Asgpr-binding compounds for the delivery of oligonucleotides

Abstract

This invention provides Therapeutic Oligonucleotide delivering compounds, compositions, and methods for the treatment of disorders which respond to delivery of the Therapeutic Oligonucleotide. The Therapeutic Oligonucleotide delivering compounds have an asialoglycoprotein receptor (ASGPR) Binding Ligand bound to a Therapeutic Oligonucleotide through a Linker and a Cleavable Moiety for the delivery of the Therapeutic Oligonucleotide to the liver.

Description

[0001] ASGPR-BINDING COMPOUNDS FOR THE DELIVERY OF OLIGONUCLEOTIDES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63 / 539,206, filed September 19, 2023, and U.S. Provisional Application No.63 / 637,788, filed April 23, 2024. The entirety of each of these applications is hereby incorporated by reference for all purposes. INCORPORATION BY REFERENCE The contents of the XML file named “19121-034WO1_ST26.xml” which was created on September 19, 2024, and is 454 KB in size, are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION This invention provides Therapeutic Oligonucleotide delivering compounds, compositions, and methods for the treatment of disorders which respond to delivery of the Therapeutic Oligonucleotide. The Therapeutic Oligonucleotide delivering compounds have an asialoglycoprotein receptor (ASGPR) Binding Ligand bound to a Therapeutic Oligonucleotide through a Linker and a Cleavable Moiety for the delivery of the Therapeutic Oligonucleotide to the liver. BACKGROUND OF THE INVENTION The asialoglycoprotein receptor (ASGPR) is a Ca2+-dependent lectin that is primarily expressed in parenchymal hepatocyte cells. The main role of ASGPR is to help regulate serum glycoprotein levels by mediating endocytosis of desialylated glycoproteins. The receptor binds ligands with a terminal galactose or N-acetylgalactosamine. Asialoglycoproteins bind to ASGPRs and are then cleared by receptor-mediated endocytosis. The receptor and the protein are dissociated in the acidic endosomal compartment and the protein is eventually degraded by lysosomes. Heterobifunctional compounds have been developed that use an ASGPR ligand to either deliver a therapeutic nucleotide to the liver or to degrade an extracellular protein. Publications describing various ASGPR ligands include: U.S. Patent Nos. 9,340,553; 9,617,293; 10,039,778; 10,376,531, and 10,813,942 assigned to Pfizer Inc.; Sanhueza et al. (JACS, 2017, 139, 3528); Petrov et al. (Bioorganic and Medicinal Chemistry Letters, 2018, 28, 382); WO 2018 / 223073 and WO 2018 / 223081 assigned to Pfizer Inc. and Wave Life Sciences Ltd.; WO 2024 / 182749 and WO 2018 / 223056 assigned to Wave Sciences Ltd.; Schmidt et al. (Nucleic Acids Research, 2017, 45, 2294); Huang et al. (Bioconjugate Chem.2017, 28, 283); WO 2020 / 132100 assigned to The Board of Trustees of the Leland Stanford Junior University; WO 2021 / 142377, WO 2023 / 288033, WO 2024 / 155746, WO 2024 / 155747, and WO 2024 / 155750 assigned to Lycia Therapeutics; Banik et al. (Nature, 2020, 584, 291); WO 2023 / 178179, WO 2023 / 178202, WO 2022 / 192478, WO 2022 / 178425, WO 2021 / 072269, WO 2021 / 072246, WO 2019 / 199621, and WO 2019 / 199634, assigned to Yale University; WO 2022 / 084331 assigned to Sanofi; WO 2022 / 192478 assigned to Biohaven Therapeutics; an article from the Bertozzi group titled “LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation,” (Ahn, et al. Nat. Chem. Biol. (2021)) published in the journal Nature Chemical Biology; and WO 2021 / 155317, WO 2022 / 035997, WO 2022 / 235699, WO 2023 / 009554, WO 2023 / 028338, WO 2024 / 098039, and WO 2024 / 182772 assigned to Avilar Therapeutics Inc. While some progress has been made in the area of nucleotide delivery, there remains a need for additional therapeutic compounds and methods for their use and manufacture for the delivery of therapeutic nucleotides to the liver. SUMMARY OF THE INVENTION Novel Therapeutic Oligonucleotide delivering compounds and their pharmaceutically acceptable salts and compositions thereof and their methods of use and manufacture are provided. The Therapeutic Oligonucleotide delivering compounds of the present invention contain an ASGPR Binding Ligand covalently attached by a Linker and a Cleavable Moiety to a Therapeutic Oligonucleotide. The ASGPR Binding Ligands used in the Therapeutic Oligonucleotide delivering compounds described herein include derivatives of six-carbon pyranose moieties, specifically galactose and talose. These two sugars, shown below, differ only in the stereochemistry of the C2substituent. The “down” C2configuration corresponds to the stereochemistry of galactose, while the C2substituent in the “up” configuration corresponds to the stereochemistry of talose. In certain embodiments the Therapeutic Oligonucleotide delivering compound of the present invention is in the Galactose stereochemistry configuration. It has been discovered that certain derivatives of these sugars described herein can be used to deliver a Therapeutic Oligonucleotide to the liver. For example, in certain embodiments the Therapeutic Oligonucleotide delivering compound of the present invention results in a significantly higher proportion of the Therapeutic Oligonucleotide in the liver than in the plasma when compared to delivery of the Therapeutic Oligonucleotide separately from a compound of the present invention. In certain aspects the Therapeutic Oligonucleotide delivering compound is administered or formulated with an oral uptake increasing agent such as 8-(N-2-hydroxy-5-chlorobenzoyl)-amino- caprylic acid (5-CNAC) or N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC). In certain aspects a formulation comprising a Therapeutic Oligonucleotide delivering compound is formulated for delivery to the gastrointestinal tract and optionally comprises 5-CNAC or SNAC or a salt thereof. In certain embodiments the salt of 5-CNAC is a monosodium salt or a disodium salt. In certain aspects a Therapeutic Oligonucleotide delivering compound of Formula I, Formula II, or Formula III is provided:

[0002] ; or a pharmaceutically acceptable salt thereof; wherein ASGPR Binding Ligand is a compound selected from:

[0003] ; Q is -O- or -N(R10)-; in certain embodiments Q is -O-; in certain embodiments Q is -N(R10)-; in certain embodiments Q is -NH-; R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0- C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3; in certain embodiments R1is hydrogen; R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3; in certain embodiments R10is hydrogen; R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80; R80is independently selected at each instance from the group consisting of alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3; LinkerAis a bond or a moiety that covalently links LinkerB, LinkerC, or LinkerDto the ASGPR Binding Ligand; LinkerBis a bond or a moiety that covalently links LinkerAto the Therapeutic Oligonucleotide; LinkerCis a chemical group that links each LinkerAto the Therapeutic Oligonucleotide; LinkerDis a chemical group that links each LinkerAto the Therapeutic Oligonucleotide; and Cleavable Moiety is a chemical moiety that can be cleaved to release the oligionucleotide; in certain aspects Cleavable Moiety is a means to release an oligionucleotide; in certain aspects Cleavable Moiety is a bond, wherein the Therapeutic Oligonucleotide is attached to the -P-; in certain embodiments the cleavable moiety comprises R42is hydrogen, alkyl, alkyl-O-alkyl, or C(O)R43; R43is selected from the group consisting of hydrogen, alkyl, and haloalkyl; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, haloalkyl, and halogen; in certain embodiments Base is selected from wherein RB1and RB2are independently selected from H, C1-C4alkyl, F, Cl, and C1-C4haloalkyl; RB3is C1-C4alkyl or H; RB4and RB5are independently selected from H, C1-C4alkyl, C(O)C1-C4alkyl, C1-C4haloalkyl, and C(O)C1-C4haloalkyl; in certain embodiments Base is selected from in certain embodiments Cleavable Moiety is , , wherein the Therapeutic Oligonucleotide is attached to the -P-. In other embodiments Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. Therapeutic Oligonucleotide is an antisense oligonucleotide, siRNA, shRNA, DNA aptamer, RNA aptamer, miRNA, miRNA mimic, antimiRNA, DNA decoy, RNA decoy, or CpG oligonucleotide. In certain aspects Therapeutic Oligonucleotide is a means to treat a medical disorder. In another aspect the ASGPR Binding Ligand for use in a compound of Formula I, Formula II, or Formula III is a compound selected from: wherein Q2is selected from -O-, -N(R10)-, S, S(O), C(R4a)(R4b), and S(O)2; L is selected from is heteroaryl or phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R65; R4ais selected from hydrogen, alkyl, haloalkyl, and halogen; and R4bis selected from hydrogen, alkyl, haloalkyl, halogen, C0-C6alkyl-OR6, C0-C6alkyl-SR6, and C0-C6alkyl-NR6R7. In certain aspects the Therapeutic Oligonucleotide is a nucleotide described in Table 1. In certain embodiments the Therapeutic Oligonucleotide is a nucleotide that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleotide described in Table 1. In alternative embodiments, R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, C0-C6alkyl-N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3. In non-limiting embodiments, LinkerAand LinkerBare independently selected from: ; LinkerCis selected from: LinkerDis selected from: wherein: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O- (CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; R22is independently at each occurrence selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; X- is an anionic group, for example Br- or Cl-;and all other variables are as defined herein. In alternative embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[C(O)-CH2- NR6]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In certain embodiments LinkerAis bond and LinkerBis . In certain embodiments LinkerBis bond and LinkerAis . In certain embodiments LinkerAis bond and LinkerBis . In certain embodiments LinkerBis bond and LinkerAis . In certain embodiments LinkerAis bond and LinkerBis . In certain embodiments LinkerBis bond and LinkerAis . In certain embodiments LinkerAis bond and LinkerBis . In certain embodiments LinkerBis bond and LinkerAis . In certain embodiments LinkerCis . In certain embodiments LinkerDis In certain embodiments ASGPR Binding Ligand is a compound selected from:

[0004] In certain embodiments the ASGPR Binding Ligand is:

[0005] In certain embodiments the ASGPR Binding Ligand is:

[0006] In other embodiments ASGPR Binding Ligand is selected from : In certain embodiments, the compound of the present invention is of the formula or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0007] or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0009] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof.

[0010] In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof.

[0011] In certain embodiments, the compound of the present invention is selected from:

[0012] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the compound of the present invention is selected from:

[0014] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0015] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is In other embodiments the compound of the present invention is of Formula:

[0016] or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments the compound of the present invention is of Formula: , or a pharmaceutically acceptable salt thereof.

[0018] In other embodiments the compound of the present invention is of Formula: ,

