of 3 atoms.

[0499] In certain embodiments, the tether has a structure selected from the following: [ka] wherein each n is independently 1 to 20; Each p is from 1 to about 6.

[0500] In certain embodiments, the tether has a structure selected from the following: [ka]

[0501] In certain embodiments, the tether has a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0502] In certain embodiments, the tether has a structure selected from the following: [ka] wherein L is either a phosphorus linking group or a neutral linking 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 0 to 20, and at least one m1 is 0 for each tether. Exceeds.

[0503] In certain embodiments, the tether has a structure selected from the following: [ka]

[0504] In certain embodiments, the tether has a structure selected from the following: [ka] wherein Z2 is H or CH3; Each m1 is independently 0 to 20, and at least one m1 is 0 for each tether. Exceeds.

[0505] In certain embodiments, the tether is [ka] and having a structure selected from wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0506] In certain embodiments, the tether comprises a phosphorus linking group. In certain embodiments, the tether does not contain any amide bonds. contains a phosphorus linking group and does not contain any amide linkages. 3. A specific ligand

[0507] In certain embodiments, the present disclosure provides ligands in which each ligand is covalently attached to a tether. In certain embodiments, each ligand is at least In certain embodiments, the nucleotides are selected to have affinity for at least one receptor. and a ligand having affinity for at least one receptor on the surface of mammalian liver cells. In certain embodiments, a hepatic asialoglycoprotein receptor (A A ligand is selected that has affinity for SGP-R. In certain embodiments, In certain embodiments, each ligand is a carbohydrate. lactose, N-acetylgalactosamine, mannose, glucose, glucosamine, and fucose. In certain embodiments, each ligand is independently selected from: In certain embodiments, the galactosamine is N-acetylgalactosamine (GalNAc). In certain embodiments, the targeting moiety comprises 2 to 6 ligands. In certain embodiments, the targeting moiety comprises three N-acetyl groups. Contains a galactosamine ligand.

[0508] In certain embodiments, the ligand is a carbohydrate, a carbohydrate derivative, a modified carbohydrate , a polyvalent carbohydrate cluster, a polysaccharide, a modified polysaccharide, or a polysaccharide derivative. In this embodiment, the ligand is an amino sugar or a thio sugar. For example, an amino sugar is a thio sugar, as described in the art. Any number of compounds known in the art, such as glucosamine, sialic acid, α-D-galactosamine, amine, N-acetylgalactosamine, 2-acetamido-2-deoxy-D-galactopyranoside Lanose (GalNAc), 2-amino-3-O-[(R)-1-carboxyethyl]- 2-Deoxy-β-D-glucopyranose (β-muramic acid), 2-deoxy-2-methyl Amino-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di -O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose Ranose, N-sulfo-D-glucosamine, and N-glycoloyl-α-neuraminidase For example, the thio sugar may be selected from 5-thio-β-D-glucopyranose, methylamino acid, 2,3,4-tri-O-acetyl-1-thio-6-O-trityl-α-D-glucopeptide Lanoside, 4-thio-β-D-galactopyranose, and ethyl 3,4,6,7-tetrate La-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside may be selected from the group consisting of:

[0509] In certain embodiments, "GalNac" or "Gal-NAc" is used in the literature. 2-(acetylamino)-2-deoxygalactosamine, commonly known as N-acetylgalactosamine In certain embodiments, "N-acetylgalactopyranose" refers to N-D-galactopyranose. "Tosamine" refers to 2-(acetylamino)-2-deoxy-D-galactopyranose In certain embodiments, "GalNac" or "Gal-NAc" refers to 2-( acetylamino)-2-deoxy-D-galactopyranose. In the present specification, "GalNac" or "Gal-NAc" refers to the β-form: 2-(acetylamino) β-D-galactopyranose and α-form: 2-(acetylamino )-2-deoxy-D-galactopyranose, In certain embodiments, the β form: -(acetylamino)-2-deoxy-β-D-galactopyranose and α-form: 2- (acetylamino)-2-deoxy-D-galactopyranose are both used synonymously. Therefore, in structures where one form is shown, these structures may also be used in other forms. Also intended to include, for example, the alpha form: 2-(acetylamino)-2-deoxy- When the structure of D-galactopyranose is shown, this structure is intended to include other forms as well. In certain embodiments, in certain preferred embodiments, the β form Form: 2-(acetylamino)-2-deoxy-D-galactopyranose is the preferred embodiment It is a posture. [ka] [ka] [ka]

[0510] In certain embodiments, one or more ligands have a structure selected from the following: Has, [ka] wherein each R1 is selected from OH and NHCOOH.

[0511] In certain embodiments, one or more ligands have a structure selected from the following: Has. [ka]

[0512] In certain embodiments, one or more ligands have a structure selected from the following: Has. [ka]

[0513] In certain embodiments, one or more ligands have a structure selected from the following: Has. [ka] i. Certain conjugates

[0514] In certain embodiments, the conjugate group comprises the structural features described above. In such embodiments, the conjugated group has the structure: [ka] wherein each n is independently 1 to 20.

[0515] In certain such embodiments, the conjugate group has the structure: [ka]

[0516] In certain such embodiments, the conjugate group has the structure: [ka] wherein each n is independently 1 to 20; Z is H or a bound solid support; Q is an antisense compound; X is O or S; Bx is a heterocyclic base moiety.

[0517] In certain such embodiments, the conjugate group has the structure: [ka]

[0518] In certain such embodiments, the conjugate group has the structure: [ka]

[0519] In certain such embodiments, the conjugate group has the structure: [ka]

[0520] In certain such embodiments, the conjugate group has the structure: [ka]

[0521] In certain such embodiments, the conjugate group has the structure: [ka]

[0522] In certain such embodiments, the conjugate group has the structure: [ka]

[0523] In certain such embodiments, the conjugate group has the structure: [ka]

[0524] In certain such embodiments, the conjugate group has the structure: [ka]

[0525] In certain embodiments, the conjugate does not comprise pyrrolidine.

[0526] In certain such embodiments, the conjugate group has the structure: [ka]

[0527] In certain such embodiments, the conjugate group has the structure: [ka]

[0528] In certain such embodiments, the conjugate group has the structure: [ka]

[0529] In certain such embodiments, the conjugate group has the structure: [ka]

[0530] In certain such embodiments, the conjugate group has the structure: [ka]

[0531] In certain such embodiments, the conjugate group has the structure: [ka]

[0532] In certain such embodiments, the conjugate group has the structure: [ka]

[0533] In certain such embodiments, the conjugate group has the structure: [ka]

[0534] In certain such embodiments, the conjugate group has the structure: [ka]

[0535] In certain such embodiments, the conjugate group has the structure: [ka]

[0536] In certain such embodiments, the conjugate group has the structure: [ka]

[0537] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 6 to 11 consecutive bonded atoms.

[0538] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 10 consecutive bond atoms.

[0539] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 4 to 11 consecutive bonded atoms, contains exactly one amide bond.

[0540] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] In the formula, Y and Z are C1 to C 12 Substituted or unsubstituted alkyl, alkenyl, or is an alkynyl group, or an ether, ketone, amide, ester, carbamate, amine, Piperidine, phosphate, phosphodiester, phosphorothioate, triazole, The groups are independently selected from groups containing loridine, disulfide, or thioether.

[0541] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] In the formula, Y and Z are C1 to C 12 a substituted or unsubstituted alkyl group, or exactly one ether or exactly two ethers, amides, amines, piperidines, phosphates , phosphodiester, or phosphorothioate containing groups.

[0542] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] In the formula, Y and Z are C1 to C 12 Independently selected from substituted or unsubstituted alkyl groups do.

[0543] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] In the formula, m and n are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. are independently selected from

[0544] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] wherein m is 4, 5, 6, 7, or 8, and n is 1, 2, 3, or 4.

[0545] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 4 to 13 consecutive bonded atoms; Contains no ter groups.

[0546] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 8 consecutive bond atoms, and X is an ether group. Does not include.

[0547] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 4 to 13 consecutive bonded atoms, contains exactly one amide bond and X does not contain an ether group.

[0548] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] wherein X is a substituted or unsubstituted tether of 4 to 13 consecutive bonded atoms, is an amide bond and substituted or unsubstituted C2-C 11 It consists of an alkyl group.

[0549] In certain embodiments, the cell targeting portion of the conjugate group has the structure: [ka] In the formula, Y is C1 to C 12 Substituted or unsubstituted alkyl, alkenyl, or alkynyl or ethers, ketones, amides, esters, carbamates, amines, piperidines , phosphate, phosphodiester, phosphorothioate, triazole, pyrrolidine, The group is selected from groups containing disulfides or thioethers.

[0550] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] In the formula, Y is C1 to C 12 substituted or unsubstituted alkyl groups, or ethers, amines, Piperidine, phosphate, phosphodiester, or phosphorothioate containing groups are selected.

[0551] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] In the formula, Y is C1 to C 12 It is selected from substituted or unsubstituted alkyl groups.

[0552] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0553] In certain such embodiments, the cell targeting portion of the conjugate group has the structure: , [ka] wherein n is 4, 5, 6, 7, or 8. b. Certain conjugated antisense compounds

[0554] In certain embodiments, the conjugate is at the 2', 3', or 5' position of the nucleoside. In certain embodiments, the antisense oligonucleotide is linked to a nucleoside. wherein the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, B is a cleavable moiety, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0555] In certain embodiments, the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, C is a conjugated linker; D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5. In certain such embodiments, the conjugated linker comprises at least one cleavable Contains bonds. In certain such embodiments, the branching group comprises at least one cleavable bond. Includes. In certain embodiments, each tether comprises at least one cleavable bond.

[0556] In certain embodiments, the conjugate is at the 2', 3', or 5' position of the nucleoside. It is attached to the nucleoside of the antisense oligonucleotide.