[0019] or a pharmaceutically acceptable salt thereof. In certain embodiments R2is The compounds of the present invention can deliver a Therapeutic Oligonucleotide to the liver. These Therapeutic Oligonucleotide delivering compounds feature select ASGPR ligands that provide high binding affinity for ASGPR. As a result of this high ASGPR binding affinity, these compounds may be administered in lower doses, have fewer side effects, decreased side effects, increased efficacy, faster therapeutic effect, longer metabolic stability, and / or longer therapeutic benefit than conventional Therapeutic Oligonucleotide delivery compounds. A compound of the present invention can be particularly beneficial in the treatment of a disorder of the liver, such as acute hepatic porphyria. In certain embodiments a compound of the present invention is used to treat primary hyperoxaluria type 1, heterozygous familial hypercholesterolemia, clinical atherosclerotic cardiovascular disease, or hemophilia. In other aspects a compound of the present invention is used to lower the concentration of cholesterol such as low-density lipoprotein cholesterol. In certain aspects the disorder treated by a compound of the present invention is selected from acute hepatic porphyria (AHP), hyperoxaluria type 1 (PH1), hypercholesterolemia, hemophilia, a complement mediated disorder, HBV, hypertension, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, hyperoxaluria type 2, hyperoxaluria type 3, β-thalassemia, immunoglobulin A nephropathy (IgAN), angioedema, myelodysplastic disorder, and treatment resistant hypertension. In certain aspects a compound of the present invention is administered prophylactically. For example, when the Therapeutic Oligonucleotide is an antithrombin lowering agent such as fitusiran the compound of the present invention may be administered prophylactically to decrease the risk of excessive bleeding events. In certain embodiments the compound of the present invention is provided as an isotopically enriched compound, for example a compound with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope. For example, deuterium can replace one or more hydrogens and13C can replace one or more carbon atoms. In one embodiment, the isotopic substitution is in one or more positions of the ASGPR Binding Ligand. In another embodiment, the isotopic substitution is in one or more positions of the Linker portion of the molecule (Cleavable Moiety, LinkerA, LinkerB, LinkerC, or LinkerD). In another embodiment, the isotopic substitution is in one or more positions of the Therapeutic Oligonucleotide portion of the molecule. The present invention thus includes at least the following features: (i) A Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof; (ii) Use of a Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof, in treating a medical disorder, for example a disorder of the liver; (iii) An isotopically enriched derivative of a Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof; (iv) A process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder, characterized in that a Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof is used in the manufacture; (v) A Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof in a purified or substantially pure form (e.g., at least 90, 95, 96, 97, 98, 99, 99.5, or 99.9%); (vi) A Therapeutic Oligonucleotide delivering compound described herein or a pharmaceutically acceptable salt thereof to treat a disorder described herein; and (vii) A method for the manufacture of a Therapeutic Oligonucleotide delivering compound described herein. BRIEF DESCRIPTION OF THE FIGURES FIG. 1A, FIG. 1B, FIG. 1C, and FIG. 1D are dose-response curves showing siRNA silencing of the target gene in a primary human hepatocyte assay (Example 7). Two exemplary Therapeutic Oligonucleotide delivering compounds were tested against the compound Givosiran. After 48 hours of incubation, both Therapeutic Oligonucleotide delivering compounds silenced the target gene more potently than Givosiran. FIG.2A and FIG.2B are time course plots of test articles (Compound 1 and Givosiran) at two different concentrations 2.3 nM and 9.4 nM respectively. At both concentrations, Compound 1 silenced the target gene more potently than Givosiran at each time point (16 hours, 24 hours, 48 hours, and 72 hours). The experiment was conducted according to the procedure of Example 7. FIG. 3 is a time course plot of Compound 1 concentration in Rat plasma. It describes pharmacokinetics of Compound 1 (5 mg / kg dose) in Rat for IV bolus and SC administration. Initial plasma concentration of Compound 1 in IV dosed rats was detected to be >10 µg / mL and drops to about 100 ng / mL within 0.5 hour. Initial plasma concentration of Compound 1 in SC dosed rats was detected to be >100 ng / mL and drops to about 100 ng / mL at 4 hours. The experiment was conducted according to the procedure of Example 8. FIG.4 is a boxplot of dose dependent liver exposure for Compound 1 and Givosiran at 1 mg / kg, 2.5 mg / kg, 5 mg / kg, and 10 mg / kg dosages in rats at 72 hours post administration. For each dosage Compound 1 shows lower liver concentration than Givosiran at 72 hours. At 10 mg / kg dosage, Givosiran concentration in liver was about 28 µg / g, while Compound 1 concentration in liver was about half (~14 µg / g). The experiment was conducted according to the procedure of Example 9. FIG.5A and FIG.5B show ALAS1 mRNA suppression at 72 hours, where rats were dosed SC with vehicle, Givosiran or Compound 1 at 1, 2.5, 5 or 10 mg / kg and livers were harvested for target mRNA analysis 72 hours later. FIG.5A is a dose response curve showing Mean + SD of % knock down for 5 rats per dose group. FIG.5B is a boxplot showing the dose response area under the curve (AUC). Unpaired t test with Welch’s correction (SD not assumed equal) were performed at each dose group between Givosiran and Compound 1, *p<0.05. The experiment was conducted according to the procedure of Example 9. DETAILED DESCRIPTION OF THE INVENTION Compounds and their pharmaceutically acceptable salts and compositions thereof that deliver a Therapeutic Oligonucleotide, as well as starting materials and intermediates for such Therapeutic Oligonucleotide delivering compounds and their methods of use and manufacture are provided. These Therapeutic Oligonucleotide delivering compounds are highly potent binders of ASGPR and include a Cleavable Moiety and a Therapeutic Oligonucleotide. In certain embodiments the Therapeutic Oligonucleotide delivering compound binds to ASGPR and is then trafficked into the cell where the Cleavable Moiety is cleaved and the Therapeutic Oligonucleotide is released. In some embodiments, a Therapeutic Oligonucleotide delivering compound that incorporates one of the high binding ASGPR ligands as described herein can be sufficiently active in the form of a monodentate compound (i.e., 1:1 ratio of Therapeutic Oligonucleotide to ASGPR ligand in the therapeutic molecule). In certain embodiments, the Therapeutic Oligonucleotide delivering compound selectively delivers the therapeutic nucleotide to the liver. I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The compounds described herein include independently the enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The present invention includes compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Examples of isotopes that can be incorporated into compounds, of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36Cl, and125I respectively. In one embodiment, isotopically labeled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by using a readily available isotopically labeled reagent instead of a non-isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may optionally be used anywhere in described structures that achieves the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In one embodiment, the isotopic substitution is accomplished by replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect). Isotopic substitutions, for example deuterium substitutions, is typically partial. Partial isotopic substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 80, 85, 90, 95 or 99% or more enriched in an isotope at any location of interest. In certain embodiments deuterium is 80, 85, 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in certain nonlimiting embodiments is enough to alter a detectable property of the drug in a human. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include intravenous formulations, solid dosage forms, tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, parenteral, systemic, topical, gel, mucosal, implant, and the like. “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other pharmaceutically acceptable substance, such as a carrier. The present invention includes pharmaceutical compositions of the Therapeutic Oligonucleotide delivering compounds. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms. A “pharmaceutically acceptable salt” is a derivative of the disclosed compound wherein the parent molecule is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salt of a Therapeutic Oligonucleotide delivering compound can be synthesized by reaction of a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of a Therapeutic Oligonucleotide delivering compound with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of Therapeutic Oligonucleotide delivering compound with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption. Examples, of such salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4-COOH, and the like, or using an acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a pharmaceutically acceptable diluent, excipient, or vehicle with which an active compound is provided. A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition / combination that is generally safe, acceptable for human consumption, and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use. A “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein. Typically, the host, patient, or subject is a human. A “patient” or “host” or “subject” may in certain embodiments where warranted include a veterinary application, for example, to a mammal, primate (e.g., human), horse, dog, cat, cow, sheep, goat, and the like. A “therapeutically effective amount” of a Therapeutic Oligonucleotide delivering compound, pharmaceutical composition, or combination of this invention means an amount that when administered to a host provides a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself. In one embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within any variable group. For example, when any variable group is, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in nonlimiting embodiments, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3etc.). In certain other embodiments, a variable group has a “ ‘ “ or an “a” designation, which in one embodiment can be deuterated. The term “immunoglobulin,” typically refers to a large Y-shaped protein (e.g. an antibody) that identifies and neutralizes a foreign compound or object such as a pathogen or disease tissue. Non-limiting examples of immunoglobulin proteins include IgA, IgD, IgE, IgG, and IgM. An immunoglobulin as used herein may also include a binding fragment as known to the skilled worker. The term “polypeptide” as used herein, refers to any polymeric chain of amino acids. The terms “peptide” and “protein” are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids. The term “polypeptide” encompasses native or artificial proteins, protein fragments, and polypeptide analogs of a protein sequence. A polypeptide may be monomeric or polymeric. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through carbon of the keto (C=O) group. The term “percent (%) identity”, “sequence identity”, “percent sequence identity”, or “percent identical” in the context of nucleic acid sequences or amino acid sequences refers to the residues in the two sequences which are the same when aligned for correspondence. Unless otherwise specified, it is to be understood that a percentage of identity is a minimum level of identity and encompasses all higher levels of identity up to 100% identity to the reference sequence. For example, “95% identity” and “at least 95% identity” may be used interchangeably and include 95, 96, 97, 98, 99 up to 100% identity to the referenced sequence, and all fractions therebetween. The length of sequence identity comparison may be over the full-length of the genome, the full-length of a gene coding sequence, a fragment of a gene coding sequence, a fragment of at least about 500 to about 5000 nucleotides, the full-length of an amino acid sequence, a fragment of an amino acid sequence, a fragment of at least about 8 to about 200 amino acids, is desired. Generally, when referring to “identity”, “homology”, or “similarity” between two different sequences, “identity”, “homology” or “similarity” is determined in reference to “aligned” sequences. “Aligned” sequences or “alignments” refer to more than one nucleic acid sequences or amino acid sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Multiple sequence alignment programs are also available for nucleic acid sequences and amino acid sequences. Examples of such programs include, “Clustal Omega”, “Clustal W”, “CAP Sequence Assembly”, “BLAST”, “MAP”, and “MEME”, which are accessible through Web Servers on the internet. Other sources for such programs are known to those skilled in the art. The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O) then two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group. Unless denoted otherwise, “alkyl” is typically C1-C12alkyl. In certain embodiments the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms, or from 1 to 3 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5or C1- C6. The specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose as individual species each member of the range described as a unique species. For example, the term C1-C6alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cn alkyl is used herein in conjunction with another group, for example, (C3- C7cycloalkyl)C0-C4alkyl, or –C0-C4alkyl(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in –O-C0-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert- pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3- dimethylbutane, and hexyl. When a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. “Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Unless denoted otherwise, “alkenyl” is typically C2-C12alkenyl. Nonlimiting examples are C2-C8alkenyl, C2- C7alkenyl, C2-C6alkenyl, C2-C5alkenyl and C2-C4alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. Unless denoted otherwise, “alkynyl” is typically C2-C12alkynyl. In certain embodiments alkynyl is C2-C8alkynyl or C2-C6alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl. “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above. “Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl. “Aryl" indicates an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. The term “aryl” includes groups where a saturated or partially unsaturated carbocycle group is fused with an aromatic ring. The term “aryl” also includes groups where a saturated or partially unsaturated heterocycle group is fused with an aromatic ring so long as the attachment point is the aromatic ring. Such compounds may include aryl rings fused to a 4 to 7 or a 5 to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O. The term “heterocycle” includes monocyclic 3-12 membered rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro, bicyclic ring systems). It does not include rings containing - O-O- or -S-S- portions. Examples of saturated heterocycle groups include saturated 4- to 7- membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7- trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H- benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro-lH-lλ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. “Bicyclic heterocycle” includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. “Bicyclic heterocycle” also includes heterocyclic radicals that are fused or bridged with a carbocycle radical. For example partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms. Non-limiting examples of bicyclic heterocycles include: , Unless otherwise drawn or clear from the context, the term “bicyclic heterocycle” includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include: . In certain alternative embodiments the term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, O, B, Si, and P. “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms. In some embodiments bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8 or 10 ring atoms in which one 5, 6, or 7-member aromatic ring is fused to a second aromatic or non-aromatic ring wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. “Heteroaryloxy” is a heteroaryl group as described bound to the group it substituted via an oxygen, -O-, linker. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. “Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein. “Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein. Embodiments of “alkyl” In certain embodiments “alkyl” is a C1-C10alkyl, C1-C9alkyl, C1-C8alkyl, C1-C7alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1-C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment the “alkyl” group is optionally substituted. In an alternative embodiment the “alkenyl” group is optionally substituted. In an alternative embodiment the “alkynyl” group is optionally substituted. Embodiments of “haloalkyl” In certain embodiments “haloalkyl” is a C1-C10haloalkyl, C1-C9haloalkyl, C1-C8haloalkyl, C1-C7haloalkyl, C1-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, and C1- C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: , Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: Embodiments of “heteroaryl” Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: , In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: , In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Embodiments of “heterocycle” In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocyclic ring. For example, is a “heterocycle” group. However, is an “aryl” group. Non-limiting examples of “heterocycle” also include: . Additional non-limiting examples of “heterocycle” include: . Additional non-limiting examples of “heterocycle” include: . Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include: . Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include: Embodiments of “Aryl” In certain embodiments “aryl” is a 6 carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10 carbon aromatic group (naphthyl). In certain embodiments “aryl” is a 6 carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example is an “aryl” group. However, is a “heterocycle” group. Embodiments of “arylalkyl” Non-limiting examples of “arylalkyl” include: . In certain embodiments “arylalkyl” is In certain embodiments the “arylalkyl” refers to a 2 carbon alkyl group substituted with an aryl group. Non-limiting examples of “arylalkyl” include: II. THERAPEUTIC OLIGONUCLEOTIDE In certain embodiments, the Therapeutic Oligonucleotide is an antisense oligonucleotide. Antisense oligonucleotides are composed of linked nucleosides, wherein each nucleoside has a sugar moiety and a nucleobase. Nucleosides are linked together through internucleoside linkages (e.g. phosphates) to form an oligonucleotide. The structure of an antisense oligonucleotide may be considered in terms of chemical features (e.g., modifications and patterns of modifications) and nucleobase sequence (e.g., sequence of antisense oligonucleotide, identity and sequence of target nucleic acid). In certain embodiments, the Therapeutic Oligonucleotide is a DNA fragment. A DNA fragment is made up of linked nucleosides, each nucleoside comprising a sugar moiety and a nucleobase. The structure of a DNA fragment may be considered in terms of chemical features (e.g., modifications and patterns of modifications) and nucleobase sequence (e.g., sequence of oligonucleotides or identity). In certain embodiments, the Therapeutic Oligonucleotide is an siRNA. An siRNA Therapeutic Nucleotide can have linked nucleosides, each nucleoside comprising a sugar moiety and a nucleobase. The siRNA can include modifications that stabilize the oligonucleotide, either stabilize or derivatize the nucleobase sequence or make conservative or non-conservative nucleotide substitutions. In certain embodiments, the Therapeutic Oligonucleotide contains a nucleoside which is a modified form of a natural or nonnatural nucleoside. In certain embodiments, the Therapeutic Oligonucleotide has one or more modified nucleosides and / or modified internucleoside linkages. In certain embodiments, a modified nucleoside is modified at the sugar moiety and / or the nucleobase. Modified Sugar Moieties In certain embodiments, one or more of the nucleosides in a Therapeutic Oligonucleotide has a modified sugar moiety. A Therapeutic Oligonucleotide with one or more modified sugar moieties may have desirable properties, such as enhanced nuclease stability. The one or more modified sugar moieties can also increase the binding affinity of the Therapeutic Oligonucleotide for its target nucleic acid sequence. In certain embodiments, a modified sugar moiety is a substituted sugar moiety. In certain embodiments, a modified sugar moiety is a sugar surrogates. A sugar surrogate is a nonnatural molecule which can mimic one or more functions of the nucleoside sugar moiety. For example, the nucleoside reverse-transcriptase inhibitor emtricitabine is a nucleoside which has a 1,3 oxothiolane sugar surrogate. In certain embodiments, a modified sugar moiety is a substituted sugar moiety comprising one or more non-bridging sugar substituents, including but not limited to substituents at the 2' and / or 5' positions. Where a substituent introduces chirality, the modified nucleoside can be in any desired ratio of R- and S-enantiomers, including a racemic mixture and pure enantiomers. In some embodiments, the modified nucleoside can be at least 90% free of the opposite enantiomer. In some embodiments, the modified nucleoside can be at least about 75%, 80%, 85%, 90%, 95%, 98%, 99%, or even 100% free of the opposite enantiomer. Where multiple substituents form diastereomers, the modified nucleoside can be in any desired ratio of diastereomers (for example, cis and trans diastereomers). In certain embodiments, the modified nucleoside is diastereopure. In certain embodiments, the modified nucleoside is a 1:1 mixture of diastereomers. In certain embodiments, the modified nucleoside is at least 75%, 80%, 85%, 90%, 95%, 98%, 99% or even 100% diastereopure. In certain embodiments, the modified sugar moiety is substituted with a 1’-substituent. Examples of a 1’-substituent include but are not limited to fluoro, chloro, bromo, cyano, di-C1- C6alkylamino, C1-C6alkylamino, amino, C1-C6alkoxy and azido. In certain embodiments, the modified sugar moiety is substituted with a 2’-substituent. In certain embodiments, the modified sugar moiety is substituted with two 2’-substituents. Examples of a 2’-position substituent include but are not limited to fluoro, chloro, bromo, cyano, di-C1- C6alkylamino, C1-C6alkylamino, amino, C1-C6alkoxy, azido and 2'-O(CH2)2OCH3(methoxyethyl, MOE). In certain embodiments, a sugar substituent at the 2' position is selected from allyl, amino, azido, thio, O-allyl, O-C1-C10alkyl, OCF3, O(CH2)2SCH3, O(CH2)2O-N(Rm)(Rn), and O- CH2C(=O)-N(Rm)(Rn), where each Rm and Rn is independently, H or C1-C10alkyl. In certain embodiments, a 2'-substituted nucleoside comprises a 2'-substituent group selected from halo (including fluoro, chloro or bromo), allyl, amino, azido, SH, CN, OCN, CF3, OCF3, O-alkyl, S-alkyl, or N(Ro)-alkyl; O-alkyl-O-alkyl, alkynyl, alkenyl, arylalkyl, O-arylalkyl, O(CH2)2SCH3, O-(CH2)2O-N(Ro)(Rp) or O-CH2C(=O)-N(Ro)(Rp), where each Ro and Rp is, independently, H, an amino protecting group or C1-C10alkyl. A 2'-substituent group can be further substituted as allowed by valence with one or more substituent groups independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl and alkynyl. In certain embodiments, a 2'-substituted nucleoside comprises a 2'-substituent group selected from F, NH2, N3, OCF3, O-CH3, O(CH2)3NH2, CH2CH=CH2, O-CH2CH=CH2, OCH2CH2OCH3, O(CH2)2SCH3, O-(CH2)2O-N(Rq)(Rr), O(CH2)2O(CH2)2N(CH3)2, and N- substituted acetamide (O-CH2C(=O)-N(Rq)(Rr) where each Rq and Rr is independently, H, an amino protecting group or C1-C10alkyl. In certain embodiments, a 2'-substituted nucleoside has a sugar moiety substituted with a 2'-substituent group selected from F, OCF3, O-CH3, OCH2CH2OCH3, O(CH2)2SCH3, O-(CH2)2O-N(CH3)2, -O(CH2)2O(CH2)2N(CH3)2, and O-CH2C(=O)-N(H)CH3. In certain embodiments, a 2'-substituted nucleoside has a sugar moiety comprising a 2'- substituent group selected from F, O-CH3, and OCH2CH2OCH3. In certain embodiments, the modified sugar moiety is substituted with a 4’-substituent. Examples of a 4’-substituent include but are not limited to fluoro, chloro, bromo, cyano, di-C1- C6alkylamino, C1-C6alkylamino, amino, C1-C6alkoxy and azido. In certain embodiments, the modified sugar moiety is substituted with a 5’-substituent. In certain embodiments, the modified sugar moiety is substituted with two 5’-substituents. Examples of a 5'-position substituent include, but are not limited to, 5'-methyl, 5'-vinyl, and 5'-methoxy. In certain embodiments, substituted sugars have more than one non-bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties (see, e.g., PCT International Application WO 2008 / 101157, for additional 5', 2'-bis substituted sugar moieties and nucleosides). In certain embodiments, the modified sugar moiety is a bicyclic sugar. In certain embodiments, the bicyclic sugar has a bridge between the 4'- and the 2'-positions. A nucleoside with a bicyclic sugar moiety is referred to as a bicyclic nucleoside or BNAs. Bicyclic nucleosides include, but are not limited to, (A) a-L-Methyleneoxy (4'-CH2O-2') BNA , (B) Methyleneoxy (4'- CH2O-2') BNA (also referred to as locked nucleic acid or LNA) , (C) Ethyleneoxy (4'-(CH2)2O-2') BNA , (D) Aminooxy (4'-CH2O-N(R)-2') BNA, (E) Oxyamino (4'-CH2N(R)-O-2') BNA, (F) Methyl(methyleneoxy) (4'-CH(CH3)-O-2') BNA (also referred to as constrained ethyl or cEt), (G) methylene-thio (4'-CH2S-2') BNA, (H) methylene-amino (4'-CH2-N(R)-2') BNA, (I) methyl carbocyclic (4' -CH2CH(CH3)-2') BNA, and (J) propylene carbocyclic (4' -(CH2)2-2') BNA as depicted below. wherein Bx is Base and R is H, a protecting group, or C1-C12alkyl. Additional bicyclic sugar moieties are known in the art, for example: Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 129(26) 8362-8379 (Jul.4, 2007); Elayadi et al., Curr. Opinion Invens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8, 1-7; Orum et al., Curr. Opinion Mal. Ther., 2001, 3, 239-243; U.S. Patent Nos.7,053,207, 6,268,490, 6,770,748, 6,794,499, 7,034,133, 6,525,191, 6,670,461, and 7,399,845; WO 2004 / 106356, WO 1994 / 14226, WO 2005 / 021570, and WO 2007 / 134181; U.S. Patent Publication Nos. US2004 / 0171570, US2007 / 0287831, and US2008 / 0039618; U.S. Patent Serial Nos. 12 / 129,154, 60 / 989,574, 61 / 026,995, 61 / 026,998, 61 / 056,564, 61 / 086,231, 61 / 097,787, and 61 / 099,844; and PCT International Applications Nos. PCT / US2008 / 064591, PCT / US2008 / 066154, and PCT / US2008 / 068922. In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, a nucleoside comprising a 4'-2' methylene-oxy bridge, may be in the L configuration or in the D configuration. Additional nonlimiting examples of such 4' to 2' sugar substituents include -[C(Ra)(Rb)]n- , -[C(Ra)(Rb)]n-O-, -C(RaRb)-N(R)-O, -C(RaRb)-O-N(R)-; 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)2-2', 4'-(CH2)-O-2' (LNA); 4'-(CH2)-S-2'; 4'-(CH2)2O-2' (ENA); 4'-CH(CH3)-O-2' (cEt) and 4'- CH(CH2OCH3)-O-2', and analogs thereof (see, e.g., U.S. Patent 7,399,845, issued on July 15, 2008); 4'-C(CH3)(CH3)-O-2' and analogs thereof, (see, e.g., WO 2009 / 006478, published January 8, 2009); 4'-CH2N(OCH3)-2' and analogs thereof (see, e.g., WO 2008 / 150729, published December 11, 2008); 4'-CH2O-N(CH3)-2' (see, e.g., US2004 / 0171570, published September 2, 2004 ); 4'-CH2O-N(R)-2', and 4'-CH2N(R)-O-2'-, wherein each R is independently H, a protecting group, or C1-C12alkyl; 4'-CH2N(R)-O-2', wherein R is H, C1-C12alkyl, or a protecting group (see, U.S. Patent 7,427,672, issued on September 23, 2008); 4'-CH2C(H)(CH3)-2' (see, e.g., Chattopadhyaya, et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH2C(=CH2)-2' and analogs thereof (see, published PCT International Application WO 2008 / 154401, published on December 8, 2008). In certain embodiments, such 4' to 2' bridges independently comprise from 1 to 4 linked groups independently selected from -[C(Ra)(Rb)]n-, -C(Ra)=C(Rb)-, -C(Ra)=N-, -C(=NRa)-, -C(=O)-, -C(=S)-, -O-, -Si(Ra)2, -S(=O)x-, and -N(Ra)-; wherein: x is 0, 1, or 2; n is 1, 2, 3, or 4; each Ra and Rb is independently H, a protecting group, hydroxyl, C1-C12alkyl, substituted C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, phenyl, heterocycle, heteroaryl, halogen, COOJ1, COJ1, acyl, S(=O)2J1, or S(=O)J1; and each J1 is independently H, C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, phenyl, acyl, heterocycle, C1-C12aminoalkyl, or a protecting group. In certain embodiments, a substituted sugar moiety is modified with a substituent and a bridge (e.g., 5'-substituted and 4'-2' bridged sugars). In certain embodiments, a modified sugar moiety is a sugar surrogate. In certain such embodiments, the oxygen atom of the naturally occurring sugar is substituted, e.g., with a sulfur, carbon or nitrogen atom. In certain embodiments, the sugar surrogate has bridging and / or non- bridging substituents as described above. For example, sugar surrogates can 4'-sulfur atom and a substitution at the 2'-position and / or the 5' position (see, e.g., published U.S. Patent Application US2005 / 0130923). By way of additional example, carbocyclic bicyclic nucleosides having a 4'-2' bridge have been described (see, e.g., Freier et al., Nucleic Acids Research, 1997, 25(22), 4429- 4443 and Albaeketal., J. Org. Chem., 2006, 71, 7731-7740). In certain embodiments, a sugar surrogate has a ring with other than 5-atoms. For example, in certain embodiments, a sugar surrogate comprises a morpholino. Morpholino compounds and their use in oligomeric compounds has been reported in numerous patents and published articles (see for example: Braasch et al., Biochemistry, 2002, 41, 4503-4510; and U.S. Patents 5,698,685; 5,166,315; 5,185,444; and 5,034,506). As used here, the term "morpholino" means a sugar surrogate having the following structure: . In certain embodiments, a morpholino may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as "modified morpholinos." In certain embodiments, a sugar surrogate is a tetrahydropyran. A tetrahydropyran sugar surrogate may be further modified or substituted. Nucleosides comprising modified tetrahydropyrans include, but are not limited to, hexitol nucleic acid (HNA), anitol nucleic acid (ANA), mannitol nucleic acid (MNA) (see Leumann, CJ. Bioorg. & Med. Chem. (2002) 10:841- 854), fluoro HNA (F-HNA), and those compounds having Formula VI wherein Formula VI is: . T3and T4are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the rest of the Therapeutic Oligonucleotide or one of T3and T4is an internucleoside linking group linking the tetrahydropyran nucleoside analog to the Therapeutic Oligonucleotide and the other of T3and T4is H, a hydroxyl protecting group, a linked conjugate group, or a 5’ or 3’-terminal group; in certain embodiments T3and T4are -P(=O)(OH)-, -OP(=O)(OH)-, -P(=S)(OH)-, or -OP(=S)(OH)- wherein the O of the tetrahydropyran is attached to the P of T3or T4, and bond. q1, q2, q3, q4, q5, q6, and q7, are each independently H, C1-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl; and each of Rc and Rd is independently selected from among: hydrogen, halogen, alkoxy, NJ2H, SJ2, N3, OC(=X)J2, OC(=X)NJ2H, NJ2C(=X)NJ3H and CN, wherein X is O, S or NJ2, and each J2and J3is independently H or C1-C6alkyl. In certain embodiments, the modified THP nucleosides of Formula VI are provided wherein q1, q2, q3, q4, q5, q6 and q7 are each H. In certain embodiments, at least one of q1, q2, q3, q4, q5, q6 and q7 is other than H. In certain embodiments, at least one of q1, q2, q3, q4, q5, q6 and 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 and R2 is H, R1 is methoxy and R2 is H, and R1 is methoxyethoxy and R2 is H. Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds (see, e.g., review article: Leumann, J. C, Bioorganic & Medicinal Chemistry, 2002, 10, 841-854). Combinations of modifications are also provided without limitation, such as 2'-F-5'-methyl substituted nucleosides (see PCT International Application WO 2008 / 101157 for additional 5', 2'- bis substituted nucleosides) and replacement of the ribosyl ring oxygen atom with S and further substitution at the 2'-position (see published U.S. Patent Application US2005-0130923, published on June 16, 2005) or alternatively 5'-substitution of a bicyclic nucleic acid (see PCT International Application WO 2007 / 134181, published on 11 / 22 / 07 wherein a 4'-CH2O-2' bicyclic nucleoside is further substituted at the 5' position with a 5'-methyl or a 5'-vinyl group). The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described (see, e.g., Srivastava et al., J. Am. Chem. Soc. 2007, 129(26), 8362-8379). In certain embodiments, the present disclosure provides a compound comprising a Therapeutic Oligonucleotide with one or more modified nucleosides. The one or more modified nucleotides may include modified sugars, modified nucleobases, and / or modified linkages. The specific modifications are selected such that the resulting oligonucleotides possess desirable characteristics, such as increased plasma stability or increased efficacy. In certain embodiments, oligonucleotides comprise one or more RNA-like nucleosides. In certain embodiments, oligonucleotides comprise one or more DNA-like nucleotides. In certain embodiments, a modified sugar moiety replaces a modified or unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, a modified sugar moiety replaces a modified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, a modified sugar moiety replaces an unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. For example, in certain embodiments the Therapeutic Oligonucleotide corresponds to Nucleotide 1 in Table 1 wherein the first sugar of the antisense strand is replaced with an LNA sugar moiety. In other embodiments the Therapeutic Oligonucleotide corresponds to Nucleotide 1 in Table 1 wherein the first sugar of the sense strand is replaced with an LNA sugar moiety. In certain embodiments, two modified sugar moieties replace a modified or unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, two modified sugar moieties replace a modified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, two modified sugar moieties replace an unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, three modified sugar moieties replace a modified or unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, three modified sugar moieties replace a modified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, three modified sugar moieties replace an unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, four modified sugar moieties replace a modified or unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, four modified sugar moieties replace a modified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, four modified sugar moieties replace an unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, five modified sugar moieties replace a modified or unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, five modified sugar moieties replace a modified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments, five modified sugar moieties replace an unmodified sugar moiety of the nucleotide sequence of the Therapeutic Oligonucleotide. In certain embodiments the modified sugar is an unlocked nucleic acid (UNA). An unlocked nucleic acid has the following formula: . Gapmer Sugar Motifs In certain embodiments, the Therapeutic Oligonucleotide has a region with a gapmer sugar motif, which comprises two external regions or "wings" and a central or internal region or "gap." The three regions of a gapmer sugar motif (the 5'-wing, the gap, and the 3'-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. For example, the nucleosides of the wings may be ribonucleosides and the nucleosides of the gap may be deoxynucleosides. Alternatively, the nucleosides of the wings may be deoxynucleosides and the nucleosides of the gap may be ribonucleosides. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3'-most nucleoside of the 5'-wing and the 5'-most nucleoside of the 3'-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap. In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleosides having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric sugar gapmer). In certain embodiments, the sugar motifs of the 5'-wing differs from the sugar motif of the 3'-wing (asymmetric sugar gapmer). 5’ Wings In certain embodiments, the 5'-wing of a gapmer consists of 1 to 8 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 7 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 6 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 5 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 2 to 5 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 3 to 5 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 4 or 5 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 to 3 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 or 2 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 2 to 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 2 or 3 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 3 or 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 1 nucleoside. In certain embodiments, the 5'- wing of a gapmer consists of 2 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 3 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 4 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 5 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer consists of 6 linked nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least two bicyclic nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises at least three bicyclic nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises at least four bicyclic nucleosides. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one LNA nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a bicyclic nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a constrained ethyl nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a LNA nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one 2'- substituted nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one 2'- MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one 2'-OMe nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a non-bicyclic modified nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a 2'- substituted nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a 2'- MOE nucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a 2'-OMe nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one 2'-deoxynucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a 2'-deoxynucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one ribonucleoside. In certain embodiments, each nucleoside of the 5'-wing of a gapmer is a ribonucleoside. In certain embodiments, one, more than one, or each of the nucleosides of the 5'-wing is an RNA-like nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-deoxynucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 5'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-deoxynucleoside. 3’ Wings In certain embodiments, the 3'-wing of a gapmer consists of 1 to 8 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 7 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 6 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 5 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 2 to 5 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 3 to 5 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 4 or 5 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 to 3 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 or 2 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 2 to 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 2 or 3 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 3 or 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 1 nucleoside. In certain embodiments, the 3'- wing of a gapmer consists of 2 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 3 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 4 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 5 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer consists of 6 linked nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a bicyclic nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a constrained ethyl nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a LNA nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least two non- bicyclic modified nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises at least three non-bicyclic modified nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises at least four non-bicyclic modified nucleosides. In certain embodiments, the 3'-wing of a gapmer comprises at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one 2'-OMe nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a non-bicyclic modified nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a 2'-substituted nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a 2'-MOE nucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one 2'-deoxynucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one ribonucleoside. In certain embodiments, each nucleoside of the 3'-wing of a gapmer is a ribonucleoside. In certain embodiments, one, more than one, or each of the nucleosides of the 5'-wing is an RNA-like nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one non-bicyclic modified nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-substituted nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'- MOE nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-OMe nucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3' -wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one non-bicyclic modified nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one non- bicyclic modified nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-substituted nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'- substituted nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-substituted nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-MOE nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'-MOE nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-MOE nucleoside, and at least one 2'- deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one bicyclic nucleoside, at least one 2'-OMe nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one constrained ethyl nucleoside, at least one 2'-OMe nucleoside, and at least one 2'-deoxynucleoside. In certain embodiments, the 3'-wing of a gapmer comprises at least one LNA nucleoside, at least one 2'-OMe nucleoside, and at least one 2'- deoxynucleoside. Central Regions In certain embodiments, the gap of a gapmer consists of 6 to 20 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 15 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 12 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 to 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 or 7 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 to 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 or 8 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 8 to 10 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 8 or 9 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 6 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 7 linked nucleosides. In certain embodiments, 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 consists of 11 linked nucleosides. In certain embodiments, the gap of a gapmer consists of 12 linked nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer is a 2'-deoxynucleoside. In certain embodiments, the gap comprises one or more modified nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer is a 2'-deoxynucleoside or is a modified nucleoside that is "DNA-like." In certain embodiments, "DNA-like" means that the nucleoside has similar characteristics to DNA, such that a duplex comprising the gapmer and an RNA molecule is capable of activating RNase H. For example, under certain conditions, 2'-(ara)-F have been shown to support RNase H activation, and thus is DNA-like. In certain embodiments, one or more nucleosides of the gap of a gapmer is not a 2'-deoxynucleoside and is not DNA-like. In certain such embodiments, the gapmer nonetheless supports RNase H activation (e.g., by virtue of the number or placement of the non-DNA nucleosides). In certain embodiments, gaps comprise a stretch of unmodified 2'-deoxynucleoside interrupted by one or more modified nucleosides, thus resulting in three sub-regions (two stretches of one or more 2'-deoxynucleosides and a stretch of one or more interrupting modified nucleosides). In certain embodiments, no stretch of unmodified 2'-deoxynucleosides is longer than 5, 6, or 7 nucleosides. In certain embodiments, such short stretches is achieved by using short gap regions. In certain embodiments, short stretches are achieved by interrupting a longer gap region. In certain embodiments, the gap comprises one or more modified nucleosides. In certain embodiments, the gap comprises one or more modified nucleosides selected from among cEt, FHNA, LNA, and 2-thio-thymidine. In certain embodiments, the gap comprises one modified nucleoside. In certain embodiments, the gap comprises a 5'-substituted sugar moiety selected from among 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. In certain embodiments, the gap comprises two or more modified nucleosides and each modified nucleoside is the same. In certain embodiments, the gap comprises two or more modified nucleosides and each modified nucleoside is different. In certain embodiments, the gap comprises one or more modified linkages. In certain embodiments, the gap comprises one or more methyl phosphonate linkages. In certain embodiments the gap comprises two or more modified linkages. In certain embodiments, the gap comprises one or more modified linkages and one or more modified nucleosides. In certain embodiments, the gap comprises one modified linkage and one modified nucleoside. In certain embodiments, the gap comprises two modified linkages and two or more modified nucleosides. Nucleobase Modifications In certain embodiments, a Therapeutic Oligonucleotide of the present disclosure has one or more unmodified nucleobases. In certain embodiments, a Therapeutic Oligonucleotide of the present disclosure has one or more modified nucleobases. In certain embodiments, the one or more modified nucleobases are selected from: universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases as defined herein. 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil; 5-propynylcytosine; 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (-CC-CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2- amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine, 3- deazaguanine and 3-deazaadenine, universal bases, hydrophobic bases, promiscuous bases, size- expanded bases, and fluorinated bases as defined herein. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine( [5,4-b] [1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[5,4-b][l,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g.9-(2-aminoethoxy)-H-pyrimido [5, 4-b] [1, 4]benzoxazin- 2(3 H)-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). A modified nucleobase may also be a nucleobase in which the purine or pyrimidine base is replaced with another heterocycle, for example 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in United States Patent No.3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J.I., Ed., John Wiley & Sons, 1990, 858-859; those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; and those disclosed by Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, Crooke, S.T. and Lebleu, B., Eds., CRC Press, 1993, 273-288. Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, U.S. 3,687,808; 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; 5,681,941; 5,750,692; 5,763,588; 5,830,653 and 6,005,096; each of which is herein incorporated by reference in its entirety. In certain embodiments, a Therapeutic Oligonucleotide of the present disclosure has one or more chemical modifications to one or more nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or nucleobases modification motif. In certain embodiments, nucleobase modifications are arranged in a gapped motif. In certain embodiments, nucleobase modifications are arranged in an alternating motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are chemically modified. In certain embodiments, a Therapeutic Oligonucleotide of the present disclosure has 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 within 3 nucleotides of the 3'-end of the oligonucleotide. In certain such embodiments, the block is at the 5'-end of the oligonucleotide. In certain embodiments the block is within 3 nucleotides of the 5'-end of the oligonucleotide. In certain embodiments, a nucleobase modification is a function of the natural base at a particular position of an oligonucleotide. For example, in certain embodiments each purine or each pyrimidine in an oligonucleotide is modified. In certain embodiments, each adenine 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. In certain embodiments, some, all, or none of the cytosine moieties in an oligonucleotide are 5-methyl cytosine moieties. Herein, 5-methyl cytosine is not a "modified nucleobase." Accordingly, unless otherwise indicated, unmodified nucleobases include both cytosine residues having a 5-methyl and those lacking a 5 methyl. In certain embodiments, the methylation state of all or some cytosine nucleobases is specified. In certain embodiments, chemical modifications to nucleobases include attachment of certain conjugate groups to nucleobases. In certain embodiments, each purine or each pyrimidine in an oligonucleotide may be optionally modified to comprise a conjugate group. Oligonucleotide Length In certain embodiments, a Therapeutic Oligonucleotide of the present disclosure is any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number of nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 161718, 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, 44, 45, 46, 47, 48, 49, and 50. For example, in certain embodiments, the oligonucleotide may consist of 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 21, 8 to 22, 8 to 23, 8 to 24, 8 to 25, 8 to 26, 8 to 27, 8 to 28, 8 to 29, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 21, 9 to 22, 9 to 23, 9 to 24, 9 to 25, 9 to 26, 9 to 27, 9 to 28, 9 to 29, or 9 to 30 linked nucleosides. For example, in certain embodiments, the oligonucleotide may consist of 10 to 11, 10 to 12, 10 to 13, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 21, 10 to 22, 10 to 23, 10 to 24, 10 to 25, 10 to 26, 10 to 27, 10 to 28, 10 to 29, 10 to 30, 11 to 12, 11 to 13, 11 to 14, 11 to 15, 11 to 16, 11 to 17, 11 to 18, 11 to 19, 11 to 20, 11 to 21, 11 to 22, 11 to 23, 11 to 24, 11 to 25, 11 to 26, 11 to 27, 11 to 28, 11 to 29, 11 to 30, 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, or 12 to 30 linked nucleosides. For example, in certain embodiments, the oligonucleotide may consist of 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, or 15 to 30 linked nucleosides. For example, in certain embodiments, the oligonucleotide may consist of 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, or 21 to 30 linked nucleosides. For example, in certain embodiments, the oligonucleotide may consist of 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides. In embodiments where the number of nucleosides of an oligonucleotide of a compound is limited, whether to a range or to a specific number, the compound may, nonetheless further comprise additional other substituents. For example, an oligonucleotide comprising 8-30 nucleosides excludes oligonucleotides having 31 nucleosides, but, unless otherwise indicated, such an oligonucleotide may further comprise, for example one or more conjugate groups, terminal groups, or other substituents. Further, where an oligonucleotide is described by an overall length range and by regions having specified lengths, and where the sum of specified lengths of the regions is less than the upper limit of the overall length range, the oligonucleotide may have additional nucleosides, beyond those of the specified regions, provided that the total number of nucleosides does not exceed the upper limit of the overall length range. Internucleoside Linkage Modifications In a Therapeutic Oligonucleotide, an internucleoside linkage is used to link the nucleosides together. In certain embodiments, the Therapeutic Oligonucleotide comprises one or more modified linkage moieties. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters (PO), phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates (PS). Representative non- phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2N(CH3)-O-CH2), thiodiester (-O-C(O)-S-), thionocarbamate (-O-C(O)(NH)-S-); siloxane (-O-Si(H)2O-); and N,N'-dimethylhydrazine (-CH2N(CH3)-N(CH3)-). Modified linkages, compared to natural phosphodiester linkages, can be used to alter and typically increase nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, as separate enantiomers, or a mixture of enantiomers. In certain embodiments, the chiral phosphorus atom can be at least 80%, 85%, 90%, 95%, 98%, 99% or even 100% free of the opposite stereoisomer. Representative chiral linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. The oligonucleotides described herein typically contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), sugar anomers, or as (D) or (L) such as for amino acids, etc. Neutral internucleoside linkages include without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2N(CH3)-O-5'), amide-3 (3'-CH2C(=O)-N(H)-5'), amide-4 (3'- CH2N(H)-C(=O)-5'), formacetal (3'-O-CH2O-5'), and thioformacetal (3'-S-CH2O-5'). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). In certain embodiments the Therapeutic Oligonucleotide is a Therapeutic Oligonucleotide described herein with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 internucleoside linkage modifications. In certain embodiments, oligonucleotides comprise modified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or modified internucleoside linkage motif. In certain embodiments, oligonucleotides comprise a region having an alternating internucleoside linkage motif. In certain embodiments, oligonucleotides of the present disclosure comprise a region of uniformly modified internucleoside linkages. In certain such embodiments, the oligonucleotide comprises a region that is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide is uniformly linked by phosphorothioate internucleoside linkages. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate. In certain embodiments, each internucleoside linkage of the oligonucleotide is selected from phosphodiester and phosphorothioate and at least one internucleoside linkage is phosphorothioate. In certain embodiments, the oligonucleotide comprises at least 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 7 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 9 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 11 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 12 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 13 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least 14 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 6 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 7 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 8 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 9 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises at least block of at least one 12 consecutive phosphorothioate internucleoside linkages. In certain such embodiments, at least one such block is located at the 3' end of the oligonucleotide. In certain such embodiments, at least one such block is located within 3 nucleosides of the 3' end of the oligonucleotide.In certain embodiments, the oligonucleotide comprises less than 15 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 14 phosphoro-thioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 13 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 12 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 11 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 10 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 9 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 8 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 7 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 6 phosphorothioate internucleoside linkages. In certain embodiments, the oligonucleotide comprises less than 5 phosphorothioate internucleoside linkages. In certain embodiments the Therapeutic Oligonucleotide has chiral internucleoside linkages with high chiral purity. Non-limiting examples of techniques to prepare Therapeutic Oligonucleotides with highly pure chiral internucleoside linkages include those described in Knouse et al. “Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods can Augment Existing Strategies” ACS Central Science (2021) 7, 1473. In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is In certain embodiments one or more internucleoside linkage is Complementary Nucleotides In certain embodiments, the Therapeutic Oligonucleotide is an antisense oligonucleotide having a sequence complementary to a target nucleic acid. Antisense compounds are capable of hybridizing to a target nucleic acid, resulting in antisense activity. In certain embodiments, antisense compounds specifically hybridize to one or more target nucleic acid sequences. In certain embodiments, a specifically hybridizing antisense compound has a nucleobase sequence comprising a region having sufficient complementarity to a target nucleic acid to allow hybridization and result in antisense activity and insufficient complementarity to an off-target so as to avoid or reduce non-specific hybridization to non-target nucleic acid sequences under conditions in which specific hybridization is desired (e.g., under physiological conditions for in vivo or therapeutic uses). In certain embodiments, oligonucleotides are selective between a target and non-target, even though both target and non-target comprise the target sequence. In such embodiments, selectivity may result from relative accessibility of the target region of one nucleic acid molecule compared to the other. In certain embodiments, the Therapeutic Oligonucleotide is an antisense compound comprising oligonucleotides that are fully complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, the Therapeutic Oligonucleotide is 99% complementary to the target nucleic acid. In certain embodiments, the Therapeutic Oligonucleotide is 95% complementary to the target nucleic acid. In certain embodiments, the Therapeutic Oligonucleotide is 90% complementary to the target nucleic acid. In certain embodiments, the Therapeutic Oligonucleotide is 85% complementary to the target nucleic acid. In certain embodiments, the Therapeutic Oligonucleotide is 80% complementary to the target nucleic acid. In certain embodiments, the Therapeutic Oligonucleotide comprises a region that is fully complementary to a target nucleic acid and is at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, the region of full complementarity is from 6 to 14 nucleobases in length. In certain embodiments, the Therapeutic Oligonucleotide comprises a hybridizing region and a terminal region. In certain such embodiments, the hybridizing region consists of 12-30 linked nucleosides and is fully complementary to the target nucleic acid. In certain embodiments, the hybridizing region includes one mismatch relative to the target nucleic acid. In certain embodiments, the hybridizing region includes two mismatches relative to the target nucleic acid. In certain embodiments, the hybridizing region includes three mismatches relative to the target nucleic acid. In certain embodiments, the terminal region consists of 1-4 terminal nucleosides. In certain embodiments, the terminal nucleosides are at the 3' end. In certain embodiments, one or more of the terminal nucleosides are not complementary to the target nucleic acid. Antisense mechanisms or antisense activity include(s) any mechanism involving the hybridization of an oligonucleotide with target nucleic acid, wherein the hybridization results in a biological effect. In certain embodiments, such hybridization results in either target nucleic acid degradation or occupancy with concomitant inhibition or stimulation of the cellular machinery involving, for example, translation, transcription, or splicing of the target nucleic acid. One type of antisense mechanism involving degradation of target RNA is RNase H mediated antisense. RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are "DNA-like" elicit RNase H activity in mammalian cells. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of DNA-like oligonucleotide-mediated inhibition of gene expression. Table 1. Exemplary Therapeutic Oligonucleotides In certain embodiments the Therapeutic Oligonucleotide is givosiran. In certain embodiments the Therapeutic Oligonucleotide is lumasiran. In certain embodiments the Therapeutic Oligonucleotide is inclisiran. In certain embodiments the Therapeutic Oligonucleotide is fitusiran. In certain embodiments the Therapeutic Oligonucleotide is cemdisiran. In certain embodiments the Therapeutic Oligonucleotide is ALN-HBV02. In certain embodiments the Therapeutic Oligonucleotide is ALN-AGT. In certain embodiments the Therapeutic Oligonucleotide is ALN-HSD. In certain embodiments the Therapeutic Oligonucleotide is olpasiran. In certain embodiments the Therapeutic Oligonucleotide is nedosiran. In certain embodiments the Therapeutic Oligonucleotide is xalnesiran. In certain embodiments the Therapeutic Oligonucleotide is zerlasiran. In certain embodiments the Therapeutic Oligonucleotide is pelacarsen. In certain embodiments the Therapeutic Oligonucleotide is IONIS-APOCIII-LRx. In certain embodiments the Therapeutic Oligonucleotide is IONIS-FB-LRx. In certain embodiments the Therapeutic Oligonucleotide is fesomersen. In certain embodiments the Therapeutic Oligonucleotide is donidalorsen. In certain embodiments the Therapeutic Oligonucleotide is tonlamarsen. In certain embodiments the Therapeutic Oligonucleotide is ARO-HBV. In certain embodiments the Therapeutic Oligonucleotide is IONIS-AGT-LRx. In certain embodiments the Therapeutic Oligonucleotide is AB-729. In certain embodiments the Therapeutic Oligonucleotide is SLN-124. When an embodiment, formula, or claim refers to a Therapeutic Oligonucleotide by name and that therapeutic nucleotide has a GalNAc delivery component, then the embodiment, formula, or claim refers to the oligonucleotide portion of the molecule. Similarly, when an embodiment, formula, or claim refers to a therapeutic nucleotide with a phosphate or thiophosphate group at the attaching point to the cleavable moiety and that structure, embodiment, or claim already has a drawn phosphate group thiophosphate or portion of a phosphate or thiophosphate group the skilled artisan will understand that the drawn or claimed structure has one phosphate or thiophosphate group in that position. For example, Compound 1 is drawn in the following shorthand forms in this application for convenience and the skilled artisan will recognize, and it is contemplated in this application, that the drawn phosphate group attached to the 3’ sense strand is the phosphate of that sequence and that the resulting structure is: In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is:

[0020] ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is:

[0021] ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is:

[0022] ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is: or a pharmaceutically acceptable salt thereof. Examples of publications describing the use of ASGPR ligands for the delivery of oligonucleotides include: an article from MiNA Therapeutics titled “Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drugs” (Debacker, et al. Molecular Therapy (2022), 28;8, 1759); an article from GlycoNovo Technologies Co. titled “Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation” (Cui et al. ACS Omega (2021), 6, 16259); WO 2014 / 179626 and US 2022 / 153775 assigned to Ionis Pharmaceuticals, Inc.; WO 2020 / 163747 assigned to Arrowhead Pharmaceuticals Inc.; WO 2022 / 098990 assigned to Arbutus Biopharma Corporation; and WO 2022 / 226217 assigned to Civi Biopharma, Inc. Additional examples of patents and patent applications describing therapeutic oligonucleotides include US 8,106,022 US 8,450,467, US 8,828,956, 9,352,048, 9,370,581, US 9,370,582, US 9,814,777, US 9,828,606, US 9,867,882, US 10,125,369, and US 10,131,907, assigned to Alnylam Pharmaceuticals, Inc.; and US 9,150,605, US 9,708,610, and US 11,078,485 assigned to Ionis Pharmaceuticals, Inc. Abbreviations have the following meanings: Table 2. Exemplary modified nucleotides

[0023]

[0024] In certain embodiments the Therapeutic Oligonucleotide is a siRNA. A siRNA is a doublestranded RNA that can operate within the RNA interference pathway. RNA interference is a defense against viral infection used by many eukaryotic species. Once inside the cell, a siRNA can bind to a complementary mRNA sequence and induce degradation of that mRNA sequence. Reducing the amount of mRNA encoding a protein can result in reduced translation of the protein. In certain embodiments, the mRNA sequence that the siRNA can bind to encodes a protein related to a disease. In certain embodiments the siRNA is between 20 and 24 base pairs in length. In certain embodiments the Therapeutic Oligonucleotide is a shRNA. A shRNA (short hairpin RNA) is an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference. RNA interference using a shRNA molecule can lead to long-lasting reduction in protein expression. In certain embodiments the Therapeutic Oligonucleotide is a DNA aptamer. A DNA aptamer is a single-stranded DNA molecule that can bind to a specific target with high affinity. A DNA aptamer can be produced through systematic evolution of ligands by exponential enrichment (SELEX), a form of combinatorial screening wherein aptamers that bind the desired target are subjected to subsequent rounds of optimization. In certain embodiments the Therapeutic Oligonucleotide is an RNA aptamer. An RNA aptamer is a single-stranded RNA molecule that can bind to a specific target with high affinity. In certain embodiments the Therapeutic Oligonucleotide is a miRNA. A miRNA (MicroRNA) is a small, highly conserved non-coding RNA molecule involved in the regulation of gene expression. MicroRNAs are typically transcribed by RNA polymerases II and III. In certain embodiments the Therapeutic Oligonucleotide is a miRNA mimic. A miRNA mimic is a nonnatural double-stranded miRNA-like RNA fragment. The RNA fragment is typically designed to have its 5'-end bearing a partially complementary motif to the selected sequence in the 3'UTR unique to the target gene. In certain embodiments the Therapeutic Oligonucleotide is a DNA decoy. A DNA decoy is a non-natural DNA probe that binds a target DNA-binding protein. In certain embodiments the Therapeutic Oligonucleotide is an RNA decoy. A RNA decoy is a non-natural RNA probe that binds a target RNA-binding protein. In certain embodiments the Therapeutic Oligonucleotide is a CpG oligonucleotide. A CpG oligonucleotide is a short single-stranded synthetic DNA molecule that contain a cytosine triphosphate deoxynucleotide. Non-limiting examples of compounds of the present invention include:

[0025] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof.