[0557] In certain embodiments, the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, B is a cleavable moiety, C is a conjugated linker; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0558] In certain embodiments, the conjugate is at the 2', 3', or 5' position of the nucleoside. In certain embodiments, the antisense oligonucleotide is linked to a nucleoside. wherein the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, C is a conjugated linker; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0559] In certain embodiments, the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, B is a cleavable moiety, D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0560] In certain embodiments, the conjugated antisense compound has the structure: [ka] During the ceremony, A is an antisense oligonucleotide, D is a branched group; Each E is a tether, each F is a ligand; q is an integer of 1 to 5.

[0561] In certain such embodiments, the conjugated linker comprises at least one cleavable Contains bonds.

[0562] In certain embodiments, each tether comprises at least one cleavable bond.

[0563] In certain embodiments, the conjugated antisense compound has a structure selected from the following: It has a structure. [ka]

[0564] In certain embodiments, the conjugated antisense compound has a structure selected from the following: It has a structure. [ka]

[0565] In certain embodiments, the conjugated antisense compound has a structure selected from the following: It has a structure. [ka]

[0566] In certain embodiments, the conjugated antisense compound has the structure: [ka]

[0567] The conjugates, conjugated antisense compounds, tethers, linkers, branching groups, ligands, and cleavage Representative U.S. patents that teach certain preparations of possible moieties, as well as other modifications, include U.S. Pat. Publications and international patent applications include U.S. Patent Nos. 5,994,517, 6,994,518, 6,994,519 ... ,300,319, 6,660,720, 6,906,182, 7, No. 262,177, No. 7,491,805, No. 8,106,022, No. 7,7 No. 23,509, No. 2006 / 0148740, No. 2011 / 0123520, International Publication Nos. WO2013 / 033230 and WO2012 / 037254 These include, but are not limited to, each of which is incorporated herein by reference in its entirety. be absorbed.

[0568] The conjugates, conjugated antisense compounds, tethers, linkers, branching groups, ligands, and cleavage Representative publications that teach certain preparations of possible moieties, as well as other modifications, include BIE SSEN et al., “The Cholesterol Derivative of a Triantennary Galactoside with High Affinity for the Hepatic Asialoglycoprot ein Receptor:a Potent Cholesterol Loweri ng Agent”J.Med.Chem.(1995)38:1846-1852、B IESSEN et al.,“Synthesis of Cluster Gala ctosides with High Affinity for the Hepa tic Asialoglycoprotein Receptor”J.Med.Ch em.(1995)38:1538-1546、LEE et al.,“New an d more efficient multivalent glyco-ligan ds for asialoglycoprotein receptor of ma mmalian hepatocytes”Bioorganic & Medicin al Chemistry(2011)19:2494-2500、RENSEN et al.,“Determination of the Upper Size Li mit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on H epatocytes in Vitro and in Vivo”J.Biol.C hem.(2001)276(40):37577-37584、RENSEN et al.,“Design and Synthesis of Novel N-Ace tylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hep atic Asialoglycoprotein Receptor”J.Med.C hem.(2004)47:5798-5808, SLIEDREGT et al., “esign and Synthesis of Novel Amphiphili c Dendritic Galactosides for Selective T argeting of Liposomes to the Hepatic Asi aloglycoprotein Receptor”J.Med.Chem.(199 9)42:609-618, and Valentijn et al., “Solid- phase synthesis of lysine-based clusters galactosides with high affinity for the Asialoglycoprotein Receptor”Tetrahedron, 1997,53(2),759-770, each of which is not limited to the above. each of which is incorporated herein by reference in its entirety.

[0569] In certain embodiments, the conjugated antisense compound is an RNase H-based antisense compound. oligonucleotides (e.g., gapmers) or splice control oligonucleotides (fully modified decorated oligonucleotides, and at least one, two, or three GalNAc groups. In certain embodiments, the conjugated antisense compound may comprise an optional conjugate group comprising: , the following references: Lee, Carbohydr Res, 1978, 67, 509-5 14, Connolly et al., J Biol Chem, 1982, 257, 939-945, Pavia et al., Int J Pep Protein R es,1983,22,539-548、Lee et al.,Biochem,19 84,23,4255-4261、Lee et al.,Glycoconjugat and J,1987,4,317-328、Toyokuni et al.,Tetra hedron Lett,1990,31,2673-2676、Biessen et al.,J Med Chem,1995,38,1538-1546、Valent ijn et al.,Tetrahedron,1997,53,759-770、K and et al.,Tetrahedron Lett,1997,38,3487- 3490、Lee et al.,Bioconjug Chem,1997,8,76 2-765、Kato et al.,Glycobiol,2001,11,821- 829、Rensen et al.,J Biol Chem,2001,276,3 7577–37584、Lee et al.,Methods Enzymol,20 03,362,38-43、Westerlind et al.,Glycoconj J,2004,21,227-241、Lee et al.,Bioorg Med Chem Lett,2006,16(19),5132-5135、Maierho fer et al.,Bioorg Med Chem,2007,15,7661- 7676、Khorev et al.,Bioorg Med Chem,2008, 16,5216-5231、Lee et al.,Bioorg Med Chem, 2011,19,2494-2500、Kornilova et al.,Analy t Biochem,2012,425,43-46、Pujol et al.,An gew Chemie Int Ed Engl,2012,51,7445-7448 、Biessen et al.,J Med Chem,1995,38,1846- 1852、Sliedregt et al.,J Med Chem,1999,42 ,609-618、Rensen et al.,J Med Chem,2004,4 7,5798-5808、Rensen et al.,Arterioscler T hromb Vasc Biol,2006,26,169-175、van Ross enberg et al.,Gene Ther,2004,11,457-464、 Sato et al.,J Am Chem Soc,2004,126,14013 -14022、Lee et al.,J Org Chem,2012,77,756 4-7571、Biessen et al.,FASEB J,2000,14,17 84-1792、Rajur et al.,Bioconjug Chem,1997 ,8,935-940、Duff et al.,Methods Enzymol,2 000,313,297-321、Maier et al.,Bioconjug C hem,2003,14,18-29、Jayaprakash et al.,Org Lett,2010,12,5410-5413、Manoharan,Antise nse Nucleic Acid Drug Dev,2002,12,103-12 8、Merwin et al.,Bioconjug Chem,1994,5,61 2-620、Tomiya et al.,Bioorg Med Chem,2013 ,21,5275-5281, International Publication No. WO1998 / 013381, International Publication No. WO20 11 / 038356, WO1997 / 046098, WO2008 / 098 788, WO2004 / 101619, WO2012 / 037254, WO2011 / 120053, WO2011 / 100131, WO201 1 / 163121, WO2012 / 177947, WO2013 / 0332 No. 30, same No. WO2013 / 075035, same No. WO2012 / 083185, same No. WO2012 / 083046, WO2009 / 082607, WO2009 / 134487, WO2010 / 144740, WO2010 / 14801 3, WO1997 / 020563, WO2010 / 088537, W O2002 / 043771, WO2010 / 129709, WO2012 / Nos. WO2009 / 126933 and WO2004 / 024757 No., WO2010 / 054406, WO2012 / 089352, WO 2012 / 089602, WO2013 / 166121, WO2013 / 1 65816, U.S. Patent Nos. 4,751,219, 8,552,163, and 6, No. 908,903, No. 7,262,177, No. 5,994,517, No. 6,3 No. 00,319, No. 8,106,022, No. 7,491,805, No. 7,49 No. 1,805, No. 7,582,744, No. 8,137,695, No. 6,383 , No. 812, No. 6,525,031, No. 6,660,720, No. 7,723, No. 509, No. 8,541,548, No. 8,344,125, No. 8,313,7 No. 72, No. 8,349,308, No. 8,450,467, No. 8,501,93 No. 0, No. 8,158,601, No. 7,262,177, No. 6,906,182 No. 6,620,916, No. 8,435,491, No. 8,404,862 , No. 7,851,615; Published U.S. Patent Application Publication No. US2011 / 009726 4, US2011 / 0097265, US2013 / 0004427, No. US2005 / 0164235, No. US2006 / 0148740, No. US2 008 / 0281044, US2010 / 0240730, US2003 / No. 0119724, No. US2006 / 0183886, No. US2008 / 0206 869, US2011 / 0269814, US2009 / 0286973 , US2011 / 0207799, US2012 / 0136042, U S2012 / 0165393, US2008 / 0281041, US200 9 / 0203135, US2012 / 0035115, US2012 / 00 95075, US2012 / 0101148, US2012 / 012876 0, US2012 / 0157509, US2012 / 0230938, US2012 / 0230938, No. US2013 / 0109817, No. US2013 / 0121954, No. US2 013 / 0178512, US2013 / 0236968, US2011 / 0123520, US2003 / 0077829, US2008 / 0108 801, and US2009 / 0203132. and any conjugated groups, each of which is incorporated by reference in its entirety. C. Certain Uses and Features

[0570] In certain embodiments, conjugated antisense compounds potently inhibit target RNA in vivo. In certain embodiments, the unconjugated antisense compound accumulates in the kidney. In certain embodiments, the conjugated antisense compound accumulates in the liver. In certain embodiments, the conjugated antisense compounds are well tolerated. The properties may be used to conjugate antisense compounds to treat metabolic, cardiovascular, and other diseases, disorders, or The present invention is directed to the inhibition of many target RNAs, including, but not limited to, target RNAs involved in diseases such as Thus, liver tissue is useful for treating diseases, disorders, or conditions associated with such diseases. Such diseases can be prevented by contacting the patient with a conjugated antisense compound that targets the RNA. Provided herein are methods for treating a disease, disorder, or condition. Antisense compounds can be used to treat a variety of metabolic, cardiovascular, and other diseases, disorders, or Methods for ameliorating any of the conditions are also provided.

[0571] In certain embodiments, the conjugated antisense compound exhibits a similar activity to the unconjugated antisense compound at a particular tissue concentration. without wishing to be bound by any theory or mechanism. In certain embodiments, the conjugate may be used to more efficiently transduce the antisense compound to cells. This may allow the ATP to enter the cell more efficiently or more productively. In this configuration, conjugated antisense compounds have a higher targeting activity compared to their unconjugated counterparts. A decrease in the concentration of both the conjugated antisense compound and its unconjugated counterpart may be observed. For example, in certain embodiments, the conjugated antisense compound is , may exhibit higher target reduction compared to their unconjugated counterparts, Both ribozyme and its unconjugated counterpart are present in the liver at identical concentrations.

[0572] Productive and non-productive uptake of oligonucleotides has been discussed previously (e.g. For example, Geary, RS, E. Wancewicz, et al. (2009). Effect of Dose and Plasma Concentration on Liver Uptake and Pharmacologic Activi ty of a 2'-Methoxyethyl Modified Chimeri c Antisense Oligonucleotide Targeting PT EN.”Biochem.Pharmacol.78(3):284-91, and Ko ller, E., TMVincent, et al. (2011). isms of single-stranded phosphorothioate modified antisense oligonucleotide accu mulation in hepatocytes.”Nucleic Acids R 39(11):4795-807). The conjugated groups described herein are This may improve productive uptake.

[0573] In certain embodiments, the conjugate groups described herein may be used to treat certain types of cells or tissues. Further improving potency by increasing the affinity of the conjugated antisense compound for tissue In certain embodiments, the conjugate groups described herein may be attached to one or more cell surface Further improving potency by increasing the recognition of conjugated antisense compounds by receptors In certain embodiments, the conjugate groups described herein may be conjugated to antisense molecules. Potency can be further improved by promoting endocytosis of the compound.

[0574] In certain embodiments, the cleavable moiety allows the conjugated antisense compound to enter a cell. allowing the conjugate to be cleaved from the antisense oligonucleotide after Thus, in certain embodiments, conjugated amines may be used to further improve the strength. The antisense compounds are administered at lower doses than those required for unconjugated antisense oligonucleotides. It can be administered at

[0575] Phosphorothioate linkages have previously been incorporated into antisense oligonucleotides. Such phosphorothioate bonds are resistant to nucleases and are therefore suitable for oligonucleotide synthesis. Furthermore, phosphorothioate bonds improve the stability of certain proteins. It also binds to the liver, leading to accumulation of the antisense oligonucleotide in the liver. Oligonucleotides with no phosphorothioate linkages accumulate less in the liver and less in the kidney. Accumulates more in the liver (e.g., Geary, R., "Pharmacokinetic Properties of 2'-O-(2-Methoxyethyl)-Mod ified Oligonucleotide Analogs in Rats,”J ournal of Pharmacology and Experimental Therapeutics-, Vol.296, No.3, 890-897, and Ph armacological properties of 2'-O-Methoxy ethyl Modified Oligonucleotides in Antis Sense a Drug Technology,Chapter 10,Crooke , ST, ed., 2008). In certain embodiments, The phosphorothioate internucleoside linkage and the more phosphodiester nucleosides Oligonucleotides with inter-chain bonds accumulate less in the liver and more in the kidney. When treating liver diseases, this is because (1) the drug is at the desired site of action (the liver). (2) the drug is excreted in the urine; and (3) the kidneys receive relatively high concentrations of the drug, which can cause kidney toxicity. This is undesirable for several reasons, including exposure to drugs that can cause Thus, in the case of liver disease, phosphorothioate linkages offer important benefits.

[0576] However, in certain embodiments, phosphorothioate internucleoside linkages Administration of homogeneously linked oligonucleotides induces one or more proinflammatory responses (e.g., J Lab Clin Med. 1996 Sep;128(3):32 9-38.“Amplification of antibody producti on by phosphorothioate oligodeoxynucleot See, e.g., Toxicolog. ic Properties in Antisense a Drug Techno logy,Chapter 12,pages 342-351,Crooke,ST ., ed., 2008). In certain embodiments, the internucleoside bond Administration of oligonucleotides, many of which contain phosphorothioate internucleoside linkages, Induce one or more proinflammatory responses.

[0577] In certain embodiments, the degree of pro-inflammatory activity may be determined by several variables (e.g., bone may depend on nucleotide modifications, off-target effects, nucleobase modifications, and / or nucleoside modifications (e.g., Toxicologic Properties in Antisense a Drug Technology,Chapter 12,pages 342- 351, Crooke, ST, ed., 2008). In some embodiments, the degree of pro-inflammatory activity can be reduced by adjusting one or more variables. For example, the extent of the pro-inflammatory effect of a given oligonucleotide can be determined by the presence of any number of phosphodiesterases. thioate internucleoside linkages were replaced with phosphodiester internucleoside linkages, This is mitigated by reducing the total number of phosphorothioate internucleoside linkages. It is possible.

[0578] In certain embodiments, it is desirable to reduce the number of phosphorothioate linkages. This will prevent loss of stability and alter distribution from the liver to the kidney. For example, in certain embodiments, phosphorothioates The number of bonds can be increased by replacing phosphorothioate bonds with phosphodiester bonds. In such embodiments, fewer phosphorothioate linkages and Antisense compounds with more phosphodiester bonds show a lower pro-inflammatory response Induce fewer phosphorothioate bonds and more phosphatidylcholine Antisense compounds with phosphodiester bonds induce a lower proinflammatory response, but An anion with fewer phosphorothioate bonds and more phosphodiester bonds The anti-phosphorothioate compounds do not accumulate in the liver and have more phosphorothioate bonds. The efficacy may be lower at the same or similar doses compared to the sense compounds. In certain embodiments, multiple phosphodiester bonds and multiple phosphorothioates are used. Antisense compounds with oate linkages but also with stability and good liver distribution - Patents.com It is desirable to design

[0579] In certain embodiments, some of the phosphorothioate linkages are proinflammatory. Even when replaced with a lower phosphodiester internucleoside bond, the conjugated antisense The conjugated compounds accumulate more in the liver and less in the kidney compared to their unconjugated counterparts. In certain embodiments, some of the phosphorothioate linkages are proinflammatory. Even when the less stable phosphodiester internucleoside linkage is replaced, the conjugated antisense The ance compound accumulates more in the liver compared to its unconjugated counterpart, In certain embodiments, the use of conjugates provides a more potent This allows for the design of better tolerated antisense drugs. In certain embodiments, the conjugated antisense compounds have a greater therapeutic index than their unconjugated counterparts. This is because there is a lower risk of proinflammatory responses and a lower risk of nephrotoxicity. This allows the conjugated antisense compound to be administered at a higher absolute dose. Higher doses are likely to be given less frequently because elimination (metabolism) is expected to be similar. Furthermore, as mentioned above, the compounds are more potent and therefore do not lose their therapeutic activity. lower concentrations before the next dose without the need for a steroid, allowing for a longer period between doses .

[0580] In certain embodiments, the inclusion of some phosphorothioate linkages is still desirable. For example, certain embodiments may require terminal binding because the terminal binding is vulnerable to exonucleases. In some embodiments, these bonds are phosphorothioate or other modified bonds. The internucleoside bond connecting the oxynucleosides is vulnerable to endonucleases. Therefore, in certain embodiments, these linkages are phosphorothioate. or other modified linkage. The internucleoside bond between the modified nucleoside and the deoxynucleoside in In certain embodiments, these bonds are vulnerable to cleavage. In this case, the modified nucleoside is phosphorothioate or other modified linkage. between two modified nucleosides of a certain kind, and between two deoxyribonucleotides of a certain kind, The internucleoside bond between the nucleoside and the modified nucleoside is sufficient for nuclease digestion. To tolerate this, the linkage may be phosphodiester.

[0581] In certain embodiments, the antisense oligonucleotide of the conjugated antisense compound In certain embodiments, the covalent bond contains fewer than 16 phosphorothioate linkages. The antisense oligonucleotide of the antisense compound contains less than 15 phosphorothioates. In certain embodiments, the antisense group of the conjugated antisense compound contains an ate bond. The oligonucleotide contains fewer than 14 phosphorothioate linkages. In this embodiment, the antisense oligonucleotide of the conjugated antisense compound is less than 13 In certain embodiments, the conjugate antisense The antisense oligonucleotide of the compound contains fewer than 12 phosphorothioate linkages. In certain embodiments, the antisense oligonucleotide of the conjugated antisense compound In certain embodiments, the covalent bond contains fewer than 11 phosphorothioate linkages. The antisense oligonucleotide of the antisense compound contains less than 10 phosphorothioates. In certain embodiments, the antisense group of the conjugated antisense compound contains an ate bond. The oligonucleotide contains fewer than nine phosphorothioate linkages. In some embodiments, the antisense oligonucleotide of the conjugate antisense compound comprises less than 8 Contains phosphorothioate linkages.

[0582] In certain embodiments, antisense oligonucleotides comprising one or more conjugate groups as described herein are The compounds exhibit increased activity compared to parent antisense compounds lacking such one or more conjugated groups. have the desired activity and / or potency and / or tolerability. In some embodiments, attachment of such conjugate groups to oligonucleotides is desirable. The conjugate group can be attached to the 5' and / or 3' end of the oligonucleotide. In certain cases, attachment at the 5' end is synthetically desirable. The nucleotides can be prepared by linking the 3'-terminal nucleoside to a solid support using techniques well known in the art. It is synthesized by sequential coupling of nucleosides from 3' to 5'. Thus, if a conjugate group is desired at the 3'-terminus, (1) attach the conjugate group to the 3'-terminal nucleoside; and attaching the conjugated nucleoside to a solid support for subsequent preparation of oligonucleotides. or (2) post-synthesis, the conjugate group is attached to the 3' end of the complete oligonucleotide. Neither of these approaches is very efficient. These are all expensive methods, and therefore expensive. Binding of the nucleotides to a solid support is demonstrated in the examples herein, but is an inefficient process. In certain embodiments, the conjugate group can be attached to the 5'-terminal nucleoside. This is synthetically easier than attachment at the 3' end. The unconjugated 3'-terminal nucleoside is attached to a solid support, and the oligonucleotide is The 5' nucleotide with the conjugated group can then be prepared in the final coupling step. In certain embodiments, it is only necessary to attach the 3' -Conjugated oligonucleotides are typically prepared by solid support of conjugated nucleosides. The examples herein demonstrate binding at the 5' end. In addition, certain conjugated groups have synthetic advantages. For example, certain conjugated groups containing phosphorus linking groups Certain conjugated groups may be any of the conjugated groups previously reported (e.g., WO / 2012 / 0372 It is synthetically simpler and more efficiently prepared than other conjugated groups, including (No. 54).