[0026] In certain embodiments, the compound of the present invention is selected from:

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In certain embodiments, the compound of the present invention is selected from:

[0029] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is selected from:

[0030] ; or a pharmaceutically acceptable salt thereof. III. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS FOR THE THERAPEUTIC NUCLEOTIDE DELIVERING COMPOUNDS OF THE PRESENT INVENTION A Therapeutic Oligonucleotide delivering compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof as disclosed herein can be administered as a neat chemical, but is more typically administered as a pharmaceutical composition that includes an effective amount for a host, typically a human, in need of such treatment to treat a disorder that can be treated with the Therapeutic Oligonucleotide. In certain embodiments, the present invention provides pharmaceutical compositions comprising a Therapeutic Oligonucleotide delivering compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog such as a deuterated derivative, or prodrug thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the Therapeutic Oligonucleotide delivering compound is present in an effective amount, e.g., a therapeutically effective amount or a prophylactically effective amount. The ASGPR-binding Therapeutic Oligonucleotide delivering compound of the present invention can be administered in any manner that allows the delivery of the Therapeutic Oligonucleotide. As such, examples of methods to deliver the compound of the present invention include, but are not limited to, oral, intravenous, sublingual, subcutaneous, parenteral, buccal, rectal, intra-aortal, intracranial, subdermal or transnasal, or by other means, in dosage unit formulations containing one or more conventional pharmaceutically acceptable carriers, as appropriate. In certain embodiments the Therapeutic Oligonucleotide delivering compound of the present invention is administered orally. Typically, for oral administration the Therapeutic Oligonucleotide delivering compound will be formulated in a solid dosage form for oral administration or as a gel containing capsule. Non-limiting examples of solid dosage forms include capsules, tablets, and powders. In certain embodiments the pharmaceutical composition comprises a caprylic acid derivative. Non-limiting examples of caprylic acid derivatives are provided in the section “CAPRYLIC ACID DERIVATIVES.” In certain aspects the pharmaceutical composition comprising a caprylic acid derivative is delivered orally. In certain embodiments the Therapeutic Oligonucleotide delivering compound of the present invention is administered intravenously. For example, the Therapeutic Oligonucleotide delivering compound may be formulated in a liquid dosage form for intravenous injection, such as a buffered solution. Non-limiting examples of solutions for intravenous injection include phosphate buffered solution and saline buffered solution. In certain embodiments the solution is buffered with multiple salts. In certain embodiments the Therapeutic Oligonucleotide delivering compound of the present invention is administered subcutaneously. Typically, the Therapeutic Oligonucleotide delivering compound will be formulated in a liquid dosage form for subcutaneous injection, such as a buffered solution. Non-limiting examples of solutions for subcutaneous injection include phosphate buffered solution and saline buffered solution. In certain embodiments the solution is buffered with multiple salts. Therefore, the disclosure provides pharmaceutical compositions comprising an effective amount of a Therapeutic Oligonucleotide delivering compound or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any appropriate use thereof. The pharmaceutical composition may contain a Therapeutic Oligonucleotide delivering compound or salt as the only active agent, or, in an alternative embodiment, the Therapeutic Oligonucleotide delivering compound and at least one additional active agent. In certain embodiments the term pharmaceutically acceptable salt refers to a salt of the described Therapeutic Oligonucleotide delivering compound which is, within the scope of sound medical judgment, suitable for administration to a host such as a human without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. These salts can be prepared during the final isolation and purification of the Therapeutic Oligonucleotide delivering compound or by separately reacting the Therapeutic Oligonucleotide delivering compound in its free form with a suitable organic or inorganic acid and then isolating the salt thus formed. Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic Therapeutic Oligonucleotide delivering compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of acidic Therapeutic Oligonucleotide delivering compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents. Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19. Pharmaceutically acceptable excipients include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Additional acceptable excipients include cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, perfuming agents, etc., and combinations thereof. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation–exchange resins, calcium carbonate, silicates, sodium carbonate, cross–linked poly(vinyl–pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross–linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl–pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl–pyrrolidone), magnesium aluminum 32 silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, etc., and / or combinations thereof. Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Any dosage form can be used that achieves the desired results. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 1500 mg, from about 1 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 1 mg to about 250 mg, from about 5 mg to about 250 mg, from about 10 mg to about 250 mg, from about 25 mg to about 800 mg, from about 50 mg to about 800 mg, from about 75 mg to about 800 mg, from about 100 mg to about 800 mg, or from about 100 mg to about 600 mg of the Therapeutic Oligonucleotide delivering compound and optionally from about 0.1 mg to about 1500 mg, from about 1 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 1 mg to about 250 mg, from about 5 mg to about 250 mg, from about 10 mg to about 250 mg, from about 25 mg to about 800 mg, from about 50 mg to about 800 mg, from about 75 mg to about 800 mg, from about 100 mg to about 800 mg, or from about 100 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 850, 900, 950, or 1,000 mg of the Therapeutic Oligonucleotide delivering compound, or its salt. In certain embodiments the dosage form has at most about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 850, 900, 950, or 1,000 mg of the Therapeutic Oligonucleotide delivering compound, or its salt. In alternative embodiments, the pharmaceutical composition comprises from about 50 mg / mL to about 300 mg / mL, from about 100 mg / mL to about 250 mg / mL or from about 150 mg / mL to about 200 mg / mL of the Therapeutic Oligonucleotide delivering compound, or its salt. In certain embodiments, from about 0.5 mL to about 5 mL, from about 1 mL to about 2 mL or about 1.0, 1.2, 1.4, 1.6, 1.8, or 2.0 mL of the pharmaceutical composition comprising the Therapeutic Oligonucleotide delivering compound, or its salt, is administered. In certain embodiments, from about 0.5 mL to about 1.5 mL of the pharmaceutical composition comprising the Therapeutic Oligonucleotide delivering compound, or its salt, is administered subcutaneously. In certain embodiments, from about 1 mL to about 5 mL of the pharmaceutical composition comprising the Therapeutic Oligonucleotide delivering compound, or its salt, is administered subcutaneously in one, two, three, four, or more injections. In certain embodiments, if a patient is administered multiple subcutaneous injections to reach a total dose of about 1 mL to about 5 mL, the multiple subcutaneous injection sites are spaced apart by at least about 5 cm. In alternative embodiments, the dose is from about 20 to about 300 mg, from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg of the Therapeutic Oligonucleotide delivering compound, or its salt. In certain embodiments the dose ranges from about 0.01-100 mg / kg of patient bodyweight, for example at least about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, the Therapeutic Oligonucleotide delivering compound disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, the Therapeutic Oligonucleotide delivering compound disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer. In some embodiments, the Therapeutic Oligonucleotide delivering compound disclosed herein or used as described are administered once every two days, three, days, four days, five days, six days, or once every week. In some embodiments, the Therapeutic Oligonucleotide delivering compound disclosed herein or used as described are administered once every two weeks, three weeks, or once a month. In some embodiments, the Therapeutic Oligonucleotide delivering compound disclosed herein or used as described are administered once every two, three, four, five, six, seven, eight, nine, ten, eleven months or once per year. In alternative embodiments, from about 20 to about 300 mg, from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg of the Therapeutic Oligonucleotide delivering compound, or its salt, is administered once per month. In certain embodiments, from about 50 mg to about 250 mg of the pharmaceutical composition comprising the Therapeutic Oligonucleotide delivering compound, or its salt, is administered subcutaneously once per month. In certain embodiments, from about 50 mg to about 250 mg of the pharmaceutical composition comprising the Therapeutic Oligonucleotide delivering compound, or its salt, is administered subcutaneously in one, two, three, four, or more injections which are administered once per month. In certain embodiments, the Therapeutic Oligonucleotide delivering compound of the present invention is administered at least once a day, twice a day, three times a day, or four times a day. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., a pill, capsule, tablet, an injection or infusion solution, a syrup, an inhalation formulation, a suppository, a buccal or sublingual formulation, a parenteral formulation, or in a medical device. Some dosage forms, such as tablets and capsules, can be subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert, or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the Therapeutic Oligonucleotide delivering compound is sufficient to provide a practical quantity of material for administration per unit dose of the Therapeutic Oligonucleotide delivering compound. If provided as in a liquid, it can be a solution or a suspension. Representative carriers include phosphate buffered saline, water, solvent(s), diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agent, viscosity agents, tonicity agents, stabilizing agents, and combinations thereof. In some embodiments, the carrier is an aqueous carrier. Examples of aqueous carries include, but are not limited to, an aqueous solution or suspension, such as saline, plasma, bone marrow aspirate, buffers, such as Hank’s Buffered Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringers buffer, ProVisc®, diluted ProVisc®, Provisc® diluted with PBS, Krebs buffer, Dulbecco’s PBS, normal PBS, sodium hyaluronate solution (HA, 5 mg / mL in PBS), citrate buffer, simulated body fluids, plasma platelet concentrate and tissue culture medium or an aqueous solution or suspension comprising an organic solvent. Acceptable solutions include, for example, water, Ringer’s solution and isotonic sodium chloride solutions. The formulation may also be a sterile solution, suspension, or emulsion in a non-toxic diluent or solvent such as 1,3-butanediol. Viscosity agents may be added to the pharmaceutical composition to increase the viscosity of the composition as desired. Examples of useful viscosity agents include, but are not limited to, hyaluronic acid, sodium hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof and mixtures thereof. Solutions, suspensions, or emulsions for administration may be buffered with an effective amount necessary to maintain a pH suitable for the selected administration. Suitable buffers are well known by those skilled in the art. Some examples of useful buffers are acetate, borate, carbonate, citrate, and phosphate buffers. Solutions, suspensions, or emulsions for topical, for example, ocular administration may also contain one or more tonicity agents to adjust the isotonic range of the formulation. Suitable tonicity agents are well known in the art. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the Therapeutic Oligonucleotide delivering compound of the present invention. The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of the Therapeutic Oligonucleotide delivering compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the Therapeutic Oligonucleotide delivering compound and usually at least about 5 wt.% of the Therapeutic Oligonucleotide delivering compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the Therapeutic Oligonucleotide delivering compound. Enteric coated oral tablets may also be used to enhance bioavailability of the Therapeutic Oligonucleotide delivering compound for an oral route of administration. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the Therapeutic Oligonucleotide delivering compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Therapeutic Oligonucleotide delivering compounds of the present invention and pharmaceutically acceptable composition, salts, isotopic analogs, or prodrugs thereof, may be formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions comprising a Therapeutic Oligonucleotide delivering compound as described herein will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific the Therapeutic Oligonucleotide delivering compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the Therapeutic Oligonucleotide delivering compound employed; the duration of the treatment; drugs used in combination or coincidental with the Therapeutic Oligonucleotide delivering compound employed; and like factors well known in the medical arts. The Therapeutic Oligonucleotide delivering compound and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, systemic, intravenous, intramuscular, intra–arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration). The exact amount of a Therapeutic Oligonucleotide delivering compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular Therapeutic Oligonucleotide delivering compound(s), mode of administration, and the like. The desired dosage can be delivered using any frequency determined to be useful by the health care provider, including three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). It will be also appreciated that a Therapeutic Oligonucleotide delivering compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents. The Therapeutic Oligonucleotide delivering compound or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder (for example, a Therapeutic Oligonucleotide delivering compound can be administered in combination with an anti– inflammatory agent, anti–cancer agent, immunosuppressant, etc.), and / or it may achieve different effects (e.g., control of adverse side–effects, e.g., emesis controlled by an antiemetic). The Therapeutic Oligonucleotide delivering compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents. In general, each agent will be administered at a dose and / or on a time schedule determined for that agent. It will further be appreciated that the additional therapeutically active agent used in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the Therapeutic Oligonucleotide delivering compound with the additional therapeutically active agent and / or the desired therapeutic effect to be achieved. In general, it is expected that additional therapeutically active agents used in combination be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than those used individually. Exemplary additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drugs Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In certain embodiments, the additional therapeutically active agent is an anti-cancer agent, e.g., radiation therapy and / or one or more chemotherapeutic agents. In certain aspects, a treatment regimen is provided comprising the administration of a Therapeutic Oligonucleotide delivering compound of the present invention or a pharmaceutically acceptable composition, salt, isotopic analog (such as a deuterated derivative), or prodrug thereof in combination or in alternation with at least one additional therapeutic agent. The combinations and / or alternations can be administered for beneficial, additive, or synergistic effect in the treatment of a disorder which is treatable by the Therapeutic Oligonucleotide. IV. ASGPR BINDING LIGANDS

[0031] In certain embodiments the ASGPR Binding Ligand is selected from:

[0032] In certain embodiments the ASGPR Binding Ligand is selected from:

[0033] In certain embodiments, the ASGPR Binding Ligand is selected from

[0034]

[0035] In certain embodiments the ASGPR Binding Ligand is selected from:

[0036] In certain embodiments the ASGPR Binding Ligand is selected from:

[0037] . In certain embodiments the compound of the present invention is:

[0038] or a pharmaceutically acceptable salt thereof.

[0039] In certain embodiments the compound of the present invention is:

[0040] or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments the compound of the present invention is:

[0042] or a pharmaceutically acceptable salt thereof.

[0043] In certain embodiments the compound of the present invention is:

[0044] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is:

[0045] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is:

[0046] or a pharmaceutically acceptable salt thereof. In certain aspects the invention provides a bidentate version of a monodentate embodiment presented herein. For example, in this aspect the bidentate of the following embodiment In certain aspects the invention provides a tridentate version of a monodentate embodiment presented herein. For example, in this aspect the tridentate of the following embodiment

[0047] . Embodiments of the Linker In non-limiting embodiments, LinkerAand LinkerBare independently selected from: ; wherein: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O- (CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; and the remaining variables are as defined herein. In one embodiment LinkerAis bond and LinkerBis . In one embodiment LinkerBis bond and LinkerAis . In certain embodiments, LinkerAis selected from In certain embodiments, is selected from . In the embodiments of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20provided herein the structure can be included in the Linker as read from left to right or alternatively as read from right to left unless excluded by context. For example, when R15is and LinkerBis , LinB ker can be . In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6- , -NR6C(O)-, -O-, -NR6-, -C(R21R21)-, a divalent residue of a natural or unnatural amino acid, - CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[-NR6C(R21R21)C(O)O-]xx-, and a divalent residue of a fatty acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of bond, -O-, -NR6-, -C(R21R21)-, -CH2CH2- [O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, and -[C(O)-CH2-O]n-; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of bond, -O-, -C(R21R21)-, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, and -[C(O)-CH2-O]n-; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6- , -NR6C(O)-, -O-, -NR6-, -C(R21R21)-, a divalent residue of a natural or unnatural amino acid, - CH2CH2-[O-(CH2)2]n-NR6-, and -[-NR6C(R21R21)C(O)O-]xx-; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In alternative embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of bond, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6- , -NR6C(O)-, -O-, -NR6-, -C(R21R21)-, a divalent residue of a natural or unnatural amino acid, - CH2CH2-[O-(CH2)2]n-NR6-, and -[-NR6C(R21R21)C(O)-]xx-; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21. In one embodiment, a divalent residue of an amino acid is selected from , , wherein the amino acid can be oriented in either direction and wherein the amino acid can be in the L- or D-form. For example, when R15isB and Linker is LinkerBcan be In certain embodiments, LinkerA, LinkerB, LinkerC, or LinkerDcomprises a polymer linker. In certain embodiments, the polymer linker is a copolymer. In certain embodiments the polymer linker is a block copolymer linker. In certain embodiments, the polymer linker is an alternating copolymer linker. In certain embodiments, the polymer linker is a random copolymer. In certain embodiments, the polymer linker is not branched. In certain embodiments, the polymer linker is branched. For example, a polymer comprising ethylene glycol monomers does not have a branch point. However, a polymer comprising propylene glycol monomers contains a branch point. In certain embodiments, a branch point is an R21group. In certain embodiments, the polymer linker has one branch point. In certain embodiments, the polymer linker has two, three, four, five, six, seven, eight, nine, or ten branch points. In certain embodiments, the R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20group is branched by one R21group. In certain embodiments, the R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20group is branched by two R21groups. In certain embodiments, the R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20group is branched by three R21groups. In certain embodiments, the R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20group is branched by four R21groups. For example, when R11is -[-(CH2)2-O-]n-, the ethylene glycol monomer can be mono-, di-, or tribranched depending on the number of R21substituents and regiochemistry of R21substituents: Linker monomers of different structures can be combined in a repeating or random pattern and can be oriented in either direction such that a stable compound results. For example, if R13, R15, R17are -[-(CH2)2-O-]n- substituted by one R21group; R14, R16, and R18are -[-NR6C(R21aR21b)C(O)-]xx-; n is 3; xx is 3; R21is CH3, R21aand R21bare hydrogen; and R6is CH3;the alternating block copolymer linker would be of the formula: . In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)- ,-SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21aR21b)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)- O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[-NR6C(R21aR21b)C(O)O-]xx- a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid, , , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; wherein za, zb, zc, zd, ze, zf, zg, zh, zi, and zj are independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and wherein the sum of za, zb, zc, zd, ze, zf, zg, zh, zi, and zj is not more than 50. In certain embodiments, the sum of the sum of za, zb, zc, zd, ze, zf, zg, zh, zi, and zj is not more than 30. In certain embodiments, the sum of za, zb, zc, zd, ze, zf, zg, zh, zi, and zj is not more than 25. In certain embodiments, the sum of za, zb, zc, zd, ze, zf, zg, zh, zi, and zj is not more than 15. In certain embodiments, the sum of za, zb, zc, zd, ze, zf, zg, zh, zi, and zj is not more than 10. In alternative embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-,-SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21aR21b)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[-NR6C(R21aR21b)C(O)-]xx- a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid, , , , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; For example, a polymer linker can comprise an alternating block copolymer of the formula Linker monomers can be oriented in either direction. For example, when R15is za is four, and LinkerBisB then Linker can be: In certain embodiments, the polymer linker is a random copolymer. A random copolymer linker is a linker without a repeating pattern of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20monomer groups. In some embodiments, a random copolymer linker has different groups for each of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20. In certain embodiments, two, three, four or five of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20in a random copolymer linker are the same group, but are present in a random order. For example, a random block copolymer linker can comprise a polymer of the formula In certain embodiments, the random copolymer linker is a polymer linker comprised of up to 50, up to 30, up to 25, up to 20, or up to 15 randomly attached linker monomers selected from -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[-NR6C(R21aR21b)C(O)O-]xx-, In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of , , , In the embodiments of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20provided herein the structure can be included in the Linker as read from left to right or alternatively as read from right to left unless excluded by context. For example, when R15isB and Linker is . In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least three of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least four of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least five of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least six of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least seven of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least eight of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, at least nine of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are each independently selected from the group consisting of . In certain embodiments, LinkerBis selected from:

[0048] (SEQ ID NO: 58). In certain embodiments, the Linker is a sequence comprising SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or a sequence that has at least 80%, 85%, 90%, 95%, or 98% sequence identity to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. SEQ ID NO: 1 SPSTPPTPSPSTPP SEQ ID NO: 2 SPSTPPTPSPSTPPSPSTPP SEQ ID NO: 3 SPTSPPSPTPTSPP SEQ ID NO: 4 PPTSPSPTPPTSPS SEQ ID NO: 5 PPTSPSPTPPTSPSPP SEQ ID NO: 6 SPPSTPSPTPTSPP SEQ ID NO: 7 SPSTPSTPSPSTPP SEQ ID NO: 8 PPTSPSPTPPTSPSSPSTPP SEQ ID NO: 9 PPSTPTPSPPSTPS SEQ ID NO: 10 PPSTPTPSPPSTPSPP In certain embodiments, Linker is an amino acid sequence comprising a peptide that contains between 1 and 10 prolines and optionally between 1 and 10 amino acids selected from serine and threonine. In one embodiment, a divalent residue of a dicarboxylic acid is generated from a nucleophilic addition reaction: Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a nucleophilic addition reaction include: , As used in the embodiments herein, xx is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25. As used in the embodiments herein, yy is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25. In one embodiment, a divalent residue of a dicarboxylic acid is generated from a condensation reaction: . Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a condensation include: Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include: Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include: Non-limiting embodiments of a divalent residue of a saturated monocarboxylic acid is selected from butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), lauric acid (-OC(O)(CH2)10CH2-), myristic acid (-OC(O)(CH2)12CH2-), pentadecanoic acid (-OC(O)(CH2)13CH2-), palmitic acid (-OC(O)(CH2)14CH2-), stearic acid (-OC(O)(CH2)16CH2-), behenic acid (-OC(O)(CH2)20CH2-), and lignoceric acid (-OC(O)(CH2)22CH2-). Non-limiting embodiments of a divalent residue of a fatty acid include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid: , Non-limiting embodiments of a divalent residue of a fatty acid is selected from linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (–C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), alpha-linolenic acid (–C(O)(CH2)7(CHCHCH2)3CH2-) stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y-linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3,(CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), paullinic acid (-C(O)(CH2)11CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (- C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2)13CHCH(CH2)7CH2-), mead acid (- C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2)11CHCH(CH2)7CH2-). In certain embodiments LinkerCis selected from: . wherein: R22is independently at each occurrence selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and the remaining variables are as defined herein. In certain embodiments LinkerDis selected from: wherein: R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; X- is an anionic group, for example Br- or Cl-;and all other variables are as defined herein. In certain embodiments, LinkerCis selected from In certain embodiments, LinkerCis selected from .