[0583] In certain embodiments, the conjugated antisense compound is administered to a subject. In such embodiments, the antisense compounds comprising one or more conjugate groups described herein are , increased activity and activity compared to parent antisense compounds lacking such one or more conjugation groups. and / or strength and / or tolerance. The functional group is believed to aid in distribution, delivery, and / or uptake into target cells or tissues. In certain embodiments, upon entry into the target cell or tissue, all or part of the conjugate group is Preferably, the oligonucleotide is cleaved to release the active oligonucleotide. In embodiments, not all conjugate groups need to be cleaved from the oligonucleotide. For example, in Example 20, conjugated oligonucleotides were administered to mice, each of which Several different species were detected containing different portions of the conjugated group remaining on the leutide (Table 23). a) This conjugated antisense compound showed good potency (Table 23). In certain embodiments, such metabolite profiles of multiple partial cleavages of the conjugate group However, in certain embodiments, the prodrug may be used in combination with other prodrugs. It is desirable for each conjugated oligonucleotide to yield a single active compound. In certain cases, when multiple forms of the active compound are found, the relative amounts of each form and In certain embodiments, regulatory investigations may be required. In some cases (e.g., USFDA or equivalent), it may have a single (or primarily a single) active species. In certain such embodiments, such a single active species is preferably conjugated. Preferably, the antisense oligonucleotide lacks any portion of the group. In this embodiment, the conjugate group at the 5' end is likely to result in complete metabolism of the conjugate group. Without being constrained by a mechanism, the 5' end (e.g., 5' nuclease) is involved in the metabolism of In certain embodiments, the endogenous enzyme responsible for the cleavage may be more active / efficient than its 3' counterpart. In certain embodiments, these particular conjugate groups are more amenable to metabolism to a single active species. In embodiments, certain conjugate groups are more amenable to metabolism into oligonucleotides. D. Antisense

[0584] In certain embodiments, the oligomeric compounds of the invention are antisense compounds. In such embodiments, the oligomeric compound is complementary to the target nucleic acid. In certain embodiments, the target nucleic acid is RNA. In certain embodiments, the target nucleic acid is a non-coding RNA. In certain embodiments, the target nucleic acid is an mRNA, a pre-mRNA, Non-coding RNAs, including microRNAs, small non-coding RNAs, and promoter-directed R In certain embodiments, the oligomeric compound comprises two or more targets selected from the group consisting of NA. For example, the oligomeric compounds of the present invention are at least partially complementary to a target nucleic acid. CloRNA mimics, which typically bind to multiple targets.

[0585] In certain embodiments, antisense compounds have at least one nucleotide sequence that matches the nucleobase sequence of a target nucleic acid. In certain embodiments, the nucleic acid sequence of the nucleic acid fragment is at least 70% complementary to the nucleic acid fragment of ... Antisense compounds are compounds that contain nucleobase sequences that are at least 80% complementary to the nucleobase sequence of a target nucleic acid. In certain embodiments, the antisense compound comprises a portion having a sequence of a target nucleic acid. The nucleic acid sequence of a particular nucleic acid sequence is at least 90% complementary to the nucleic acid sequence of the particular nucleic acid sequence. In one embodiment, the antisense compound has at least 95 base pairs that match the nucleobase sequence of the target nucleic acid. In certain embodiments, the antisense oligonucleotide comprises a portion having a complementary nucleobase sequence. The compound has a nucleobase sequence that is at least 98% complementary to the nucleobase sequence of the target nucleic acid. In certain embodiments, the antisense compound comprises a nucleobase moiety of a target nucleic acid. In certain embodiments, the nucleic acid sequence of ... Antisense compounds have a nucleobase sequence similar to that of a target nucleic acid over the entire length of the antisense compound. At least 70%, 80%, 90%, 95%, 98%, or 100% complementary to the sequence .

[0586] The antisense mechanism involves hybridization of an oligomeric compound with a target nucleic acid. This hybridization includes any mechanism by which this hybridization produces a biological effect. In this embodiment, such hybridization may be, for example, the hybridization of the target nucleic acid, involves the translation, transcription, or polyadenylation of a nucleic acid with which the target nucleic acid may otherwise interact. Concomitant inhibition or stimulation of cellular machinery leads to either degradation or occupation of target nucleic acids. bring about.

[0587] One type of antisense mechanism that involves degradation of target RNA is RNase H-mediated antisense. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. "DNA-like" single-stranded antisense compounds promote RNA synthesis in mammalian cells. It is known in the art that RNase H activity is induced. Activation of the ATP leads to cleavage of the RNA target, thereby inhibiting the DNA-like oligonucleotide regulation of gene expression. Significantly improves the efficiency of leutide-mediated inhibition.

[0588] The antisense mechanism also includes the RNAi mechanism that utilizes the RISC pathway. Such RNAi mechanisms include, but are not limited to, siRNA, ssRNA, and microRNA. Such mechanisms include, but are not limited to, microRNA mimics. This includes the creation of mimetics and / or anti-microRNAs.

[0589] The antisense mechanism involves hybridizing microRNA or non-coding RNA other than mRNA. This includes, but is not limited to, mechanisms that reduce or mimic the Non-coding RNAs contain promoter-directed RNAs that direct the transcription or translation of one or more nucleic acids. These include, but are not limited to, NAs as well as short and long RNAs.

[0590] In certain embodiments, an oligonucleotide comprising a conjugate described herein comprises: In certain embodiments, the conjugates described herein are RNAi compounds. The ligomeric oligonucleotide is an ssRNA compound. The oligonucleotide comprising the conjugate described herein is paired with a second oligomeric compound. In certain such embodiments, the second oligo The second oligomeric compound also includes conjugates. In certain embodiments, the second oligomeric compound is , any modified or unmodified nucleic acid. In certain embodiments, The oligonucleotide containing the conjugate is the antisense strand in the siRNA compound. In certain embodiments, the oligonucleotides comprising the conjugates described herein are The sense strand in an iRNA compound. The conjugated oligomeric compound is a double-stranded siRnA. In some embodiments, the conjugate is located on the sense strand, on the antisense strand, or on the sense strand and It may be present in both the antisense and antisense strands. C. Apolipoprotein(a) (apo(a))

[0591] In certain embodiments, the conjugate antisense compound can bind to any apo(a) nucleic acid. In certain targeted embodiments, the target nucleic acid is a clinically relevant apo(a) target. In such embodiments, modulation of the target nucleic acid has clinical benefit. Brings benefits.

[0592] The target process is such that the antisense interaction occurs and the desired effect results. Typically, this involves determining at least one target region, segment, or site within the target nucleic acid.

[0593] In certain embodiments, the target region is a structurally defined region of the nucleic acid. For example, in certain such embodiments, the target region includes the 3'UTR, 5'UTR, exons, introns, coding regions, translation initiation regions, translation termination regions, or other defined regions The nucleic acid sequence may include a defined nucleic acid region or target segment.

[0594] In certain embodiments, the target segment is the region to which the conjugate antisense compound is targeted. The target segment is at least about an 8 nucleobase portion of the target region. DNA or RNA containing at least 8 consecutive nucleic acid bases from the 5' end of one of A sequence (the remaining nucleobases may begin immediately upstream of the 5' end of the target segment, A continuous stretch of identical DNA or RNA that continues until the DNA or RNA contains about 8 to about 30 nucleic acid bases The target segment is a nucleotide sequence that is a nucleotide sequence of the target segment. It can also be represented by a DNA or RNA sequence containing at least eight consecutive nucleic acid bases from either end. (The remaining nucleobases begin immediately downstream of the 3' end of the target segment and are A continuous stretch of identical DNA or RNA that continues until it contains about 8 to about 30 nucleobases The target segment is an RNA fragment containing at least 8 fragments from the internal portion of the target segment sequence. It is also represented by a DNA or RNA sequence containing 20 consecutive nucleobases, and the conjugate antisense The nucleic acid compound may extend in either or both directions until it contains from about 8 to about 30 nucleobases. do.

[0595] In certain embodiments, antisense compounds targeted to apo(a) nucleic acids include: It may be modified as described herein. In certain embodiments, antisense The compounds may contain modified sugar moieties, unmodified sugar moieties, or modified and unmodified sugar moieties as described herein. In certain embodiments, the antisense compound may have a mixture of the The modified internucleoside linkages, unmodified internucleoside linkages, or modified and unmodified nucleoside linkages described In certain embodiments, the antisense compounds may have a mixture of internucleotide linkages. The product may be a modified nucleobase, an unmodified nucleobase, or a modified and unmodified nucleobase as described herein. In certain embodiments, the antisense compounds may have a mixture of groups. The motif may be as described in

[0596] In certain embodiments, antisense compounds targeted to apo(a) nucleic acids include: It may be conjugated as described herein.

[0597] One apo(a) protein is connected to a single apolipoprotein via disulfide bonds. Lipoprotein B (apoB) protein binds to lipoprotein(a) (Lp(a)) particles. This apo(a) protein specifically binds to proteins within the kringle IV type 2 repeat domain. It shares a high degree of homology with lasminogen. The kringle repeat domain of apo(a) is Its prothrombotic and antifibrinolytic properties may contribute to the progression of atherosclerosis. Apo(a) is transcriptionally regulated by IL-6 and is thought to enhance I In a study of patients with rheumatoid arthritis treated with an L-6 inhibitor (tocilizumab), After 3 months of treatment, plasma levels of Apo(a) decreased by 30%. Apo(a) preferentially binds oxidized phospholipids. It has been shown that Lp(a) particles bind to and enhance vascular inflammation. It also stimulates endothelial permeability, induces plasminogen activator inhibitor type 1 expression, and inhibits macrophages. These results suggest that phage can activate interleukin-8 secretion. Genetic association studies have linked Lp(a) to myocardial infarction, stroke, peripheral vascular disease, and abdominal aorta. Furthermore, premature coronary artery disease (PR) was an independent risk factor for aneurysms. In the OCARDIS study, Clarke et al. Furthermore, Solf et al. Rizzi et al. reported that increased serum Lp(a) is a predictor of Alzheimer's disease (AD). These results suggest that antisense targeting apo(a) may be involved in the increased risk of The compound is described in International Publication No. WO2005 / 00094, which is incorporated herein by reference in its entirety. 0201 and previously disclosed in US Pat. No. US2010-0331390. ISIS-APOA, an antisense oligonucleotide targeting Apo(a) Rx of It was evaluated in a Phase I clinical trial to examine its safety profile. Certain conjugated antisense compounds targeting Apo(a) nucleic acids

[0598] In certain embodiments, the conjugate antisense compound is ) Accession number NM_005577.2 (incorporated herein as SEQ ID NO: 1); GENBANK accession number NT_ cut from 3230000-3380000 007422.12 (incorporated herein as SEQ ID NO: 2); nucleotide 651 GENBANK accession number NT_02574, cut from 20000-65258000 1.15 (designated herein as SEQ ID NO:3); and GENBANK Accession No. N Ap having the sequence M_005577.1 (incorporated herein as SEQ ID NO: 4) o(a) targeting a nucleic acid. In certain such embodiments, the conjugate antisense The compound has a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 1 to 4, and at least Both are 95% or 100% complementary.

[0599] In a particular embodiment, the nucleic acid sequence of any one of SEQ ID NOs: 1 to 4 is targeted The conjugate antisense compound for use in the present invention is any one of SEQ ID NOs: 12 to 130, 133, and 134. The nucleic acid sequence of the present invention comprises at least 8 consecutive nucleic acid bases selected from the nucleic acid sequences of the present invention. In certain embodiments, a conjugate antisense targeting any of SEQ ID NOs: 1-4 is The nucleic acid compound is composed of any one of the nucleic acid base sequences of SEQ ID NOs: 12 to 130, 133, and 134. The nucleic acid sequence includes a nucleic acid sequence selected from the group consisting of: [Table 1] Apo(a) treatment index

[0600] In certain embodiments, the present invention provides conjugated antisera that target apo(a) nucleic acids. Methods for modulating the expression of apo(a) in a subject using agonist compounds are provided. In certain embodiments, the expression of apo(a) is reduced.

[0601] In certain embodiments, administering one or more pharmaceutical compositions described herein In certain embodiments, the present invention provides a method for treating a subject, comprising: Treating subjects with conjugated antisense compounds that target apo(a) nucleic acids in pharmaceutical compositions In certain embodiments, the individual is diagnosed with an apo(a)-associated disease. In certain embodiments, the individual has an Lp(a)-associated disease. In certain embodiments, the individual is diagnosed with an inflammatory, cardiovascular, and / or metabolic disease, disorder, or Harm or condition.

[0602] In certain embodiments, the subject is diagnosed with an inflammatory, cardiovascular, and / or metabolic disease. Having a disease, disorder, or condition.

[0603] In certain embodiments, the cardiovascular disease, disorder, or condition includes chylomyocarditis, hypertension, Hyperglycemia, aortic stenosis, aneurysm (e.g., abdominal aortic aneurysm), angina, irregular heartbeat Pulse, atherosclerosis, cerebrovascular disease, coronary artery disease, coronary heart disease, dyslipidemia , hypercholesterolemia, dyslipidemia, hypertension, hypertriglyceridemia, myocardial infarction, These include, but are not limited to, peripheral vascular disease (eg, peripheral arterial disease), stroke, and the like.

[0604] In certain embodiments, the apo(a) targeting compounds described herein are Modulating a physiological marker or phenotype of a cardiovascular disease, disorder, or condition, for example: Administration of this compound to animals resulted in a reduction in the number of steroid hormones in these animals compared to untreated animals. In certain embodiments, the LDL and cholesterol levels associated with steroids can be reduced. In this study, modulation of physiological markers or phenotypes was associated with the inhibition of apo(a) by compounds. It can be connected.

[0605] In certain embodiments, the physiological marker for a cardiovascular disease, disorder, or condition is For example, LDL or cholesterol levels can be measured, e.g., by measuring the normal Such markers can be measured and quantified by lipid tests. In some embodiments, the marker is about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% , or may decrease to a range defined by any two of these values.

[0606] To prevent, treat, or ameliorate symptoms associated with cardiovascular diseases, disorders, or conditions Preventing, treating, or preventing symptoms associated with a cardiovascular disease, disorder, or condition in a subject in need thereof; Also provided are methods for improving or ameliorating cardiovascular disease. Methods for reducing the incidence of symptoms associated with a disorder or condition are provided. In certain embodiments, reducing the severity of symptoms associated with a cardiovascular disease, disorder, or condition. In such embodiments, the method comprises administering to a subject a therapeutically effective amount of administering to an individual in need thereof an amount of a compound that targets apo(a) nucleic acid. .

[0607] A cardiovascular disease, disorder, or condition can be characterized by many physical symptoms. Any symptom known to one of skill in the art associated with a condition, disorder, or disease may be treated with the compounds and methods described herein. and methods that are used to prevent, treat, ameliorate, or otherwise modulate In certain embodiments, symptoms include angina, chest pain, shortness of breath, palpitations, weakness, , dizziness, nausea, sweating, tachycardia, bradycardia, arrhythmia, atrial fibrillation, swelling of the lower extremities, cyanosis, fatigue fainting, facial numbness, limb numbness, lameness or muscle cramps, abdominal swelling, or fever It can be, but is not limited to, any of the following:

[0608] In certain embodiments, the metabolic disease, disorder, or condition includes hyperglycemia, prediabetes, Disease, diabetes (type I and type II), obesity, insulin resistance, metabolic syndrome, and diabetes These include, but are not limited to, dyslipidemia.

[0609] In certain embodiments, the apo(a) targeting compounds described herein are Modulating a physiological marker or phenotype of a metabolic disease, disorder, or condition. administration of the compound to animals resulted in a decrease in the activity of the compound in these animals compared to untreated animals. It can reduce glucose and insulin resistance levels. In this study, modulation of physiological markers or phenotypes was observed following inhibition of apo(a) by compounds. It may be relevant.

[0610] In certain embodiments, the physiological marker of a metabolic disease, disorder, or condition is: For example, glucose levels or insulin resistance may be measured using methods known in the art. Such markers can be measured and quantified by known standard tests. In certain embodiments, the marker is about 5, 10, 15, 20, 25, 30, 35 , 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or may be reduced to 99%, or to a range defined by any two of these values. In examples, insulin sensitivity is measured and quantified by standard tests known in the art. For such markers, in certain embodiments, the marker is , about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%, or any two of these values The range may be increased to a range defined by one of the following:

[0611] Need to prevent, treat, or ameliorate symptoms associated with a metabolic disease, disorder, or condition and / or to prevent, treat, or alleviate symptoms associated with a metabolic disease, disorder, or condition in a subject in need thereof. Also provided are methods for ameliorating metabolic diseases, disorders, or methods for reducing the incidence of symptoms associated with a condition are provided. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, ... In such embodiments, the method comprises administering a therapeutically effective amount of a o(a) administering a nucleic acid-targeting compound to an individual in need thereof.

[0612] A metabolic disease, disorder, or condition can be characterized by many physical symptoms. Any symptom known to one of skill in the art associated with a disease, injury, or condition may be treated with the compounds and The method may be used to prevent, treat, ameliorate, or otherwise modulate In certain embodiments, the symptoms include excessive urine production (polyuria), excessive thirst, and Increased fluid intake (polydipsia), blurred vision, weight loss, and lethargy Possible, but not limited to, these.

[0613] In certain embodiments, the inflammatory disease, disorder, or condition includes aortic stenosis, aortic stenosis, coronary artery disease (CAD), Alzheimer's disease, and thromboembolic disease, Certain thromboembolic diseases, disorders, or conditions include, but are not limited to: Harms or conditions include, but are not limited to, stroke, thrombosis, myocardial infarction, and peripheral vascular disease. Not limited to:

[0614] In certain embodiments, the apo(a) targeting compounds described herein are modulates the physiological markers or phenotype of an inflammatory disease, disorder, or condition. The administration of the compound to animals reduces inflammation in these animals compared to untreated animals. It can reduce the levels of pro-inflammatory cytokines or other markers of inflammation. In some embodiments, the modulation of a physiological marker or phenotype is determined by the compound's apo(a ) may be associated with inhibition of

[0615] In certain embodiments, the physiological marker of an inflammatory disease, disorder, or condition is: For example, cytokine levels can be measured using standard tests known in the art. For such markers, certain embodiments may be used. In the 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, Defined by 85%, 90%, 95%, or 99%, or any two of these values. The amount of the ion exchange may be reduced to the range defined by the formula.

[0616] A drug intended to prevent, treat, or ameliorate symptoms associated with an inflammatory disease, disorder, or condition and / or to prevent, treat, or alleviate symptoms associated with an inflammatory disease, disorder, or condition in a subject in need thereof. Also provided are methods for ameliorating inflammatory diseases, disorders, or methods for reducing the incidence of symptoms associated with a condition are provided. In some embodiments, the present invention provides a method for reducing the severity of symptoms associated with an inflammatory disease, disorder, or condition. In such embodiments, the method comprises administering a therapeutically effective amount of a o(a) administering a nucleic acid-targeting compound to an individual in need thereof.