[0049] In certain embodiments, LinkerCis selected from . In certain embodiments, LinkerCis selected from

[0050] In certain embodiments, LinkerCis selected from (SEQ ID NO: 59);

[0051] . In certain embodiments, LinkerCis selected from:

[0052] In certain embodiments, LinkerCis selected from:

[0053] (SEQ ID NO: 60); and In certain embodiments, LinkerCis selected from:

[0054] In certain embodiments, LinkerAor LinkerBis independently selected from

[0055] . In certain embodiments, LinkerAor LinkerBis independently selected from

[0056] In certain embodiments, LinkerAor LinkerBis independently selected from In certain embodiments, LinkerAor LinkerBis independently selected from

[0057] In certain embodiments, LinkerAor LinkerBis independently selected from (SEQ ID NO: 61); . In certain embodiments, LinkerAor LinkerBis independently selected from: . In certain embodiments, LinkerAor LinkerBis independently selected from (SEQ ID NO: 62); and In certain embodiments, LinkerAor LinkerBis independently selected from: . In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, R16, R17, R18, R19, and R20are bond. In certain embodiments, R17, R18, R19, and R20are bond. In certain embodiments, R18, R19, and R20are bond. In certain embodiments, nine of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, eight of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, seven of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, six of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, five of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, four of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, three of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, two of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond. In certain embodiments, one of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20is bond. In certain embodiments, LinkerAis

[0058] wherein each heteroaryl, heterocycle, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl. In certain embodiments, R11, R12, R13, R15, R16, R18, R19, and R20are independently selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)- , alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, and -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments, LinkerAis selected from . In certain embodiments, R11, R12, R13, R18, R19, and R20are independently selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, and -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments, R11is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, R20is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, LinkerAis selected from . In certain embodiments, R12is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, R19is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, LinkerAis selected from . In certain embodiments, R13is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, R18is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-. In certain embodiments, aryl is phenyl. In certain embodiments, heteroaryl is selected from In certain embodiments, heteroaryl is selected from In certain embodiments, heterocycle is selected from . In certain embodiments, LinkerAis selected from , In certain embodiments, LinkerAis selected from In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments, LinkerBis: ; wherein: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, and -CH2CH2-[O-(CH2)2]n-NR6-; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle. In certain embodiments of LinkerB, R11, R12, R13, R14, R15, R16, and R17are bond. In certain embodiments of LinkerB, five of R11, R12, R13, R14, R15, R16, R17, R18, and R19are bond. In certain embodiments of LinkerB, four of R11, R12, R13, R14, R15, R16, R17, R18, and R19are bond. In certain embodiments of LinkerB, three of R11, R12, R13, R14, R15, R16, R17, R18, and R19are bond. In certain embodiments of LinkerB, R18, R19, and R20are independently selected from bond, alkyl, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, and -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with one R21substituent. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with two R21substituents, wherein the substituents are selected such that a stable compound results. For example, if R11is –(CR21R21)-, then the R21groups are not independently hydroxyl and fluorine. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with three R21substituents, wherein the substituents are selected such that a stable compound results. In certain embodiments, R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with four R21substituents, wherein the substituents are selected such that a stable compound results. In certain embodiments, R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, amino, -NR6R7, haloalkyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, F, hydroxyl, alkoxy, amino, -NR6R7, haloalkyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, F, hydroxyl, alkoxy, amino, -NR6R7, and haloalkyl. Additional embodiments of LinkerAIn the embodiments of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20provided herein the structure can be included in the Linker as read from left to right or alternatively as read from right to left unless excluded by context. For example, when R15is and LinkerAis . A1. In certain embodiments of LinkerA, R11is bond. A2. In certain embodiments of LinkerA, R11is alkyl. A3. In certain embodiments of LinkerA, R11is -C(O)-. A4. In certain embodiments of LinkerA, R11is -C(O)O-. A5. In certain embodiments of LinkerA, R11is -C(O)NR6-. A6. In certain embodiments of LinkerA, R11is -NR6C(O)-. A7. In certain embodiments of LinkerA, R11is -NR6-. A8. In certain embodiments of LinkerA, R11is -O-. A9. In certain embodiments of LinkerA, R11is -C(R21R21)-. A10. The LinkerAof embodiment A9, wherein both R21groups are hydrogen. A11. In certain embodiments of LinkerA, R11is -CH2CH2-[O-(CH2)2]n-O-. A12. In certain embodiments of LinkerA, R11is aryl. A13. The LinkerAof embodiment A12, wherein R11is phenyl. A14. The LinkerAof embodiment A12, wherein R11is naphthyl. A15. In certain embodiments of LinkerA, R11is heterocycle. A16. The LinkerAof embodiment A15, wherein R11is piperidinyl. A17. The LinkerAof embodiment A16, wherein R11is A18. The LinkerAof embodiment A16, wherein R11is A19. The LinkerAof embodiment A15, wherein R11is piperizinyl. A20. The LinkerAof embodiment A19, wherein R11is A21. The LinkerAof embodiment A15, wherein R11is pyrrolidinyl. A22. The LinkerAof embodiment A21, wherein R11is A23. The LinkerAof embodiment A21, wherein R11is A24. In certain embodiments of LinkerA, R11is heteroaryl. A25. The LinkerAof embodiment A24, wherein R11is pyridinyl. A26. The LinkerAof embodiment A25, wherein R11is A27. The LinkerAof embodiment A25, wherein R11is A28. The LinkerAof embodiment A25, wherein R11is A29. The LinkerAof embodiment A24, wherein R11is pyrimidinyl. A30. The LinkerAof embodiment A29, wherein R11is A31. The LinkerAof embodiment A29, wherein R11is A32. The LinkerAof embodiment A24, wherein R11is pyrazinyl. A33. The LinkerAof embodiment A32, wherein R11is A34. The LinkerAof embodiment A32, wherein R11is A35. The LinkerAof embodiment A24, wherein R11is pyridizinyl. A36. The LinkerAof embodiment A35, wherein R11is A37. The LinkerAof embodiment A35, wherein R11is A38. In certain embodiments of LinkerA, R11is alkynyl. A39. In certain embodiments of LinkerA, R11is alkoxy. A40. The LinkerAof any one of embodiments A1-A39, wherein R12is bond. A41. The LinkerAof any one of embodiments A1-A39, wherein R12is alkyl. A42. The LinkerAof any one of embodiments A1-A39, wherein R12is -C(O)-. A43. The LinkerAof any one of embodiments A1-A39, wherein R12is -C(O)O-. A44. The LinkerAof any one of embodiments A1-A39, wherein R12is -C(O)NR6-. A45. The LinkerAof any one of embodiments A1-A39, wherein R12is -NR6C(O)-. A46. The LinkerAof any one of embodiments A1-A39, wherein R12is -C(R21R21)-. A47. The LinkerA of embodiment A46, wherein both R21groups are hydrogen. A48. The LinkerAof any one of embodiments A1-A39, wherein R12is -CH2CH2-[O-(CH2)2]n- O-. A49. The LinkerAof any one of embodiments A1-A39, wherein R12is aryl. A50. The LinkerAof embodiment A39, wherein R12is phenyl. A51. The LinkerAof embodiment A39, wherein R12is naphthyl. A52. The LinkerAof any one of embodiments A1-A39, wherein R12is heterocycle. A53. The LinkerAof embodiment A52, wherein R12is piperidinyl. A54. The LinkerAof embodiment A53, wherein R12is A55. The LinkerAof embodiment A53, wherein R12is A56. The LinkerAof embodiment A52, wherein R12is piperizinyl. A57. The LinkerAof embodiment A56, wherein R12is A58. The LinkerAof embodiment A52, wherein R12is pyrrolidinyl. A59. The LinkerAof embodiment A58, wherein R12is A60. The LinkerAof embodiment A59, wherein R12is A61. The LinkerAof any one of embodiments A1-A39, wherein R12is heteroaryl. A62. The LinkerAof embodiment A61, wherein R12is pyridinyl. A63. The LinkerAof embodiment A62, wherein R12is A64. The LinkerAof embodiment A62, wherein R12is A65. The LinkerAof embodiment A62, wherein R12is A66. The LinkerAof embodiment A61, wherein R12is pyrimidinyl. A67. The LinkerAof embodiment A66, wherein R12is A68. The LinkerAof embodiment A66, wherein R12is A69. The LinkerAof embodiment A61, wherein R12is pyrazinyl. A70. The LinkerAof embodiment A69, wherein R12is A71. The LinkerAof embodiment A68, wherein R12is A72. The LinkerAof embodiment A61, wherein R12is pyridizinyl. A73. The LinkerAof embodiment A72, wherein R12is A74. The LinkerAof embodiment A72, wherein R12is A75. The LinkerAof any one of embodiments A1-A39, wherein R12is alkynyl. A76. The LinkerAof any one of embodiments A1-A39, wherein R12is alkoxy. A77. The LinkerAof any one of embodiments A1-A76, wherein R13is bond. A78. The LinkerAof any one of embodiments A1-A76, wherein R13is alkyl. A79. The LinkerAof any one of embodiments A1-A76, wherein R13is -C(O)-. A80. The LinkerAof any one of embodiments A1-A76, wherein R13is -C(O)O-. A81. The LinkerAof any one of embodiments A1-A76, wherein R13is -C(O)NR6-. A82. The LinkerAof any one of embodiments A1-A76, wherein R13is -NR6C(O)-. A83. The LinkerAof any one of embodiments A1-A76, wherein R13is -NR6-. A84. The LinkerAof any one of embodiments A1-A76, wherein R13is -O-. A85. The LinkerAof any one of embodiments A1-A76, wherein R13is -C(R21R21)-. A86. The LinkerA of embodiment A85, wherein both R21groups are hydrogen. A87. The LinkerAof any one of embodiments A1-A76, wherein R13is -CH2CH2-[O-(CH2)2]n- O-. A88. The LinkerAof any one of embodiments A1-A76, wherein R13is aryl. A89. The LinkerAof embodiment A88, wherein R13is phenyl. A90. The LinkerAof embodiment A88, wherein R13is naphthyl. A91. The LinkerAof any one of embodiments A1-A76, wherein R13is heterocycle. A92. The LinkerAof embodiment A91, wherein R13is piperidinyl. A93. The LinkerAof embodiment A92, wherein R13is A94. The LinkerAof embodiment A92, wherein R13is A95. The LinkerAof embodiment A91, wherein R13is piperizinyl. A96. The LinkerAof embodiment A95, wherein R13is A97. The LinkerAof embodiment A91, wherein R13is pyrrolidinyl. A98. The LinkerAof embodiment A97, wherein R13is A99. The LinkerAof embodiment A97, wherein R13is A100. The LinkerAof any one of embodiments A1-A76, wherein R13is heteroaryl. A101. The LinkerAof embodiment A100, wherein R13is pyridinyl. A102. The LinkerAof embodiment A101, wherein R13is A103. The LinkerAof embodiment A101, wherein R13is A104. The LinkerAof embodiment A101, wherein R13is A105. The LinkerAof embodiment A100, wherein R13is pyrimidinyl. A106. The LinkerAof embodiment A105, wherein R13is A107. The LinkerAof embodiment A105, wherein R13is A108. The LinkerAof embodiment A100, wherein R13is pyrazinyl. A109. The LinkerAof embodiment A108, wherein R13is A110. The LinkerAof embodiment A108, wherein R13is A111. The LinkerAof embodiment A100, wherein R13is pyridizinyl. A112. The LinkerAof embodiment A111, wherein R13is A113. The LinkerAof embodiment A111, wherein R13is A114. The LinkerAof any one of embodiments A1-A76, wherein R13is alkynyl. A115. The LinkerAof any one of embodiments A1-A76, wherein R13is alkoxy. A116. The LinkerAof any one of embodiments A1-A115, wherein R14is bond. A117. The LinkerAof any one of embodiments A1-A115, wherein R14is alkyl. A118. The LinkerAof any one of embodiments A1-A115, wherein R14is -C(O)-. A119. The LinkerAof any one of embodiments A1-A115, wherein R14is -C(O)O-. A120. The LinkerAof any one of embodiments A1-A115, wherein R14is -C(O)NR6-. A121. The LinkerAof any one of embodiments A1-A115, wherein R14is -NR6C(O)-. A122. The LinkerAof any one of embodiments A1-A115, wherein R14is -S(O)-. A123. The LinkerAof any one of embodiments A1-A115, wherein R14is –S(O)2-. A124. The LinkerAof any one of embodiments A1-A115, wherein R14is -C(R21R21)-. A125. The LinkerA of embodiment A124, wherein both R21groups are hydrogen. A126. The LinkerAof any one of embodiments A1-A115, wherein R14is -CH2CH2-[O- (CH2)2]n-O-. A127. The LinkerAof any one of embodiments A1-A115, wherein R14is aryl. A128. The LinkerAof embodiment A127, wherein R14is phenyl. A129. The LinkerAof embodiment A127, wherein R14is naphthyl. A130. The LinkerAof any one of embodiments A1-A115, wherein R14is heterocycle. A131. The LinkerAof embodiment A130, wherein R14is piperidinyl. A132. The LinkerAof embodiment A131, wherein R14is A133. The LinkerAof embodiment A131, wherein R14is A134. The LinkerAof embodiment A130, wherein R14is piperizinyl. A135. The LinkerAof embodiment A134, wherein R14is A136. The LinkerAof embodiment A130, wherein R14is pyrrolidinyl. A137. The LinkerAof embodiment A136, wherein R14is A138. The LinkerAof embodiment A136, wherein R14is A139. The LinkerAof any one of embodiments A1-A115, wherein R14is heteroaryl. A140. The LinkerAof embodiment A139, wherein R14is pyridinyl. A141. The LinkerAof embodiment A140, wherein R14is A142. The LinkerAof embodiment A140, wherein R14is A143. The LinkerAof embodiment A140, wherein R14is A144. The LinkerAof embodiment A139, wherein R14is pyrimidinyl. A145. The LinkerAof embodiment A144, wherein R14is A146. The LinkerAof embodiment A144, wherein R14is A147. The LinkerAof embodiment A139, wherein R14is pyrazinyl. A148. The LinkerAof embodiment A147, wherein R14is A149. The LinkerAof embodiment A147, wherein R14is A150. The LinkerAof embodiment A139, wherein R14is pyridizinyl. A151. The LinkerAof embodiment A150, wherein R14is A152. The LinkerAof embodiment A150, wherein R14is A153. The LinkerAof any one of embodiments A1-A115, wherein R14is alkynyl. A154. The LinkerAof any one of embodiments A1-A115, wherein R14is alkoxy. A155. The LinkerAof any one of embodiments A1-A154, wherein R15is bond. A156. The LinkerAof any one of embodiments A1-A154, wherein R15is alkyl. A157. The LinkerAof any one of embodiments A1-A154, wherein R15is -C(O)-. A158. The LinkerAof any one of embodiments A1-A154, wherein R15is -C(O)O-. A159. The LinkerAof any one of embodiments A1-A154, wherein R15is -C(O)NR6-. A160. The LinkerAof any one of embodiments A1-A154, wherein R15is -NR6C(O)-. A161. The LinkerAof any one of embodiments A1-A154, wherein R15is -NR6-. A162. The LinkerAof any one of embodiments A1-A154, wherein R15is -O-. A163. The LinkerAof any one of embodiments A1-A154, wherein R15is -C(R21R21)-. A164. The LinkerA of embodiment A163, wherein both R21groups are hydrogen. A165. The LinkerAof any one of embodiments A1-A154, wherein R15is -CH2CH2-[O- (CH2)2]n-O-. A166. The LinkerAof any one of embodiments A1-A154, wherein R15is aryl. A167. The LinkerAof embodiment A166, wherein R15is phenyl. A168. The LinkerAof embodiment A166, wherein R15is naphthyl. A169. The LinkerAof any one of embodiments A1-A154, wherein R15is heterocycle. A170. The LinkerAof embodiment A169, wherein R15is piperidinyl. A171. The LinkerAof embodiment A170, wherein R15is A172. The LinkerAof embodiment A170, wherein R15is A173. The LinkerAof embodiment A169, wherein R15is piperizinyl. A174. The LinkerAof embodiment A173, wherein R15is A175. The LinkerAof embodiment A169, wherein R15is pyrrolidinyl. A176. The LinkerAof embodiment A175, wherein R15is A177. The LinkerAof embodiment A175, wherein R15is A178. The LinkerAof any one of embodiments A1-A154, wherein R15is heteroaryl. A179. The LinkerAof embodiment A178, wherein R15is pyridinyl. A180. The LinkerAof embodiment A179, wherein R15is A181. The LinkerAof embodiment A179, wherein R15is A182. The LinkerAof embodiment A179, wherein R15is A183. The LinkerAof embodiment A178, wherein R15is pyrimidinyl. A184. The LinkerAof embodiment A183, wherein R15is A185. The LinkerAof embodiment A183, wherein R15is A186. The LinkerAof embodiment A178, wherein R15is pyrazinyl. A187. The LinkerAof embodiment A186, wherein R15is A188. The LinkerAof embodiment A186, wherein R15is A189. The LinkerAof embodiment A178, wherein R15is pyridizinyl. A190. The LinkerAof embodiment A189, wherein R15is A191. The LinkerAof embodiment A189, wherein R15is A192. The LinkerAof any one of embodiments A1-A154, wherein R15is alkynyl. A193. The LinkerAof any one of embodiments A1-A154, wherein R15is alkoxy. A194. The LinkerAof any one of embodiments A1-A193, wherein R16is bond. A195. The LinkerAof any one of embodiments A1-A193, wherein R16is alkyl. A196. The LinkerAof any one of embodiments A1-A193, wherein R16is -C(O)-. A197. The LinkerAof any one of embodiments A1-A193, wherein R16is -C(O)O-. A198. The LinkerAof any one of embodiments A1-A193, wherein R16is -C(O)NR6-. A199. The LinkerAof any one of embodiments A1-A193, wherein R16is -NR6C(O)-. A200. The LinkerAof any one of embodiments A1-A193, wherein R16is -S(O)-. A201. The LinkerAof any one of embodiments A1-A193, wherein R16is -S(O)2-. A202. The LinkerAof any one of embodiments A1-A193, wherein R16is -C(R21R21)-. A203. The LinkerA of embodiment A202, wherein both R21groups are hydrogen. A204. The LinkerAof any one of embodiments A1-A193, wherein R16is -CH2CH2-[O- (CH2)2]n-O-. A205. The LinkerAof any one of embodiments A1-A193, wherein R16is aryl. A206. The LinkerAof embodiment A205, wherein R16is phenyl. A207. The LinkerAof embodiment A205, wherein R16is naphthyl. A208. The LinkerAof any one of embodiments A1-A193, wherein R16is heterocycle. A209. The LinkerAof embodiment A208, wherein R16is piperidinyl. A210. The LinkerAof embodiment A209, wherein R16is A211. The LinkerAof embodiment A209, wherein R16is A212. The LinkerAof embodiment A208, wherein R16is piperizinyl. A213. The LinkerAof embodiment A212, wherein R16is A214. The LinkerAof embodiment A208, wherein R16is pyrrolidinyl. A215. The LinkerAof embodiment A214, wherein R16is A216. The LinkerAof embodiment A214, wherein R16is A217. The LinkerAof any one of embodiments A1-A193, wherein R16is heteroaryl. A218. The LinkerAof embodiment A217, wherein R16is pyridinyl. A219. The LinkerAof embodiment A218, wherein R16is A220. The LinkerAof embodiment A218, wherein R16is A221. The LinkerAof embodiment A218, wherein R16is A222. The LinkerAof embodiment A217, wherein R16is pyrimidinyl. A223. The LinkerAof embodiment A222, wherein R16is A224. The LinkerAof embodiment A222, wherein R16is A225. The LinkerAof embodiment A217, wherein R16is pyrazinyl. A226. The LinkerAof embodiment A225, wherein R16is A227. The LinkerAof embodiment A225, wherein R16is A228. The LinkerAof embodiment A217, wherein R16is pyridizinyl. A229. The LinkerAof embodiment A228, wherein R16is A230. The LinkerAof embodiment A228, wherein R16is A231. The LinkerAof any one of embodiments A1-A193, wherein R16is alkynyl. A232. The LinkerAof any one of embodiments A1-A193, wherein R16is alkoxy. A233. The LinkerAof any one of embodiments A1-A232, wherein R17is bond. A234. The LinkerAof any one of embodiments A1-A232, wherein R17is alkyl. A235. The LinkerAof any one of embodiments A1-A232, wherein R17is -C(O)-. A236. The LinkerAof any one of embodiments A1-A232, wherein R17is -C(O)O-. A237. The LinkerAof any one of embodiments A1-A232, wherein R17is -C(O)NR6-. A238. The LinkerAof any one of embodiments A1-A232, wherein R17is -NR6C(O)-. A239. The LinkerAof any one of embodiments A1-A232, wherein R17is -NR6-. A240. The LinkerAof any one of embodiments A1-A232, wherein R17is -O-. A241. The LinkerAof any one of embodiments A1-A232, wherein R17is -C(R21R21)-. A242. The LinkerA of embodiment A241, wherein both R21groups are hydrogen. A243. The LinkerAof any one of embodiments A1-A232, wherein R17is -CH2CH2-[O- (CH2)2]n-O-. A244. The LinkerAof any one of embodiments A1-A232, wherein R17is aryl. A245. The LinkerAof embodiment A244, wherein R17is phenyl. A246. The LinkerAof embodiment A244, wherein R17is naphthyl. A247. The LinkerAof any one of embodiments A1-A232, wherein R17is heterocycle. A248. The LinkerAof embodiment A247, wherein R17is piperidinyl. A249. The LinkerAof embodiment A248, wherein R17is A250. The LinkerAof embodiment A248, wherein R17is A251. The LinkerAof embodiment A247, wherein R17is piperizinyl. A252. The LinkerAof embodiment A251, wherein R17is A253. The LinkerAof embodiment A247, wherein R17is pyrrolidinyl. A254. The LinkerAof embodiment A253, wherein R17is A255. The LinkerAof embodiment A253, wherein R17is A256. The LinkerAof any one of embodiments A1-A232, wherein R17is heteroaryl. A257. The LinkerAof embodiment A256, wherein R17is pyridinyl. A258. The LinkerAof embodiment A257, wherein R17is A259. The LinkerAof embodiment A257, wherein R17is A260. The LinkerAof embodiment A257, wherein R17is A261. The LinkerAof embodiment A256, wherein R17is pyrimidinyl. A262. The LinkerAof embodiment A261, wherein R17is A263. The LinkerAof embodiment A261, wherein R17is A264. The LinkerAof embodiment A256, wherein R17is pyrazinyl. A265. The LinkerAof embodiment A264, wherein R17is A266. The LinkerAof embodiment A264, wherein R17is A267. The LinkerAof embodiment A256, wherein R17is pyridizinyl. A268. The LinkerAof embodiment A267, wherein R17is A269. The LinkerAof embodiment A267, wherein R17is A270. The LinkerAof any one of embodiments A1-A232, wherein R17is alkynyl. A271. The LinkerAof any one of embodiments A1-A232, wherein R17is alkoxy. A272. The LinkerAof any one of embodiments A1-A271, wherein R18is bond. A273. The LinkerAof any one of embodiments A1-A271, wherein R18is alkyl. A274. The LinkerAof any one of embodiments A1-A271, wherein R18is -C(O)-. A275. The LinkerAof any one of embodiments A1-A271, wherein R18is -C(O)O-. A276. The LinkerAof any one of embodiments A1-A271, wherein R18is -C(O)NR6-. A277. The LinkerAof any one of embodiments A1-A271, wherein R18is -NR6C(O)-. A278. The LinkerAof any one of embodiments A1-A271, wherein R18is -S(O)-. A279. The LinkerAof any one of embodiments A1-A271, wherein R18is -S(O)2-. A280. The LinkerAof any one of embodiments A1-A271, wherein R18is -C(R21R21)-. A281. The LinkerA of embodiment A280, wherein both R21groups are hydrogen. A282. The LinkerAof any one of embodiments A1-A271, wherein R18is -CH2CH2-[O- (CH2)2]n-O-. A283. The LinkerAof any one of embodiments A1-A271, wherein R18is aryl. A284. The LinkerAof embodiment A283, wherein R18is phenyl. A285. The LinkerAof embodiment A283, wherein R18is naphthyl. A286. The LinkerAof any one of embodiments A1-A271, wherein R18is heterocycle. A287. The LinkerAof embodiment A286, wherein R18is piperidinyl. A288. The LinkerAof embodiment A287, wherein R18is A289. The LinkerAof embodiment A287, wherein R18is A290. The LinkerAof embodiment A286, wherein R18is piperizinyl. A291. The LinkerAof embodiment A290, wherein R18is A292. The LinkerAof embodiment A286, wherein R18is pyrrolidinyl. A293. The LinkerAof embodiment A292, wherein R18is A294. The LinkerAof embodiment A292, wherein R18is A295. The LinkerAof any one of embodiments A1-A271, wherein R18is heteroaryl. A296. The LinkerAof embodiment A295, wherein R18is pyridinyl. A297. The LinkerAof embodiment A296, wherein R18is A298. The LinkerAof embodiment A296, wherein R18is A299. The LinkerAof embodiment A296, wherein R18is A300. The LinkerAof embodiment A295, wherein R18is pyrimidinyl. A301. The LinkerAof embodiment A300, wherein R18is A302. The LinkerAof embodiment A300, wherein R18is A303. The LinkerAof embodiment A295, wherein R18is pyrazinyl. A304. The LinkerAof embodiment A303, wherein R18is A305. The LinkerAof embodiment A303, wherein R18is A306. The LinkerAof embodiment A295, wherein R18is pyridizinyl. A307. The LinkerAof embodiment A306, wherein R18is A308. The LinkerAof embodiment A306, wherein R18is A309. The LinkerAof any one of embodiments A1-A271, wherein R18is alkynyl. A310. The LinkerAof any one of embodiments A1-A271, wherein R18is alkoxy. A311. The LinkerAof any one of embodiments A1-A310, wherein R19is bond. A312. The LinkerAof any one of embodiments A1-A310, wherein R19is alkyl. A313. The LinkerAof any one of embodiments A1-A310, wherein R19is -C(O)-. A314. The LinkerAof any one of embodiments A1-A310, wherein R19is -C(O)O-. A315. The LinkerAof any one of embodiments A1-A310, wherein R19is -C(O)NR6-. A316. The LinkerAof any one of embodiments A1-A310, wherein R19is -NR6C(O)-. A317. The LinkerAof any one of embodiments A1-A310, wherein R19is -NR6-. A318. The LinkerAof any one of embodiments A1-A310, wherein R19is -O-. A319. The LinkerAof any one of embodiments A1-A310, wherein R19is -C(R21R21)-. A320. The LinkerA of embodiment A319, wherein both R21groups are hydrogen. A321. The LinkerAof any one of embodiments A1-A310, wherein R19is -CH2CH2-[O- (CH2)2]n-O-. A322. The LinkerAof any one of embodiments A1-A310, wherein R19is aryl. A323. The LinkerAof embodiment A322, wherein R19is phenyl. A324. The LinkerAof embodiment A322, wherein R19is naphthyl. A325. The LinkerAof any one of embodiments A1-A310, wherein R19is heterocycle. A326. The LinkerAof embodiment A325, wherein R19is piperidinyl. A327. The LinkerAof embodiment A326, wherein R19is A328. The LinkerAof embodiment A326, wherein R19is A329. The LinkerAof embodiment A325, wherein R19is piperizinyl. A330. The LinkerAof embodiment A329, wherein R19is A331. The LinkerAof embodiment A325, wherein R19is pyrrolidinyl. A332. The LinkerAof embodiment A331, wherein R19is A333. The LinkerAof embodiment A331, wherein R19is A334. The LinkerAof any one of embodiments A1-A310, wherein R19is heteroaryl. A335. The LinkerAof embodiment A334, wherein R19is pyridinyl. A336. The LinkerAof embodiment A335, wherein R19is A337. The LinkerAof embodiment A335, wherein R19is A338. The LinkerAof embodiment A335, wherein R19is A339. The LinkerAof embodiment A334, wherein R19is pyrimidinyl. A340. The LinkerAof embodiment A339, wherein R19is A341. The LinkerAof embodiment A339, wherein R19is A342. The LinkerAof embodiment A334, wherein R19is pyrazinyl. A343. The LinkerAof embodiment A342, wherein R19is A344. The LinkerAof embodiment A342, wherein R19is A345. The LinkerAof embodiment A334, wherein R19is pyridizinyl. A346. The LinkerAof embodiment A345, wherein R19is A347. The LinkerAof embodiment A345, wherein R19is A348. The LinkerAof any one of embodiments A1-A310, wherein R19is alkynyl. A349. The LinkerAof any one of embodiments A1-A310, wherein R19is alkoxy. A350. The LinkerAof any one of embodiments A1-A349, wherein R20is bond. A351. The LinkerAof any one of embodiments A1-A349, wherein R20is alkyl. A352. The LinkerAof any one of embodiments A1-A349, wherein R20is -C(O)-. A353. The LinkerAof any one of embodiments A1-A349, wherein R20is -C(O)O-. A354. The LinkerAof any one of embodiments A1-A349, wherein R20is -C(O)NR6-. A355. The LinkerAof any one of embodiments A1-A349, wherein R20is -NR6C(O)-. A356. The LinkerAof any one of embodiments A1-A349, wherein R20is -S(O)-. A357. The LinkerAof any one of embodiments A1-A349, wherein R20is -S(O)2-. A358. The LinkerAof any one of embodiments A1-A349, wherein R20is -C(R21R21)-. A359. The LinkerA of embodiment A358, wherein both R21groups are hydrogen. A360. The LinkerAof any one of embodiments A1-A349, wherein R20is -CH2CH2-[O- (CH2)2]n-O-. A361. The LinkerAof any one of embodiments A1-A349, wherein R20is aryl. A362. The LinkerAof embodiment A361, wherein R20is phenyl. A363. The LinkerAof embodiment A361, wherein R20is naphthyl. A364. The LinkerAof any one of embodiments A1-A349, wherein R20is heterocycle. A365. The LinkerAof embodiment A364, wherein R20is piperidinyl. A366. The LinkerAof embodiment A364, wherein R20is A367. The LinkerAof embodiment A364, wherein R20is A368. The LinkerAof embodiment A364, wherein R20is piperizinyl. A369. The LinkerAof embodiment A364, wherein R20is . A370. The LinkerAof embodiment A364, wherein R20is pyrrolidinyl. A371. The LinkerAof embodiment A364, wherein R20is A372. The LinkerAof embodiment A364, wherein R20is A373. The LinkerAof any one of embodiments A1-A349, wherein R20is heteroaryl. A374. The LinkerAof embodiment A373, wherein R20is pyridinyl. A375. The LinkerAof embodiment A373, wherein R20is A376. The LinkerAof embodiment A373, wherein R20is A377. The LinkerAof embodiment A373, wherein R20is A378. The LinkerAof embodiment A373, wherein R20is pyrimidinyl. A379. The LinkerAof embodiment A373, wherein R20is A380. The LinkerAof embodiment A373, wherein R20is A381. The LinkerAof embodiment A373, wherein R20is pyrazinyl. A382. The LinkerAof embodiment A373, wherein R20is A383. The LinkerAof embodiment A373, wherein R20is A384. The LinkerAof embodiment A373, wherein R20is pyridizinyl. A385. The LinkerAof embodiment A373, wherein R20is A386. The LinkerAof embodiment A373, wherein R20is A387. The LinkerAof any one of embodiments A1-A349, wherein R20is alkynyl. A388. The LinkerAof any one of embodiments A1-A349, wherein R20is alkoxy. A389. The LinkerAof any one of embodiments A1-A388, wherein R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with two R21substituents, wherein the substituents are selected such that a stable compound results. A390. The LinkerAof any one of embodiments A1-A388, wherein R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with three R21substituents, wherein the substituents are selected such that a stable compound results. A391. The LinkerAof any one of embodiments A1-A388, wherein R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with four R21substituents, wherein the substituents are selected such that a stable compound results. A392. The LinkerAof any one of embodiments A1-A388, wherein R11, R12, R13, R14, R15, R16, R17, R18, R19, or R20is substituted with one R21substituent. A393. The LinkerAof any one of embodiments A1-A392, wherein R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, amino, -NR6R7, haloalkyl, aryl, heteroaryl, and heterocycle. A394. The LinkerAof any one of embodiments A1-A393, R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, F, hydroxyl, alkoxy, amino, -NR6R7, haloalkyl, aryl, heteroaryl, and heterocycle. A395. The LinkerAof any one of embodiments A1-A394, R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, F, hydroxyl, alkoxy, amino, -NR6R7, and haloalkyl. A396. The LinkerAof any one of embodiments A1-A391, wherein one of the R21groups is hydrogen. A397. The LinkerAof any one of embodiments A1-A391, wherein one of the R21groups is fluorine. A398. The LinkerAof any one of embodiments A1-A391, wherein one of the R21groups is alkyl. A399. The LinkerAof embodiment A398, wherein one of the R21groups is methyl. A400. The LinkerAof embodiment A398, wherein one of the R21groups is ethyl. A401. The LinkerAof embodiment A398, wherein one of the R21groups is isopropyl. A402. The LinkerAof any one of embodiments A1-A391, wherein one of the R21groups is hydroxyl. A403. The LinkerAof any one of embodiments A1-A391, wherein one of the R21groups is -NR6R7. A404. The LinkerAof embodiment A403, wherein one of the R21groups is dimethylamino. A405. The LinkerAof any one of embodiments A1-A391 and A393-A398, wherein a second R21group is hydrogen. A406. The LinkerAof any one of embodiments A1-A391 and A393-A398, wherein a second R21group is fluorine. A407. The LinkerAof any one of embodiments A1-A391 and A393-A398, wherein a second R21group is alkyl. A408. The LinkerAof any one of embodiments A1-A388 and A390-A391, wherein a third R21is hydrogen. A409. The LinkerAof any one of embodiments A1-A388 and A390-A391, wherein a third R21is fluorine. A410. The LinkerAof any one of embodiments A1-A388 and A390-A391, wherein a third R21is alkyl. A411. The LinkerAof any one of embodiments A1-A388 and A391, wherein a fourth R21is hydrogen In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments LinkerAis selected from: each of which is optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein. In certain embodiments LinkerAis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerAis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerAis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerBis selected from:

[0059] In certain embodiments LinkerBis selected from:

[0060] In certain embodiments LinkerB, LinkerC, or LinkerDis selected from: , wherein tt is independently selected from 1, 2, or 3 and ss is 3 minus tt. In certain embodiments LinkerB, LinkerC, or LinkerDis selected from: , wherein tt and ss are as defined herein. In certain embodiments LinkerB, LinkerC, or LinkerDis selected from:

[0061] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein. In certain embodiments LinkerB, LinkerC, or LinkerDis selected from:

[0062] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein. In certain embodiments LinkerB, LinkerC, or LinkerDis selected from: wherein each heteroaryl and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein. In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from:

[0063] . In certain embodiments LinkerBis selected from:

[0064] In certain embodiments LinkerBis selected from:

[0065] In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: a d . In certain embodiments LinkerCis selected from:

[0066] In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from:

[0067] . In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: . In certain embodiments LinkerCis selected from:

[0068] In certain embodiments LinkerDis selected from:

[0069] In certain embodiments LinkerDis selected from:

[0070] In certain embodiments LinkerDis selected from: In certain embodiments LinkerDis selected from: In certain embodiments LinkerDis selected from: In certain embodiments LinkerDis selected from: In certain embodiments LinkerDis selected from:

[0071]

[0072] In certain embodiments, the LinkerAis selected from

[0073] In certain embodiments, the LinkerAis selected from

[0074] In certain embodiments, the LinkerAis selected from

[0075] In certain embodiments, the LinkerAis selected from

[0076] wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21. In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from: In certain embodiments LinkerAis selected from:

[0077] . In certain embodiments LinkerAis selected from:

[0078] . In certain embodiments LinkerAis selected from: . In certain embodiments LinkerAis selected from: . In certain embodiments LinkerAis selected from: . In certain embodiments LinkerAis selected from: . In certain embodiments LinkerAis selected from: . In certain embodiments LinkerAis selected from: . In certain embodiments, the LinkerBis selected from . In certain embodiments, the LinkerBis selected from . In certain embodiments, the LinkerBis selected from wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21. In certain embodiments LinkerBis selected from: , In certain embodiments LinkerBis selected from: . In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments LinkerB-LinkerAis selected from: In certain embodiments LinkerB-LinkerAis selected from: In certain embodiments, LinkerCis selected from . In certain embodiments, LinkerCis selected from In certain embodiments, LinkerCis selected from In certain embodiments, LinkerCis selected from

[0079] . In certain embodiments, LinkerCis selected from

[0080] In certain embodiments, LinkerCis selected from wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21. In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: . In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: In certain embodiments LinkerCis selected from: In certain embodiments LinkerC-(LinkerA)2is selected from: In certain embodiments LinkerC-(LinkerA)2is selected from: In certain embodiments LinkerC-(LinkerA)2is selected from: In certain embodiments LinkerC-(LinkerA)2is selected from: In certain embodiments, the LinkerDis selected from . In certain embodiments, the LinkerDis selected from In certain embodiments, the LinkerDis selected from

[0081] wherein each is optionally substituted with 1, 2, 3, or 4 substituents are selected from R21. In certain embodiments, LinkerB-(LinkerA) is selected from . In certain embodiments, LinkerC-(LinkerA) is selected from

[0082]

[0083] In certain embodiments, LinkerD-(LinkerA) is selected from In certain embodiments LinkerBis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerBis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerBis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerB, LinkerC, or LinkerDis selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments LinkerAis selected from: , . In certain embodiments LinkerAis selected from: , each of which is substituted with 1 or 2 optional substituents. In certain embodiments LinkerAis bond. In certain embodiments the left side of LinkerAis attached to the ASGPR Binding Ligand and the right side is attached to LinkerB, LinkerC, or LinkerD. In certain embodiments the right side of LinkerAis attached to the ASGPR Binding Ligand and the right side is attached to LinkerB, LinkerC, or LinkerD. In certain embodiments LinkerBis selected from: In certain embodiments LinkerBis selected from: In certain embodiments the left side of LinkerBis attached to the Extracellular Targeting Ligand and the right side is attached to LinkerA. In certain embodiments the right side of LinkerBis attached to the Extracellular Targeting Ligand and the left side is attached to LinkerA. In certain embodiments LinkerBis bond. In alternative embodiments a linker is provided as described above wherein a is replaced with a , for example where LinkerBis drawn as it is in this embodiment. In alternative embodiments a linker is provided as described above wherein a is replaced with a , for example where LinkerBis drawn as it is in this embodiment. In alternative embodiments a linker is provided as described above wherein a is replaced with a Additional Embodiments of Linker In certain embodiments, the linker includes at least a linear group comprising groups selected from alkyl, amide, disulfide, polyethylene glycol, ether, thioether (-S-) and hydroxylamino (-O-N(H)-) groups. In certain embodiments, the linear group comprises groups selected from alkyl, amide and ether groups. In certain embodiments, the linear group comprises groups selected from alkyl and ether groups. In certain embodiments, the linear group comprises 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, LinkerBis selected from: . In certain embodiments, LinkerBis selected from: wherein each L2is independently a phosphorus linking group or a neutral linking group. In certain embodiments, LinkerBis selected from:

[0084] In certain embodiments, LinkerBis selected from:

[0085] In certain embodiments, LinkerCis selected from: . In certain embodiments, LinkerCis selected from:

[0086] . In certain embodiments, LinkerCis selected from:

[0087] wherein each n is independently selected from 1 to 20, X2is O or S, and p is from 1 to 6.