[0617] In certain embodiments, a therapeutically effective amount of one or more of the pharmaceutical compositions described herein is administered. and a method for treating an individual having an apo(a)-associated disease, disorder, or condition, comprising administering a composition comprising: In certain embodiments, the individual is provided with a method for treating elevated apo(a) In certain embodiments, one of the therapeutically effective amounts described herein has a level. and administering to a subject suffering from an Lp(a)-associated disease, disorder, or condition, the subject being administered one or more of the following pharmaceutical compositions. In certain embodiments, the individual is provided with a method of treating an individual suffering from elevated blood cholesterol. In certain embodiments, the individual has an inflammatory, cardiovascular, or Lp(a) level. and / or have a metabolic disease, disorder, or condition. Administration of a therapeutically effective amount of an antisense compound targeted to apo(a) nucleic acid results in In certain embodiments, the method involves monitoring Lp(a) or Lp(a) levels. Administration of a therapeutically effective amount of an antisense compound targeted to apo(a) nucleic acid can reduce inflammatory, Cardiovascular and / or metabolic diseases or other diseases associated with the expression of apo(a) This involves monitoring markers of the process to determine the individual's response to the antisense compound. Physicians can use an individual's response to the administration of an antisense compound that targets apo(a). This allows the amount and duration of therapeutic intervention with the compound to be determined.

[0618] In certain embodiments, administration of an antisense compound targeted to an apo(a) nucleic acid The contribution is at least approximately 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% apo(a) expression, or a range defined by any two of these valu...

Claims

1. A compound comprising a modified oligonucleotide and a conjugate group, wherein said modified oligonucleotide nucleotides consisting of 12 to 30 linked nucleosides and containing nucleobase 39 of SEQ ID NO: 1 A nucleic acid comprising a portion of at least eight consecutive nucleobases complementary to an isometric portion of 01-3920. and wherein the nucleobase sequence of the modified oligonucleotide is at least one of SEQ ID NO:

1. A compound that is at least 80% complementary.

2. The modified oligonucleotide comprises at least 10, at least 15, or at least 20 nucleotides complementary to an equal length portion of SEQ ID NO:

1. At least 12, at least 14, at least 16, at least 18, at least 19, or or a portion of at least 20 consecutive nucleic acid bases. The compound described.

3. A compound comprising a modified oligonucleotide and a conjugate group, wherein said modified oligonucleotide nucleotides consisting of 12 to 30 linked nucleosides and containing nucleobase 39 of SEQ ID NO: 1 At least 8, at least 10, at least 12 complementary to an equal length portion of 00 to 3923; a portion of at least 14, at least 15, or at least 16 consecutive nucleobases wherein the nucleobase sequence of the modified oligonucleotide comprises SEQ ID NO: A compound that is at least 80% complementary to .

4. the nucleobase sequence of the modified oligonucleotide is at least 85% identical to SEQ ID NO:1; 10. The method of claim 1, wherein the nucleic acid sequence is at least 90%, at least 95%, or 100% complementary to the nucleic acid sequence of claim 1. The compound according to any one of the preceding claims.

5. A compound comprising a modified oligonucleotide and a conjugate group, wherein said modified oligonucleotide The nucleic acid sequence of SEQ ID NO: 58 is a nucleic acid sequence of SEQ ID NO: 58, wherein the nucleic acid sequence is 12 to 30 linked nucleosides. At least 8, minimum 9, minimum 10, minimum 11, at least 12, minimum 13, at least At least 14, at least 15, at least 16, minimum 17, minimum 18, minimum 19, or 20 A compound having a nucleobase sequence comprising consecutive nucleobases.

6. A compound comprising a modified oligonucleotide and a conjugate group, wherein said modified oligonucleotide nucleotides consisting of 12 to 30 linked nucleosides and at least 8, at least 9, at least 10, at least 134 nucleic acid base sequences of any of 11, at least 12, minimum 13, at least 14, at least 15, at least 16, a nucleic acid sequence containing at least 17, at least 18, at least 19, or at least 20 consecutive nucleic acid bases; A compound having

7. The compound according to any one of claims 1 to 6, wherein the modified oligonucleotide is single-stranded. 。

8. The compound of any one of claims 1 to 6, wherein the modified oligonucleotide is double-stranded. 。

9. the modified oligonucleotide comprises at least one modified internucleoside linkage. The compound according to any one of items 1 to 4.

10. 10. The method of claim 9, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

9. The compound according to claim 9.

11. the modified oligonucleotide has at least one phosphodiester internucleoside linkage 11. The compound of claim 10, comprising:

12. the modified oligonucleotide has at least two phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

13. the modified oligonucleotide has at least three phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

14. the modified oligonucleotide has at least four phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

15. the modified oligonucleotide has at least five phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

16. the modified oligonucleotide has at least six phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

17. the modified oligonucleotide has at least seven phosphodiester internucleoside linkages 11. The compound of claim 10, comprising:

18. Each internucleoside linkage of the modified oligonucleotide is a phosphodiester nucleoside. 11 to 15, wherein the internucleoside linkage is selected from internucleoside linkages and phosphorothioate internucleoside linkages.

7. The compound according to any one of claims 1 to 7.

19. Each internucleoside bond of the modified oligonucleotide is a phosphorothioate nucleoside. Any of claims 1 to 8, which contains an internucleoside bond and is a phosphorothioate internucleoside bond. The compound described in any one of the preceding claims.

20. A compound consisting of ISIS 494372 and a conjugated group.

21. 21. The oligonucleotide of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar. The compound described in any one of the preceding claims.

22. 22. The compound of claim 21, wherein at least one modified sugar is a bicyclic sugar.

23. At least one modified sugar is selected from the group consisting of 2'-O-methoxyethyl, constrained ethyl, 3'-fluoro -HNA, or 4'-(CH ２ ) ｎ -O-2' bridge, where n is 1 or 2; 22. The compound of claim 21 .

24. 24. The method of claim 1, wherein at least one nucleoside comprises a modified nucleobase. The compound described.

25. 25. The compound of claim 24, wherein the modified nucleobase is 5-methylcytosine.

26. the modified oligonucleotide consists of 12 to 30 linked nucleosides; and a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; The gap segment is located between the 5' wing segment and the 3' wing segment. each nucleoside of each wing segment comprises a modified sugar; A compound according to any one of claims 1 to 25.

27. the modified oligonucleotide is 15 to 30, 18 to 24, 19 to 22, 13 to 25, consisting of 14-25, 15-25, 16, or 20 linked nucleosides.

27. The compound according to any one of 1 to 26.

28. A compound comprising a modified oligonucleotide and a conjugate group, wherein said modified oligonucleotide The nucleotide sequence of any one of SEQ ID NO: 58 is selected from the group consisting of 20 linked nucleosides. a nucleic acid base sequence comprising at least 8 consecutive nucleic acid bases complementary to the isometric portion, The modified oligonucleotide is a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; a 3' wing segment consisting of 5 linked nucleosides; The gap segment is located between the 5' wing segment and the 3' wing segment. Each nucleoside in each wing segment is positioned between the 2'-O-methionine and the 2'-O-methyl-2'-propionate. Each internucleoside bond is a phosphorothioate bond, and each cytosine The compound wherein the cytosine residue is 5-methylcytosine.

29. The conjugate group is attached to the modified oligonucleotide at the 5' end of the modified oligonucleotide. The compound according to any one of claims 1 to 28, which is linked to

30. The conjugate group is attached to the 3' end of the modified oligonucleotide. The compound according to any one of claims 1 to 28, which is linked to

31. The compound according to any one of claims 1 to 30, wherein the conjugate group comprises exactly one ligand. thing.

32. The compound according to any one of claims 1 to 30, wherein the conjugate group comprises exactly two ligands. thing.

33. The compound of any one of claims 1 to 30, wherein the conjugate group comprises three or more ligands. 。

34. The compound according to any one of claims 1 to 30, wherein the conjugated group comprises exactly three ligands. thing.

35. Each ligand is a polysaccharide, modified polysaccharide, sugar, modified polysaccharide, mannose, galactose, or mannose. D-mannopyranose, L-mannopyranose, D-alanine derivatives, galactose derivatives, Labinose, L-galactose, D-xylofuranose, L-xylofuranose, D-glucose glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranoside D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranolate α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose Ranose, β-D-galactofuranose, glucosamine, sialic acid, α-D-galactosamine amine, N-acetylgalactosamine, 2-amino-3-O-[(R)-1-carboxye 2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino- L-Glucopyranose, 4,6-dideoxy-4-formamido-2,3-di-O-methyl 2-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycoloyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, methyl 2 ,3,4-tri-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranosyl 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetate 2,5-diethyl-2-deoxy-1,5-dithio-α-D-gluco-heptopyranoside Hydro-D-allonitrile, ribose, D-ribose, D-4-thioribose, L- ribose, L-4-thioribose, and L-4-thioribose. The compounds listed above.

36. 36. The compound of claim 35, wherein each ligand is N-acetylgalactosamine.

37. The conjugated group is 【Chemistry 1】 The compound of any one of claims 1 to 30, comprising:

38. The conjugated group is 【Chemistry 2】 The compound of any one of claims 1 to 30, comprising:

39. The conjugated group is 【Transformation 3】 The compound of any one of claims 1 to 30, comprising:

40. The conjugated group is 【Chemistry 4】 The compound of any one of claims 1 to 30, comprising:

41. The conjugated group is 【Transformation 5】 The compound of any one of claims 1 to 30, comprising:

42. 3. The conjugated group comprises at least one phosphorus or neutral linking group.

6. The compound according to any one of claims 1 to 5.

43. The conjugated group is 【Transformation 6】 and wherein n is 1 to 12; The compound according to any one of claims 1 to 42, wherein m is 1 to 12.

44. The conjugated group is 【Transformation 7】 and a tether having a structure selected from wherein L is either a phosphorus linking group or a neutral linking group; Z １ But C(=O)O-R ２ and Z ２ But H, C １ ~C ６ Alkyl, or substituted C １ ~C ６ It is Alki, R ２ But H, C １ ~C ６ Alkyl, or substituted C １ ~C ６ It is Alki, each m １ are independently 0 to 20, and at least one m １ , but 0 for each tether The compound according to any one of claims 30 to 36, wherein the compound is greater than 1000 ppm.

45. The conjugated group is 【Transformation 8】 and a tether having a structure selected from During the ceremony, Z ２ is H or CH ３ and each m １ are independently 0 to 20, and at least one m １ but for each tether 45. The compound of claim 44, wherein the R is greater than 0.

46. The conjugated group is 【Chemistry 9】 and a tether having a structure selected from wherein n is 1 to 12; The compound according to any one of claims 30 to 36, wherein m is 1 to 12.

47. 47. The method of claim 1, wherein the conjugate group is covalently attached to the modified oligonucleotide. The compound described in any one of the preceding claims.

48. The compound has the formula: 【Chemistry 10】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; B is the cleavable moiety; C is the conjugated linker; D is the branched group; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

49. The compound has the formula: 【Chemistry 11】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; B is the cleavable moiety; C is the conjugated linker; D is the branched group; each E is a tether; each F is a ligand; each n is independently 0 or 1; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

50. The compound has the formula: 【Chemistry 12】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; B is the cleavable moiety; C is the conjugated linker; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

51. The compound has the formula: 【Chemistry 13】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; C is the conjugated linker; D is the branched group; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

52. The compound has the formula: 【Chemistry 14】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; C is the conjugated linker; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

53. The compound has the formula: 【Chemistry 15】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; B is the cleavable moiety; D is the branched group; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

54. The compound has the formula: 【Chemistry 16】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; B is the cleavable moiety; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

55. The compound has the formula: 【Chemistry 17】 and having a structure represented by During the ceremony, A is the modified oligonucleotide; D is the branched group; each E is a tether; each F is a ligand; 48. The compound of claims 1 to 47, wherein q is an integer from 1 to 5.

56. The conjugated linker is [Chemistry 18] and having a structure selected from wherein each L is independently a phosphorus linking group or a neutral linking group; 56. The compound of any one of claims 48 to 55, wherein each n is independently 1 to 20.

57. The conjugated linker is 【Chemistry 19】 56. The compound of any one of claims 48 to 55, having a structure selected from:

58. The conjugated linker has the following structure: 【Chemistry 20】 The compound according to any one of claims 48 to 55, having the formula:

59. The conjugated linker is 【Chemistry 21】 56. The compound of any one of claims 48 to 55, having a structure selected from:

60. The conjugated linker is 【Chemistry 22】 56. The compound of any one of claims 48 to 55, having a structure selected from:

61. The conjugated linker is 【Chemistry 23】 56. The compound of any one of claims 48 to 55, having a structure selected from:

62. 62. The compound of any one of claims 48 to 61, wherein the conjugated linker comprises pyrrolidine.

63. The compound of any one of claims 48 to 61, wherein the conjugated linker does not contain pyrrolidine. thing.

64. The compound of any one of claims 48 to 63, wherein the conjugated linker comprises PEG.

65. 65. The compound of any one of claims 48 to 64, wherein the conjugated linker comprises an amide.

66. 65. The method according to any one of claims 48 to 64, wherein the conjugated linker comprises at least two amides. The compounds listed above.

67. The compound of any one of claims 48 to 64, wherein the conjugated linker does not comprise an amide.

68. 68. The compound of any one of claims 48 to 67, wherein the conjugated linker comprises a polyamide.

69. 69. The compound of any one of claims 48 to 68, wherein the conjugated linker comprises an amine.

70. 70. Any of claims 48 to 69, wherein the conjugated linker comprises one or more disulfide bonds. The compound described in

71. 71. The method of claim 48, wherein the conjugated linker comprises a protein-binding moiety. compound.

72. 72. The compound of claim 71, wherein the protein-binding moiety comprises a lipid.

73. The protein-binding moiety may be selected from the group consisting of cholesterol, cholic acid, adamantaneacetic acid, 1-pyrene, Butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, Ranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1, 3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleo O3-(oleoyl) cholic acid, dimethoxytrityl, or phenyl Noxadin), vitamins (e.g., folate, vitamin A, vitamin E, biotin, pyridinium saccharides), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides) , endosomolytic components, steroids (e.g., uvaol, hesigenin, diosgenin) ), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friedelin, epi friedelanol-derivatized lithocholic acid), or cationic lipids, 72. The compound of claim 71.

74. The protein binding moiety may comprise a C16-C22 long chain saturated or unsaturated fatty acid, cholesterol, or the like. cholor, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl 72. The compound of claim 71, selected from:

75. The conjugated linker is 【Chemistry 24】 and having a structure selected from wherein each n is independently 1 to 20 and p is 1 to 6. The compound according to any one of the preceding claims.

76. The conjugated linker is 【Chemistry 25】 and having a structure selected from 76. The compound of any one of claims 48 to 75, wherein each n is independently 1 to 20. thing.

77. The conjugated linker is 【Chemistry 26】 76. The compound of any one of claims 48 to 75, having a structure selected from:

78. The conjugated linker is 【Chemistry 27】 and having a structure selected from 76. The compound according to any one of claims 48 to 75, wherein n is 1 to 20.

79. The conjugated linker is 【Chemistry 28】 76. The compound of any one of claims 48 to 75, having a structure selected from:

80. The conjugated linker is 【Chemistry 29】 and having a structure selected from wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

76. The compound according to any one of claims 1 to 75.

81. The conjugated linker has the following structure: 【Transformation 30】 The compound according to any one of claims 48 to 75, having the formula:

82. The branched group has the following structure: 【Chemistry 31】 and In the formula, each A １ is independently O, S, C═O, or NH; 82. The compound of any one of claims 48 to 81, wherein each n is independently 1 to 20.

83. The branched group has the following structure: 【Chemistry 32】 and In the formula, each A １ is independently O, S, C═O, or NH; 82. The compound of any one of claims 48 to 81, wherein each n is independently 1 to 20.

84. The branched group has the following structure: 【Transformation 33】 The compound according to any one of claims 48 to 81, having the formula:

85. The branched group has the following structure: 【Transformation 34】 The compound according to any one of claims 48 to 81, having the formula:

86. The branched group has the following structure: 【Chemistry 35】 The compound according to any one of claims 48 to 81, having the formula:

87. The branched group has the following structure: 【Transformation 36】 The compound according to any one of claims 48 to 81, having the formula:

88. 82. The compound of any one of claims 48 to 81, wherein the branching group comprises an ether.

89. The branched group has the following structure: 【Chemistry 37】 and each n is independently 1 to 20; The compound according to any one of claims 48 to 81, wherein m is 2 to 6.

90. The branched group has the following structure: 【Transformation 38】 The compound according to any one of claims 48 to 81, having the formula:

91. The branched group has the following structure: 【Chemistry 39】 The compound according to any one of claims 48 to 81, having the formula:

92. The branched group is 【Chemistry 40】 Including, wherein each j is an integer from 1 to 3; 82. The compound of any one of claims 48 to 81, wherein each n is an integer from 1 to 20.

93. The branched group is 【Chemistry 41】 The compound of any one of claims 48 to 81, comprising:

94. Each tether: 【Chemistry 42】 is selected from wherein L is selected from phosphorus linking groups and neutral linking groups; Z １ But C(=O)O-R ２ and Z ２ But H, C １ ~C ６ Alkyl, or substituted C １ ~C ６ It is Alki, R ２ But H, C １ ~C ６ Alkyl, or substituted C １ ~C ６ It is Alki, each m １ are independently 0 to 20, and at least one m １ but for each tether 94. The compound of any one of claims 48 to 93, wherein the compound is greater than 0.

95. Each tether: 【Chemistry 43】 is selected from During the ceremony, Z ２ is H or CH ３ and each m １ are independently 0 to 20, and at least one m １ is 0 for each tether The compound according to any one of claims 48 to 93, wherein the compound has a molecular weight of more than 1000.

96. Each tether: 【Chemistry 44】 is selected from wherein n is 1 to 12; The compound according to any one of claims 48 to 93, wherein m is 1 to 12.

97. 94. The method of claim 48, wherein at least one tether comprises ethylene glycol. The compound described.

98. 96. The method of claim 48, wherein at least one tether comprises an amide. The compounds listed above.

99. 96. Any of claims 48-93 or 95, wherein at least one tether comprises polyamide. The compound described in

100. 96. The method of claim 48, wherein at least one tether comprises an amine. The compounds listed above.

101. 96. The method according to claim 48, wherein at least two tethers are different from each other. The compounds listed above.

102. 96. The method of claim 48, wherein all of the tethers are identical to one another. The compounds listed above.

103. Each tether: 【Chemistry 45】 is selected from wherein each n is independently 1 to 20; 94. The compound of any one of claims 48 to 93, wherein each p is from 1 to about 6.

104. Each tether: 【Chemistry 46】 The compound according to any one of claims 48 to 93, selected from:

105. Each tether has the following structure: 【Chemistry 47】 and 94. The compound according to any one of claims 48 to 93, wherein each n is independently 1 to 20. Compound.

106. Each tether has the following structure: 【Chemistry 48】 The compound according to any one of claims 48 to 93, having the formula:

107. The tether is: 【Chemistry 49】 and having a structure selected from wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

93. The compound according to any one of claims 93 to 93.

108. The tether is: [Transformation 50] 94. The compound of any one of claims 48 to 93, having a structure selected from:

109. The compound of any one of claims 47 to 108, wherein the ligand is galactose.

110. Any of claims 47 to 108, wherein the ligand is mannose-6-phosphate. The compound described in

111. Each ligand is 【Chemistry 51】 is selected from In the formula, each R １ is selected from OH and NHCOOH The compound described in any one of the preceding claims.