[0088] In certain embodiments, LinkerCis selected from: . In certain embodiments, LinkerCis selected from: In certain embodiments, LinkerDis selected from:

[0089] In certain embodiments, LinkerDis selected from:

[0090] . In certain embodiments, LinkerDis selected from:

[0091] . In certain embodiments n is independently 0, 1, 2, 3, 4, 5, 6, or 7. In certain embodiments n is 1. In certain embodiments n is 2. In certain embodiments n is 3. In certain embodiments n is 4. In certain embodiments n is 5. In certain embodiments n is 6. In certain embodiments n is 7. Embodiments of ASGPR Binding Ligand In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain embodiments ASGPR Binding Ligand is of Formula: . In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof. In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof. In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof. In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof. In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof. In certain aspects the Therapeutic Oligonucleotide delivering compound is of Formula or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments ASGPR Binding Ligand is of Formula: wherein R* is selected from: In certain embodiments the ASGPR Binding Ligand is of Formula: In certain embodiments R*is selected from: Non limiting examples of R* include: , , , In certain embodiments, ASGPR Binding Ligand is selected from

[0093] 

[0094] In certain embodiments, ASGPR Binding Ligand is selected from . In certain embodiments, ASGPR Binding Ligand is selected from: . In certain embodiments the Therapeutic Oligonucleotide delivering compound is selected from: Additional Embodiments of the ASGPR Binding Ligand In certain embodiments, R1is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0- C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3. In certain embodiments, R1is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl- S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-O-C(O)R3, and C0- C6alkyl-O-S(O)R3. In certain embodiments, R1is selected from hydrogen, alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)- C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-O-C(O)R3, and C0-C6alkyl-O-S(O)R3. In certain embodiments, R1is selected from C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0- C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0- C0-C6alkyl-N(R8)-S(O)2R3, C0- C6alkylO-C(O)R3, C0-C6alkyl-O-S(O)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3. In certain embodiments, R5is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0- C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3. In certain embodiments, R5is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl- S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-O-C(O)R3, and C0- C6alkyl-O-S(O)R3. In certain embodiments, R5is selected from hydrogen, alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)- C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-O-C(O)R3, and C0-C6alkyl-O-S(O)R3. In certain embodiments, R5is selected from C2-C6alkyl-cyano, C2-C6alkyl-OR6, C0- C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0- C0-C6alkyl-N(R8)-S(O)2R3, C0- C6alkylO-C(O)R3, C0-C6alkyl-O-S(O)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3. In certain embodiments, R3at each occurrence is independently selected from the group consisting of alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9. In certain embodiments, R3at each occurrence is independently selected from the group consisting of alkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocycle, -OR8, and - NR8R9. In certain embodiments, R3at each occurrence is independently selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9. In certain embodiments, R3at each occurrence is independently selected from the group consisting of -OR8and -NR8R9. In certain embodiments, R3at each occurrence is independently selected from the group consisting of alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R6and R7are independently selected at each occurrence from the group consisting of alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3. In certain embodiments, R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, and heterocycle. In certain embodiments, R6and R7are independently selected at each occurrence from the group consisting of C(O)R3, S(O)R3, C(S)R3, and S(O)2R3. In certain embodiments, R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3. In certain embodiments, R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R8and R9are independently selected at each occurrence from alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R8and R9are independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, and heterocycle. In certain embodiments, R10is hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3. In certain embodiments, R10is alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3. In certain embodiments, R10is hydrogen, alkyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3. In certain embodiments, R10is hydrogen, alkyl, aryl, heteroaryl, or heterocycle. In certain embodiments, R10is hydrogen, alkyl, or aryl. In certain embodiments, R10is C(O)R3, S(O)R3, C(S)R3, or S(O)2R3. In certain embodiments, R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, haloalkyl, F, Cl, Br, I, heterocycle, C0- C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl- N(R8)-S(O)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80. In certain embodiments, R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, haloalkyl, F, Cl, Br, I, heterocycle, C0- C6alkyl-C(O)R3, C0-C6alkyl-N(R8)-C(O)R3, and C0-C6alkyl-O-C(O)R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80. In certain embodiments, R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, cyano, haloalkyl, F, Cl, Br, I, heterocycle, -C(O)R3, -N(R8)-C(O)R3, -O-C(O)R3, and -O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80. In certain embodiments, R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C2-C4alkyl-cyano, haloalkyl, F, Cl, Br, I, heterocycle, C2- C4alkyl-C(O)R3, C2-C4alkyl-N(R8)-C(O)R3, and C2-C4alkyl-O-C(O)R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80. In certain embodiments, R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, haloalkyl, F, and Cl. In certain embodiments, R80is independently selected at each instance from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3. In certain embodiments, R80is independently selected at each instance from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3. In certain embodiments, R80is independently selected at each instance from the group consisting of C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, C1-C4haloalkyl, -OR6, F, Cl, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3. In certain embodiments, R80is independently selected at each instance from the group consisting of C1-C4alkyl, C1-C4haloalkyl, -OR6, F, Cl, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3. In certain embodiments, R80is independently selected at each instance from the group consisting of C1-C4alkyl, C1-C4haloalkyl, -OR6, F, Cl, -NR6R7, heterocycle, heteroaryl, and aryl. Embodiments of R1In certain embodiments R1is hydrogen. In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is In certain embodiments R1is C0-C6alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is alkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is F. In certain embodiments R1is Cl. In certain embodiments R1is Br. In certain embodiments R1is aryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is heterocycle optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R1is -O-alkenyl, -O-alkynyl, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents. Embodiments of R3In certain embodiments R3is hydrogen or alkyl. In certain embodiments R3is hydrogen. In certain embodiments R3is alkyl. In certain embodiments R3is haloalkyl. In certain embodiments R3is arylalkyl. In certain embodiments R3is heteroarylalkyl. In certain embodiments R3is alkenyl. In certain embodiments R3is alkynyl. In certain embodiments R3is aryl. In certain embodiments R3is phenyl. In certain embodiments R3is heteroaryl. In certain embodiments R3is pyridine. In certain embodiments R3is heterocycle. In certain embodiments R3is -OR8. In certain embodiments R3is -OH. In certain embodiments R3is -NR8R9. In certain embodiments R3is -NH2. Embodiments of R5In certain embodiments R5is hydrogen. In certain embodiments R5is In certain embodiments R5is In certain embodiments R5is In certain embodiments R5is In certain embodiments R5is In certain embodiments R5is In certain embodiments R5is C0-C6alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is alkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is F. In certain embodiments R5is Cl. In certain embodiments R5is Br. In certain embodiments R5is aryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is heterocycle optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments R5is -O-alkenyl, -O-alkynyl, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents. Embodiments of R6and R7In certain embodiments R6and R7are independently selected from hydrogen and alkyl. In certain embodiments R6is C(O)Me and R7is H. In certain embodiments R6is hydrogen. In certain embodiments R6is alkyl. In certain embodiments R6is methyl. In certain embodiments R6is ethyl. In certain embodiments R6is arylalkyl. In certain embodiments R6is benzyl. In certain embodiments R6is heteroarylalkyl. In certain embodiments R6is alkenyl. In certain embodiments R6is alkynyl. In certain embodiments R6is aryl. In certain embodiments R6is phenyl. In certain embodiments R6is arylalkyl. In certain embodiments R6is haloalkyl. In certain embodiments R6is trifluoromethyl. In certain embodiments R6is heteroaryl. In certain embodiments R6is heterocycle. In certain embodiments R6is -alkyl-OR8. In certain embodiments R6is -alkyl-NR8R9. In certain embodiments R6is C(O)R3. In certain embodiments R6is C(O)Me. In certain embodiments R6is S(O)R3. In certain embodiments R6is C(S)R3. In certain embodiments R6is S(O)2R3. In certain embodiments R7is hydrogen. In certain embodiments R7is alkyl. In certain embodiments R7is methyl. In certain embodiments R7is ethyl. In certain embodiments R7is arylalkyl. In certain embodiments R7is benzyl. In certain embodiments R7is heteroarylalkyl. In certain embodiments R7is alkenyl. In certain embodiments R7is alkynyl. In certain embodiments R7is aryl. In certain embodiments R7is phenyl. In certain embodiments R7is arylalkyl. In certain embodiments R7is haloalkyl. In certain embodiments R7is trifluoromethyl. In certain embodiments R7is heteroaryl. In certain embodiments R7is heterocycle. In certain embodiments R7is -alkyl-OR8. In certain embodiments R7is -alkyl-NR8R9. In certain embodiments R7is C(O)R3. In certain embodiments R7is C(O)Me. In certain embodiments R7is S(O)R3. In certain embodiments R7is C(S)R3. In certain embodiments R7is S(O)2R3. Embodiments of R8and R9In certain embodiments R8and R9are independently selected from hydrogen and alkyl. In certain embodiments R8is hydrogen. In certain embodiments R8is alkyl. In certain embodiments R8is methyl. In certain embodiments R8is ethyl. In certain embodiments R8is arylalkyl. In certain embodiments R8is benzyl. In certain embodiments R8is heteroarylalkyl. In certain embodiments R8is alkenyl. In certain embodiments R8is alkynyl. In certain embodiments R8is aryl. In certain embodiments R8is phenyl. In certain embodiments R8is arylalkyl. In certain embodiments R8is haloalkyl. In certain embodiments R8is trifluoromethyl. In certain embodiments R8is heteroaryl. In certain embodiments R8is heterocycle. In certain embodiments R9is hydrogen. In certain embodiments R9is alkyl. In certain embodiments R9is methyl. In certain embodiments R9is ethyl. In certain embodiments R9is arylalkyl. In certain embodiments R9is benzyl. In certain embodiments R9is heteroarylalkyl. In certain embodiments R9is alkenyl. In certain embodiments R9is alkynyl. In certain embodiments R9is aryl. In certain embodiments R9is phenyl. In certain embodiments R9is arylalkyl. In certain embodiments R9is haloalkyl. In certain embodiments R9is trifluoromethyl. In certain embodiments R9is heteroaryl. In certain embodiments R9is heterocycle. Embodiments of R10In certain embodiments R10is hydrogen. In certain embodiments R10is alkyl. In certain embodiments R10is haloalkyl. In certain embodiments R10is C(O)R3. Embodiments of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20In certain embodiments R11is bond. In certain embodiments R11is alkyl. In certain embodiments R11is C(O). In certain embodiments R11is -C(O)O-. In certain embodiments R11is -C(O)NR6-. In certain embodiments R11is -O-. In certain embodiments R11is -NR6-. In certain embodiments R11is a divalent residue of a natural amino acid. In certain embodiments R11is a divalent residue of an unnatural amino acid. In certain embodiments R11is -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments R11is -CH2CH2-[O-(CH2)2]n-NR6-. In certain embodiments R11is -CH2CH2-[O-(CH2)2]n-. In certain embodiments R12is bond. In certain embodiments R12is alkyl. In certain embodiments R12is a divalent residue of a natural amino acid. In certain embodiments R12is a divalent residue of an unnatural amino acid. In certain embodiments R13is bond. In certain embodiments R13is alkyl. In certain embodiments R13is C(O). In certain embodiments R13is -C(O)O-. In certain embodiments R13is -C(O)NR6-. In certain embodiments R13is -O-. In certain embodiments R13is -NR6-. In certain embodiments R13is a divalent residue of a natural amino acid. In certain embodiments R13is a divalent residue of an unnatural amino acid. In certain embodiments R13is -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments R13is -CH2CH2-[O-(CH2)2]n-NR6-. In certain embodiments R13is -CH2CH2-[O-(CH2)2]n-. In certain embodiments R14is bond. In certain embodiments R14is alkyl. In certain embodiments R14is a divalent residue of a natural amino acid. In certain embodiments R14is a divalent residue of an unnatural amino acid. In certain embodiments R15is bond. In certain embodiments R15is alkyl. In certain embodiments R15is C(O). In certain embodiments R15is -C(O)O-. In certain embodiments R15is -C(O)NR6-. In certain embodiments R15is -O-. In certain embodiments R15is -NR6-. In certain embodiments R15is a divalent residue of a natural amino acid. In certain embodiments R15is a divalent residue of an unnatural amino acid. In certain embodiments R15is -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments R15is -CH2CH2-[O-(CH2)2]n-NR6-. In certain embodiments R15is -CH2CH2-[O-(CH2)2]n-. In certain embodiments R16is bond. In certain embodiments R16is alkyl. In certain embodiments R16is a divalent residue of a natural amino acid. In certain embodiments R16is a divalent residue of an unnatural amino acid. In certain embodiments R17is bond. In certain embodiments R17is alkyl. In certain embodiments R17is C(O). In certain embodiments R17is -C(O)O-. In certain embodiments R17is -C(O)NR6-. In certain embodiments R17is -O-. In certain embodiments R17is -NR6-. In certain embodiments R17is a divalent residue of a natural amino acid. In certain embodiments R17is a divalent residue of an unnatural amino acid. In certain embodiments R17is -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments R17is -CH2CH2-[O-(CH2)2]n-NR6-. In certain embodiments R17is -CH2CH2-[O-(CH2)2]n-. In certain embodiments R18is bond. In certain embodiments R18is alkyl. In certain embodiments R18is a divalent residue of a natural amino acid. In certain embodiments R18is a divalent residue of an unnatural amino acid. In certain embodiments R19is bond. In certain embodiments R19is alkyl. In certain embodiments R19is C(O). In certain embodiments R19is -C(O)O-. In certain embodiments R19is -C(O)NR6-. In certain embodiments R19is -O-. In certain embodiments R19is -NR6-. In certain embodiments R19is a divalent residue of a natural amino acid. In certain embodiments R19is a divalent residue of an unnatural amino acid. In certain embodiments R19is -CH2CH2-[O-(CH2)2]n-O-. In certain embodiments R19is -CH2CH2-[O-(CH2)2]n-NR6-. In certain embodiments R19is -CH2CH2-[O-(CH2)2]n-. In certain embodiments R20is bond. In certain embodiments R20is alkyl. In certain embodiments R20is a divalent residue of a natural amino acid. In certain embodiments R20is a divalent residue of an unnatural amino acid. In certain embodiments n is 0. In certain embodiments n is 1. In certain embodiments n is 2. In certain embodiments n is 3. In certain embodiments n is 4. In certain embodiments n is 5. In certain embodiments n is 6. In certain embodiments n is 7. In certain embodiments n is 8. In certain embodiments n is 9. In certain embodiments n is 10. Embodiments of R21In certain embodiments R21is hydrogen. In certain embodiments R21is alkyl. In certain embodiments R21is methyl. In certain embodiments R21is F. In certain embodiments R21is Cl. In certain embodiments R21is haloalkyl. In certain embodiments R21is C(O)R3. In certain embodiments R21is NH2. In certain embodiments R21is OH. Embodiments of R22In certain embodiments R22is alkyl. In certain embodiments R22is -C(O)N-. In certain embodiments R22is -NC(O)-. In certain embodiments R22is -N-. In certain embodiments R22is -C(R21)-. In certain embodiments R22is -P(O)O-. In certain embodiments R22is -P(O)-. In certain embodiments R22is -P(O)(NR6R7)N-. In certain embodiments R22is alkenyl. In certain embodiments R22is haloalkyl. In certain embodiments R22is aryl. In certain embodiments R22is heterocycle. In certain embodiments R22is heteroaryl. Embodiments of R32In certain embodiments R32is alkyl. In certain embodiments R32is N+X-. In certain embodiments R32is -C-. In certain embodiments R32is alkenyl. In certain embodiments R32is haloalkyl. In certain embodiments R32is aryl. In certain embodiments R32is heterocycle. In certain embodiments R32is heteroaryl. In certain embodiments X- is Br-. or;In certain embodiments X- is Cl-. Embodiments of R42In certain embodiments R42is hydrogen. In certain embodiments R42is alkyl. In certain embodiments R42is alkyl-O-alkyl. In certain embodiments R42is C(O)R43. In certain embodiments R42is C(O)Me. Embodiments of R43In certain embodiments R43is hydrogen. In certain embodiments R43is alkyl. In certain embodiments R43is haloalkyl. Embodiments of R65, R66, and R67In certain embodiments R65, R66, and R67are independently selected from hydrogen, halogen, and haloalkyl. In certain embodiments R65is hydrogen. In certain embodiments R65is alkyl. In certain embodiments R65is methyl. In certain embodiments R65is halogen. In certain embodiments R65is F. In certain embodiments R65is Cl. In certain embodiments R65is haloalkyl. In certain embodiments R65is CF3. In certain embodiments R65is OMe. In certain embodiments R65is OH. In certain embodiments R65is NH2. In certain embodiments R65is NHMe. In certain embodiments R65is NMe2. In certain embodiments R65is heterocycle. In certain embodiments R66is hydrogen. In certain embodiments R66is alkyl. In certain embodiments R66is methyl. In certain embodiments R66is halogen. In certain embodiments R66is F. In certain embodiments R66is Cl. In certain embodiments R66is haloalkyl. In certain embodiments R66is CF3. In certain embodiments R66is OMe. In certain embodiments R66is OH. In certain embodiments R66is NH2. In certain embodiments R66is NHMe. In certain embodiments R66is NMe2. In certain embodiments R66is heterocycle. In certain embodiments R67is hydrogen. In certain embodiments R67is alkyl. In certain embodiments R67is methyl. In certain embodiments R67is halogen. In certain embodiments R67is F. In certain embodiments R67is Cl. In certain embodiments R67is haloalkyl. In certain embodiments R67is CF3. In certain embodiments R67is OMe. In certain embodiments R67is OH. In certain embodiments R67is NH2. In certain embodiments R67is NHMe. In certain embodiments R67is NMe2. In certain embodiments R67is heterocycle. Embodiments of R75and R76In certain embodiments R75and R76are independently selected from hydrogen, halogen, and haloalkyl. In certain embodiments R75is hydrogen. In certain embodiments R75is alkyl. In certain embodiments R75is methyl. In certain embodiments R75is halogen. In certain embodiments R75is F. In certain embodiments R75is Cl. In certain embodiments R75is haloalkyl. In certain embodiments R75is CF3. In certain embodiments R75is OMe. In certain embodiments R75is OH. In certain embodiments R75is NH2. In certain embodiments R75is NHMe. In certain embodiments R75is NMe2. In certain embodiments R75is heterocycle. In certain embodiments R76is hydrogen. In certain embodiments R76is alkyl. In certain embodiments R76is methyl. In certain embodiments R76is halogen. In certain embodiments R76is F. In certain embodiments R76is Cl. In certain embodiments R76is haloalkyl. In certain embodiments R76is CF3. In certain embodiments R76is OMe. In certain embodiments R76is OH. In certain embodiments R76is NH2. In certain embodiments R76is NHMe. In certain embodiments R76is NMe2. In certain embodiments R76is heterocycle. Embodiments of R80In certain embodiments R80is hydrogen. In certain embodiments R80is alkyl. In certain embodiments R80is methyl. In certain embodiments R80is halogen. In certain embodiments R80is F. In certain embodiments R80is Cl. In certain embodiments R80is haloalkyl. In certain embodiments R80is CF3. In certain embodiments R80is OMe. In certain embodiments R80is OH. In certain embodiments R80is NH2. In certain embodiments R80is NHMe. In certain embodiments R80is NMe2. In certain embodiments R80is -C(O)R3. Embodiments of R102In certain embodiments R102is hydrogen. In certain embodiments R102is alkyl. In certain embodiments R102is methyl. In certain embodiments R102is halogen. In certain embodiments R102is F. In certain embodiments R102is Cl. In certain embodiments R102is haloalkyl. In certain embodiments R102is CF3. In certain embodiments R102is OMe. In certain embodiments R102is OH. In certain embodiments R102is NH2. In certain embodiments R102is NHMe. In certain embodiments R102is NMe2. In certain embodiments R102is -C(O)R3. Embodiments of n, m, and p In certain embodiments nn is 0. In certain embodiments nn is 1. In certain embodiments nn is 2. In certain embodiments nn is 3. In certain embodiments m is 0. In certain embodiments m is 1. In certain embodiments m is 2. In certain embodiments m is 3. In certain embodiments p is 0. In certain embodiments p is 1. In certain embodiments p is 2. In certain embodiments p is 3.