112. Each ligand is 【Chemistry 52】 The compound according to any one of claims 47 to 108, selected from:

113. Each ligand has the following structure: 【Chemistry 53】 The compound according to any one of claims 47 to 108, having the formula:

114. Each ligand has the following structure: 【Chemistry 54】 The conjugated antisense compound of any one of claims 47 to 108, having the formula:

115. 82. The method of claim 1, wherein the conjugate group comprises a cell targeting moiety. Compound.

116. The conjugated group has the following structure: 【Transformation 55】 a cell targeting moiety having the formula:

117. The compound of claim 116, wherein each n is independently 1 to 20.

117. The cell targeting moiety has the structure 【Transformation 56】 117. The compound of any one of claims 116, having the formula:

118. The cell targeting moiety has the structure: 【Chemistry 57】 117. The compound of claim 116, wherein each n is independently 1 to 20.

119. The cell targeting moiety has the structure 【Chemistry 58】 117. The compound of claim 116, having the formula:

120. the cell targeting moiety being: 【Chemistry 59】 117. The compound of claim 116, comprising:

121. the cell targeting moiety being: 【Transformation 60】 117. The compound of claim 116, comprising:

122. the cell targeting moiety being: 【Chemistry 61】 117. The compound of claim 116, comprising:

123. the cell targeting moiety being: 【Transformation 62】 117. The compound of claim 116, comprising:

124. the cell targeting moiety being: 【Transformation 63】 117. The compound of claim 116, comprising:

125. the cell targeting moiety being: 【Chemistry 64】 117. The compound of claim 116, comprising:

126. the cell targeting moiety being: 【Transformation 65】 117. The compound of claim 116, comprising:

127. the cell targeting moiety being: 【Chemical Formula 66】 117. The compound of claim 116, comprising:

128. the cell targeting moiety being: 【Transformation 67】 117. The compound of claim 116, comprising:

129. the cell targeting moiety being: 【Transformation 68】 117. The compound of claim 116, comprising:

130. the cell targeting moiety being: 【Transformation 69】 117. The compound of claim 116, comprising:

131. the cell targeting moiety being: 【Transformation 70】 117. The compound of claim 116, comprising:

132. the cell targeting moiety being: 【Chemistry 71】 117. The compound of claim 116, comprising:

133. the cell targeting moiety being: 【Chemistry 72】 117. The compound of claim 116, comprising:

134. the cell targeting moiety being: 【Transformation 73】 117. The compound of claim 116, comprising:

135. the cell targeting moiety being: 【Chemistry 74】 117. The compound of claim 116, comprising:

136. the cell targeting moiety being: 【Chemistry 75】 117. The compound of claim 116, comprising:

137. the cell targeting moiety being: 【Transformation 76】 117. The compound of claim 116, comprising:

138. the cell targeting moiety being: 【Chemical 77】 117. The compound of claim 116, comprising:

139. the cell targeting moiety being: 【Transformation 78】 117. The compound of claim 116, comprising:

140. the cell targeting moiety being: 【Transformation 79】 117. The compound of claim 116, comprising:

141. the cell targeting moiety being: 【Chemistry 80】 Including, wherein each Y is O, S, substituted or unsubstituted C １ ~C １０ Alkyl, amino, substituted amino 117. The compound of claim 116, wherein the compound is selected from the group consisting of azide, alkenyl, and alkynyl. thing.

142. The conjugated group is 【Chemistry 81】 Including, wherein each Y is O, S, substituted or unsubstituted C １ ~C １０ Alkyl, amino, substituted amino Any of claims 1 to 30, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl azide, aryl alkenyl, and aryl alkynyl. The compound described in

143. The conjugated group is 【Chemistry 82】 Including, wherein each Y is O, S, substituted or unsubstituted C １ ~C １０ Alkyl, amino, substituted amino Any of claims 1 to 30, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl azide, aryl alkenyl, and aryl alkynyl. The compound described in

144. The conjugated group is 【Chemistry 83】 The compound of any one of claims 1 to 30, comprising:

145. The conjugated group is 【Chemical 84】 The compound of any one of claims 1 to 30, comprising:

146. The conjugated group is 【Chemical 85】 The compound of any one of claims 1 to 30, comprising:

147. The conjugated group is 【Chemical 86】 118. The compound of claim 117, comprising:

148. The conjugate group is a cleavable group selected from among a phosphodiester, an amide, or an ester.

148. The compound of any one of claims 1 to 147, comprising a moiety capable of reacting with a hydroxyl group.

149. Any of claims 1 to 147, wherein the conjugate group comprises a phosphodiester cleavable moiety. The compound described in

150. The conjugate group does not include a cleavable moiety, and the conjugate group is 148. The method according to claim 1, wherein the nucleotide sequence of the nucleotide sequence is a nucleotide sequence containing a phosphorothioate bond between the nucleotide sequence and the nucleotide sequence. compound.

151. The chemical compound of any one of claims 1 to 150, wherein the conjugate group comprises an amide cleavable moiety. Compound.

152. 151. The method of claim 1, wherein the conjugate group comprises an ester cleavable moiety. compound.

153. The compound has the following structure: 【Chemistry 87】 and wherein each n is independently 1 to 20; Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

154. The compound has the following structure: 【Chemical 88】 and wherein each n is independently 1 to 20; Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

155. The compound has the following structure: 【Chemistry 89】 and wherein each n is independently 1 to 20; Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; Z is H or a bound solid support; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

156. The compound has the following structure: [Chemical 90] and wherein each n is independently 1 to 20; Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; Z is H or a bound solid support; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

157. The compound has the following structure: 【Chemistry 91】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

158. The compound has the following structure: 【Chemistry 92】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

159. The compound has the following structure: 【Chemistry 93】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

160. The compound has the following structure: 【Chemical 94】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

161. The compound has the following structure: 【Chemical 95】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

162. The compound has the following structure: 【Chemistry 96】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

163. The compound has the following structure: 【Chemistry 97】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

164. The compound has the following structure: 【Chem.98】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

165. The compound has the following structure: 【Chem.99】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

166. The compound has the following structure: 【Chemistry 100】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

167. The compound has the following structure: 【Chemistry 101】 and In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

168. The conjugated group is 【Chemical Engineering 102】 Including, In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

169. The conjugated group is 【Chemistry 103】 Including, In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

170. The conjugated group is 【Chemical 104】 Including, In the formula, Q １３ is H or O(CH ２ ) ２ -OCH ３ and A is the modified oligonucleotide; The compound of any one of claims 1 to 30, wherein Bx is a heterocyclic base moiety.

171. B ｘ is adenine, guanine, thymine, uracil, or cytosine, or 5-methyl 171. The compound according to any one of claims 153 to 170, selected from the group consisting of lucitsine and lucitsine.

172. B ｘ The compound of any one of claims 153 to 170, wherein is adenine.

173. B ｘ The compound of any one of claims 153 to 170, wherein is thymine.

174. Q １３ is O(CH ２ ) ２ -OCH ３ According to any one of claims 153 to 170, compound.

175. Q １３ The compound of any one of claims 153 to 170, wherein is H.

176. The following formula 【Chemistry 105】 A compound having the formula: A compound wherein x is a conjugated group comprising GalNAc.

177. The following formula 【Chemistry 106】 A compound having the formula:

178. The following formula 【Chemistry 107】 A compound having the formula:

179. The following formula 【Chemistry 108】 A compound having the formula: In the formula, R １ But, -OCH ２ CH ２ OCH ３ (MOE), and R ２ Is it H or or R １ and R ２ together form a bridge, where R １ but, -O-, and R ２ But -CH ２ -, -CH(CH ３ ) - or -CH ２ CH ２ -Yes and the resulting bridge is -O-CH ２ -, -O-CH(CH ３ )-, and -O-C H ２ CH ２ R is selected from １ and R ２ are directly connected, On the same ring, independently, R ３ and R ４ For each pair of ３ is H and -OCH ２ CH ２ OCH ３ and R ４ is H or R ３ and R ４ together either form a bridge, where R ３ is —O—, and R ４ But -CH ２ -, -CH(CH ３ ) - or -CH ２ CH ２ - and the resulting bridge is - O-CH ２ -, -O-CH(CH ３ )-, and —O—CH ２ CH ２ -You can choose from Sea urchin, R ３ and R ４ are directly connected, R ５ is H and -CH ３ is selected from Z is S － and O － A compound selected from:

180. The compound according to any one of claims 1 to 179 or a salt thereof and a pharmaceutically acceptable and at least one of a carrier or a diluent.

181. A prodrug comprising the compound of any one of claims 1 to 180.

182. administering to an animal the compound or composition of any of claims 1 to 181. Including, a method.

183. 182. The method of claim 181, wherein the animal is a human.

184. whether administration of said compounds prevents cardiovascular, metabolic, and / or inflammatory disease development; 182. The method of claim 181, which treats, ameliorates, or slows the progression of a disease.

185. 183. The method of claim 182, comprising co-administering the compound or composition with a second agent. method.

186. 186. The method of claim 185, wherein the compound or composition and the second agent are administered simultaneously. method.

187. 177. The method of claim 176, wherein the administration is parenteral administration.

188. 177. The method of claim 176, wherein the administration is subcutaneous administration.

189. 1. A method for reducing apo(a) mRNA or protein expression in an animal, comprising: administering to the animal the compound or composition of any one of claims 1 to 181, a method comprising reducing apo(a) mRNA or protein expression in the animal. Law.

190. A method for reducing Lp(a) levels in an animal, comprising administering to said animal an Lp(a) inhibitor according to any one of claims 1 to 18. administering the compound or composition according to any one of claims 1 to 5, thereby increasing apo(a) expression in the animal. ) reducing mRNA or protein expression.

191. 200. A composition comprising the compound of any one of claims 1 to 190 for use in therapy.

192. Treating or preventing disorders associated with elevated apo(a) and / or elevated Lp(a) 192. A compound according to claim 191 for use in preventing or slowing the progression of a disease.

193. wherein the disease is an inflammatory, cardiovascular, or metabolic disease, disorder, or condition. Item 192. The compound according to item 191.

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