[0095] Embodiments of ASGPR Binder B1. In certain embodiments a compound of Formula I, Formula II, or Formula III is provided wherein, the ASGPR Binding Ligand is selected from: wherein Q is -O- or -N(R10)-; R1and R5are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3; in certain embodiments R1is hydrogen; R2is hydrogen, alkyl, or C(O)R3; R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3; in certain embodiments R10is hydrogen; R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80; R80is independently selected at each instance from the group consisting of alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3; B2. The compound of embodiment B1, wherein the compound is selected from . B3. The compound of embodiment B1, wherein the compound is selected from . B4. The compound of any one of embodiments B1-B3, wherein R65is not substituted with an optional substituent. B5. The compound of any one of embodiments B1-B3, wherein R65is substituted with 1 optional substituent. B6. The compound of any one of embodiments B1-B3, wherein R65is substituted with 2 optional substituents. B7. The compound of any one of embodiments B1-B3, wherein R65is substituted with 3 optional substituents. B8. The compound of any one of embodiments B1-B3, wherein R65is hydrogen. B9. The compound of any one of embodiments B1-B3, wherein R65is -CF3. B10. The compound of any one of embodiments B1-B3, wherein R65is cyano. B11. The compound of any one of embodiments B1-B3, wherein R65is F. B12. The compound of any one of embodiments B1-B3, wherein R65is Cl. B13. The compound of any one of embodiments B1-B3, wherein R65is Br. B14. The compound of any one of embodiments B1-B7, wherein R65is haloalkyl. B15. The compound of any one of embodiments B1-B7, wherein R65is heterocycle. B16. The compound of any one of embodiments B1-B7, wherein R65is haloalkoxy. B17. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-OR6. B18. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-SR6. B19. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-NR6R7. B20. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl- C(O)R3. B21. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl- S(O)R3. B22. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl- C(S)R3. B23. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl- S(O)2R3. B24. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-N(R8)- C(O)R3. B25. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-N(R8)- S(O)R3. B26. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-N(R8)- C(S)R3. B27. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-N(R8)- S(O)2R3. B28. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkylN3. B29. The compound of any one of embodiments B1-B7, wherein R65is C0-C6alkyl-cyano. B30. The compound of any one of embodiments B17-B29, wherein C0-C6alkyl is C0-alkyl (i.e. bond). B31. The compound of any one of embodiments B17-B29, wherein C0-C6alkyl is C1-alkyl. B32. The compound of any one of embodiments B17-B29, wherein C0-C6alkyl is C2-alkyl. B33. The compound of any one of embodiments B1-B7, wherein R65is -N=S(O)(R3)2. B34. The compound of any one of embodiments B1-B7, wherein R65is heterocycloalkyl. B35. The compound of any one of embodiments B1-B7, wherein R65is aryl. B36. The compound of any one of embodiments B1-B35, wherein R66is not substituted with an optional substituent. B37. The compound of any one of embodiments B1-B35, wherein R66is substituted with 1 optional substituent. B38. The compound of any one of embodiments B1-B35, wherein R66is substituted with 2 optional substituents. B39. The compound of any one of embodiments B1-B35, wherein R66is substituted with 3 optional substituents. B40. The compound of any one of embodiments B1-B35, wherein R66is hydrogen. B41. The compound of any one of embodiments B1-B35, wherein R66is -CF3. B42. The compound of any one of embodiments B1-B35, wherein R66is cyano. B43. The compound of any one of embodiments B1-B35, wherein R66is F. B44. The compound of any one of embodiments B1-B35, wherein R66is Cl. B45. The compound of any one of embodiments B1-B35, wherein R66is Br. B46. The compound of any one of embodiments B1-B37, wherein R66is haloalkyl. B47. The compound of any one of embodiments B1-B37, wherein R66is heterocycle. B48. The compound of any one of embodiments B1-B37, wherein R66is haloalkoxy. B49. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl-OR6. B50. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl-SR6. B51. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- NR6R7. B52. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- C(O)R3. B53. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- S(O)R3. B54. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- C(S)R3. B55. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- S(O)2R3. B56. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- N(R8)-C(O)R3. B57. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- N(R8)-S(O)R3. B58. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- N(R8)-C(S)R3. B59. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- N(R8)-S(O)2R3. B60. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkylN3. B61. The compound of any one of embodiments B1-B37, wherein R66is C0-C6alkyl- cyano. B62. The compound of any one of embodiments B49-B61, wherein C0-C6alkyl is C0-alkyl (i.e. bond). B63. The compound of any one of embodiments B49-B61, wherein C0-C6alkyl is C1-alkyl. B64. The compound of any one of embodiments B49-B61, wherein C0-C6alkyl is C2-alkyl. B65. The compound of any one of embodiments B1-B35, wherein R66is -N=S(O)(R3)2. B66. The compound of any one of embodiments B1-B35, wherein R66is heterocycloalkyl. B67. The compound of any one of embodiments B1-B35, wherein R66is aryl. B68. The compound of any one of embodiments B1-B67, wherein R67is not substituted with an optional substituent. B69. The compound of any one of embodiments B1-B67, wherein R67is substituted with 1 optional substituent. B70. The compound of any one of embodiments B1-B67, wherein R67is substituted with 2 optional substituents. B71. The compound of any one of embodiments B1-B67, wherein R67is substituted with 3 optional substituents. B72. The compound of any one of embodiments B1-B67, wherein R67is hydrogen. B73. The compound of any one of embodiments B1-B67, wherein R67is -CF3. B74. The compound of any one of embodiments B1-B67, wherein R67is cyano. B75. The compound of any one of embodiments B1-B67, wherein R67is F. B76. The compound of any one of embodiments B1-B67, wherein R67is Cl. B77. The compound of any one of embodiments B1-B67, wherein R67is Br. B78. The compound of any one of embodiments B1-B67, wherein R67is haloalkyl. B79. The compound of any one of embodiments B1-B65, wherein R67is heterocycle. B80. The compound of any one of embodiments B1-B67, wherein R67is haloalkoxy. B81. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl-OR6. B82. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl-SR6. B83. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- NR6R7. B84. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- C(O)R3. B85. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- S(O)R3. B86. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- C(S)R3. B87. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- S(O)2R3. B88. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- N(R8)-C(O)R3. B89. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- N(R8)-S(O)R3. B90. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- N(R8)-C(S)R3. B91. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- N(R8)-S(O)2R3. B92. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkylN3. B93. The compound of any one of embodiments B1-B67, wherein R67is C0-C6alkyl- cyano. B94. The compound of any one of embodiments B81-B93, wherein C0-C6alkyl is C0-alkyl (i.e. bond). B95. The compound of any one of embodiments B81-B93, wherein C0-C6alkyl is C1-alkyl. B96. The compound of any one of embodiments B81-B93, wherein C0-C6alkyl is C2-alkyl. B97. The compound of any one of embodiments B1-B67, wherein R67is -N=S(O)(R3)2. B98. The compound of any one of embodiments B1-B67, wherein R67is heterocycloalkyl. B99. The compound of any one of embodiments B1-B67, wherein R67is aryl. B100. The compound of embodiment B3, wherein heteroaryl is B101. The compound of embodiment B3, wherein heteroaryl is B102. The compound of embodiment B3, wherein heteroaryl is, B103. The compound of embodiment B3, wherein heteroaryl is B104. The compound of embodiment B3, wherein heteroaryl is B105. The compound of embodiment B3, wherein heteroaryl is B106. The compound of embodiment B3, wherein heteroaryl is B107. The compound of embodiment B3, wherein heteroaryl is B108. The compound of embodiment B3, wherein heteroaryl is B109. The compound of embodiment B3, wherein heteroaryl is B110. The compound of embodiment B3, wherein heteroaryl is B111. The compound of embodiment B3, wherein heteroaryl is B112. The compound of embodiment B3, wherein heteroaryl is B113. The compound of embodiment B3, wherein heteroaryl is B114. The compound of embodiment B3, wherein heteroaryl is B115. The compound of embodiment B3, wherein heteroaryl is B116. The compound of embodiment B3, wherein heteroaryl is B117. The compound of embodiment B3, wherein heteroaryl is B118. The compound of embodiment B3, wherein heteroaryl is B119. The compound of embodiment B3, wherein heteroaryl is B120. The compound of embodiment B3, wherein heteroaryl is B121. The compound of embodiment B3, wherein heteroaryl is B122. The compound of any one of embodiments B1-B121, wherein R10is hydrogen. B123. The compound of any one of embodiments B1-B121, wherein R10is alkyl. B124. The compound of any one of embodiments B1-B121, wherein R10is methyl. B125. The compound of any one of embodiments B1-B121, wherein R10is deuterium. B126. The compound of any one of embodiments B1-B121, wherein R10is C(O)R3. B127. The compound of any one of embodiments B1-B121, wherein R10is arylalkyl. B128. The compound of any one of embodiments B1-B127, wherein R1is hydrogen. B129. The compound of any one of embodiments B1-B127, wherein R1is hydrogen. B130. The compound of any one of embodiments B1-B127, wherein R1is aryl. B131. The compound of any one of embodiments B1-B127, wherein R1is phenyl. B132. The compound of any one of embodiments B1-B127, wherein R1is C(O)R3. B133. The compound of any one of embodiments B1-B127, wherein R1is arylalkyl. B134. The compound of any one of embodiments B1-B127, wherein R1is alkyl. B135. The compound of any one of embodiments B1-B127, wherein R1is haloalkyl. B136. The compound of any one of embodiments B1-B127, wherein R1is methyl. B137. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- cyano. B138. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- OR6B139. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl-SR6B140. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- NR6R7B141. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- C(O)R3B142. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- S(O)R3B143. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- S(O)2R3B144. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- N(R8)-C(O)R3B145. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- N(R8)-S(O)R3B146. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl- N(R8)-S(O)2R3B147. The compound of any one of embodiments B1-B127, wherein R1is C0-C6alkyl-O- C(O)R3B148. The compound of any one of embodiments B137-B147, wherein C0-C6alkyl is C0- alkyl (i.e. bond). B149. The compound of any one of embodiments B137-B147, wherein C0-C6alkyl is C1- alkyl. B150. The compound of any one of embodiments B137-B147, wherein C0-C6alkyl is C2- alkyl. In certain embodiments R65, R66, or R67is aryl. In certain embodiments R65, R66, or R67is heteroaryl. In certain embodiments R65, R66, or R67is heterocycle. Additional Embodiments 1. A compound of Formula: or a pharmaceutically acceptable salt thereof; wherein: ASGPR Binding Ligand is a compound selected from:

[0096] ; Q is -O- or -N(R10)-; R1and R5are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O-S(O)2R3; R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3; R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80; R80is independently selected at each instance from the group consisting of alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3; Cleavable Moiety is a bond, wherein the Therapeutic Oligonucleotide is attached to the -P-, or Cleavable Moiety is wherein the Therapeutic Oligonucleotide is bound to the -C-; R42is hydrogen, alkyl, alkyl-O-alkyl, or C(O)R43; R43is selected from the group consisting of hydrogen, alkyl, and haloalkyl; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, haloalkyl, and halogen; Therapeutic Oligonucleotide is an antisense oligonucleotide, siRNA, shRNA, DNA aptamer, RNA aptamer, miRNA, miRNA mimic, antimiRNA, DNA decoy, RNA decoy, or CpG oligonucleotide; LinkerAand LinkerBare independently selected from: ; LinkerCis selected from: LinkerDis selected from: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O- (CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; R22is independently at each occurrence selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and X- is an anionic group. 2. The compound of embodiment 1, wherein R1is hydrogen. 3. The compound of embodiment 1 or embodiment 2, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1 or embodiment 2, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1 or embodiment 2, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. 6. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is 7. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 8. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is 9. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is 10. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is

[0097] 11. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 12. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 13. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 14. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 15. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 16. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 17. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 18. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 19. The compound of any one of embodiments 1-5, wherein the ASGPR Binding Ligand is . 20. The compound of any one of embodiments 1-19, wherein Base is: . 21. The compound of any one of embodiments 1-19, wherein Base is: . 22. The compound of any one of embodiments 1-19, wherein Base is: . 23. The compound of any one of embodiments 1-19, wherein Base is: 24. The compound of any one of embodiments 1-19, wherein Cleavable Moiety is bond. 25. The compound of any one of embodiments 1-19, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 26. The compound of any one of embodiments 1-19, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 27. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 28. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 29. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 30. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 31. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 32. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. 33. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the - P-. 34. The compound of any one of embodiments 1-23, wherein Cleavable Moiety is selected from the group consisting of wherein the Therapeutic Oligonucleotide is attached to the -C-. 35. The compound of any one of embodiments 27-34, wherein R42is methyl. 36. The compound of embodiment 1, wherein the compound is selected from the group consisting of:

[0098] ; or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and 37. The compound of embodiment 36 wherein the compound is or a pharmaceutically acceptable salt thereof. 38. The compound of embodiment 36 wherein the compound is or a pharmaceutically acceptable salt thereof. 39. The compound of embodiment 36 wherein the compound is or a pharmaceutically acceptable salt thereof. 40. The compound of embodiment 1, wherein the compound is selected from the group consisting of:

[0099] or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10. 41. The compound of any embodiment 40 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. 42. The compound of any embodiment 40 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. 43. The compound of any embodiment 40 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. 44. The compound of embodiment 1, wherein the compound is selected from the group consisting of:

[0100] or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is 45. The compound of embodiment 1, wherein the compound is selected from the group consisting of: ,

[0101] or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is 46. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide described in Table 1. 47. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 80% identical to a nucleotide described in Table 1. 48. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 85% identical to a nucleotide described in Table 1. 49. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 90% identical to a nucleotide described in Table 1. 50. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 95% identical to a nucleotide described in Table 1. 51. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 96% identical to a nucleotide described in Table 1. 52. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 97% identical to a nucleotide described in Table 1. 53. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 98% identical to a nucleotide described in Table 1. 54. The compound of any one of embodiments 1-45, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 99% identical to a nucleotide described in Table 1. 55. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 1. 56. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 2. 57. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 3. 58. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 4. 59. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 5. 60. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 6. 61. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 7. 62. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 8. 63. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 9. 64. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 10. 65. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 11. 66. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 12. 67. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 13. 68. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 14. 69. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 15. 70. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 16. 71. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 17. 72. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 18. 73. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 19. 74. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 20. 75. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 21. 76. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 22. 77. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 23. 78. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 24. 79. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 25. 80. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 26. 81. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 27. 82. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 28. 83. The compound of any one of embodiments 1-54, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 29. 84. A compound selected from

[0102] or a pharmaceutically acceptable salt thereof. 85. A pharmaceutical composition comprising a compound of any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 86. A method for the treatment of a disorder comprising administering an effective amount of a compound of any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a human patient. 87. The method of embodiment 86, wherein the disorder responds to treatment with the Therapeutic Oligonucleotide. 88. The method of embodiment 86 or 87, wherein the disorder is a liver associated disorder. 89. The method of embodiment 86 or 87, wherein the disorder is selected from acute hepatic porphyria (AHP), hyperoxaluria type 1 (PH1), hypercholesterolemia, hemophilia, a complement mediated disorder, HBV, hypertension, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, hyperoxaluria type 2, hyperoxaluria type 3, β-thalassemia, immunoglobulin A nephropathy (IgAN), angioedema, myelodysplastic disorder, and treatment resistant hypertension. In certain embodiments, the invention includes: D1. A compound of Formula: or a pharmaceutically acceptable salt thereof;

[0103] wherein: ASGPR Binding Ligand is a compound selected from:

[0104] Q is -O- or -N(R10)-; R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, C0-C6alkyl-N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3; R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3; R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80; R80is independently selected at each instance from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3; Cleavable Moiety is a bond, wherein the Therapeutic Oligonucleotide is attached to the -P-, or Cleavable Moiety is wherein the Therapeutic Oligonucleotide is bound to the -C- or -N-, or Cleavable Moiety is wherein the Therapeutic Oligonucleotide is bound to the -C- or -O-; R42is hydrogen, alkyl, alkyl-O-alkyl, or C(O)R43; R43is selected from the group consisting of hydrogen, alkyl, and haloalkyl; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from oxo, alkyl, haloalkyl, alkenyl, haloalkenyl, and halogen; Therapeutic Oligonucleotide is an antisense oligonucleotide, siRNA, shRNA, DNA aptamer, RNA aptamer, miRNA, miRNA mimic, antimiRNA, DNA decoy, RNA decoy, or CpG oligonucleotide; LinkerAand LinkerBare independently selected from: LinkerCis selected from: LinkerDis selected from: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[C(O)-CH2- NR6]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; R22is independently at each occurrence selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and X- is an anionic group. D2. The compound of embodiment D1, wherein Cleavable Moiety is a bond, , , wherein the Therapeutic Oligonucleotide is attached to the -P-; or wherein the Therapeutic Oligonucleotide is bound to the -C-; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, haloalkyl, and halogen; and R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0- C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3. D3. The compound of embodiment D1, wherein R1is hydrogen. D4. The compound of any one of embodiments D1-D3, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. D5. The compound of any one of embodiments D1-D3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. D6. The compound of any one of embodiments D1-D3, wherein the compound is of formula: ; or a pharmaceutically acceptable salt thereof. D7. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D8. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D9. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D10. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is .

[0105] D11. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D12. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D13. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is

[0106] D14. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D15. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D16. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D17. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D18. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D19. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is . D20. The compound of any one of embodiments D1-D6, wherein the ASGPR Binding Ligand is D21. The compound of any one of embodiments D1-D20, wherein Base is: D22. The compound of any one of embodiments D1-D20, wherein Base is: D23. The compound of any one of embodiments D1-D20, wherein Base is: . D24. The compound of any one of embodiments D1-D20, wherein Base is: D25. The compound of any one of embodiments D1-D20, wherein Cleavable Moiety is bond. D26. The compound of any one of embodiments D1-D20, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D27. The compound of any one of embodiments D1-D20, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D28. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D29. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D30. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D31. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D32. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D33. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D34. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is wherein the Therapeutic Oligonucleotide is attached to the -P-. D35. The compound of any one of embodiments D1-D24, wherein Cleavable Moiety is , wherein the Therapeutic Oligonucleotide is bound to the -N- or - C-, or Cleavable Moiety is wherein the Therapeutic Oligonucleotide is bound to the -C- or -O-. D36. The compound of any one of embodiments D26-D33, wherein R42is methyl. D37. The compound of any one of embodiments D1-D36, wherein LinkerAis bond. D38. The compound of any one of embodiments D1-D37, wherein LinkerBis LinkerCis LinkerDis D39. The compound of embodiment D1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is D40. The compound of embodiment D39 wherein the compound is or a pharmaceutically acceptable salt thereof. D41. The compound of embodiment D39 wherein the compound is or a pharmaceutically acceptable salt thereof. D42. The compound of embodiment D39 wherein the compound is or a pharmaceutically acceptable salt thereof. D43. The compound of embodiment D1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10. D44. The compound of embodiment D43 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. D45. The compound of embodiment D43 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. D46. The compound of embodiment D43 wherein the compound is of Formula or a pharmaceutically acceptable salt thereof. D47. The compound of embodiment D1, wherein the compound is selected from the group consisting of: ,

[0107] and or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is D48. The compound of embodiment D1, wherein the compound is selected from the group consisting of: , ,

[0108] or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is D49. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide described in Table 1. D50. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 80% identical to a nucleotide described in Table 1. D51. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 85% identical to a nucleotide described in Table 1. D52. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 90% identical to a nucleotide described in Table 1. D53. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 95% identical to a nucleotide described in Table 1. D54. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 96% identical to a nucleotide described in Table 1. D55. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 97% identical to a nucleotide described in Table 1. D56. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 98% identical to a nucleotide described in Table 1. D57. The compound of any one of embodiments D1-D48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 99% identical to a nucleotide described in Table 1. D58. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 1. D59. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 2. D60. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 3. D61. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 4. D62. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 5. D63. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 6. D64. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 7. D65. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 8. D66. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 9. D67. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 10. D68. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 11. D69. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 12. D70. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 13. D71. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 14. D72. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 15. D73. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 16. D74. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 17. D75. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 18. D76. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 19. D77. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 20. D78. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 21. D79. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 22. D80. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 23. D81. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 24. D82. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 25. D83. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 26. D84. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 27. D85. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 28. D86. The compound of any one of embodiments D1-D57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 29. D87. A compound selected from

[0109] or a pharmaceutically acceptable salt thereof. D88. A pharmaceutical composition comprising a compound of any one of embodiments D1-D87 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. D89. A method for the treatment of a disorder comprising administering an effective amount of a compound of any one of embodiments D1-D87 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a human patient. D90. The method of embodiment D89, wherein the disorder responds to treatment with the Therapeutic Oligonucleotide. D91. The method of embodiment D89 or D90, wherein the disorder is a liver associated disorder. D92. The method of embodiment D89 or D90, wherein the disorder is selected from acute hepatic porphyria (AHP), hyperoxaluria type 1 (PH1), hypercholesterolemia, hemophilia, a complement mediated disorder, HBV, hypertension, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, hyperoxaluria type 2, hyperoxaluria type 3, β-thalassemia, immunoglobulin A nephropathy (IgAN), angioedema, myelodysplastic disorder, and treatment resistant hypertension. V. METHODS OF TREATMENT In certain aspects, the Therapeutic Oligonucleotide delivering compound of the current invention can be administered in an effective amount for the treatment a disorder which can be treated with the Therapeutic Oligonucleotide, for example a liver disorder. In some embodiments, provided are methods of treating a disorder comprising administering to a subject in need thereof an effective amount of a Therapeutic Oligonucleotide delivering compound as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is selected from acute coronary syndrome, acute hepatic porphyria (AHP), acute intermittent porphyria, acute porphyria, age-related macular degeneration (AMD), ALA dehydratase deficient porphyria (ADP), amyloidosis, aortic stenosis, atherosclerosis, atherosclerotic cardiovascular disease (ASCVD), atypical hemolytic uremic syndrome, autoimmune hepatitis, Berger disease, beta thalassemia intermedia, biliary atresia, cardiovascular disease, carotid artery plaque, chronic heart failure with reduced ejection fraction, chronic hepatitis A, chronic hepatitis A virus (cHAV) infection, chronic hepatitis B, chronic hepatitis B virus (cHBV) infection, chronic hepatitis C, chronic hepatitis C virus (cHCV) infection, chronic hepatitis D, chronic hepatitis D virus (cHDV) infection, cirrhosis, coronary artery disease, elevated lipoprotein(a) (Lp(a)), elevated serum lipoprotein(a) (Lp(a)), elevated triglycerides (TG), end- stage renal disease, end-stage renal disease requiring hemodialysis, generalized myasthenia gravis, geographic atrophy, hemochromatosis, hemophilia, hemophilia A, hemophilia B, hepatic impairment, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hereditary amyloidosis, hereditary angioedema, heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia (a), hypertension, hypertriglyceridemia, IgA glomerulonephritis, IgA nephropathy (IgAN), Inflammation, kidney disease, lipoproteinemia, low risk myelodysplastic syndrome, macular degeneration, metabolic-associated fatty liver disease (MAFLD), mild hypertension, mixed dyslipidemia, nonalcoholic fatty liver disease (NAFD), nonalcoholic steatohepatitis (NASH), nonalcoholic steatohepatitis (NASH) with fibrosis, non-transfusion-dependent thalassemia, paroxysmal nocturnal hemoglobinuria, phlebotomy dependent polycythemia vera, polycythemia vera, primary biliary cholangitis, primary hypercholesterolemia, primary hyperoxaluria, primary hyperoxaluria Type 1 (PH1), primary hyperoxaluria Type 2 (PH2), primary hyperoxaluria Type 3 (PH3), primary IgA nephropathy, primary sclerosing cholangitis, renal impairment, resistant hypertension, thalassemia, type 2 diabetes, urologic disease, Wilson’s disease, or very-low risk myelodysplastic syndrome...

Claims

CLAIMSWe Claim:

1. A compound of F ormula :or a pharmaceutically acceptable salt thereof;wherein: ASGPR Binding Ligand is a compound selected from:; Q is -O- or -N(R10)-; R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, C0-C6alkyl-N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3; R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;R10is hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, or S(O)2R3; R65, R66, and R67are independently selected at each occurrence from the group consisting of hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R80; R80is independently selected at each instance from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, Br, I, -NR6R7, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR6, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, and -C(O)R3; Cleavable Moiety is a bond,wherein the Therapeutic Oligonucleotide is attached to the -P-, or Cleavable Moiety iswherein the Therapeutic Oligonucleotide is bound to the -C- or -N-, orCleavable Moiety iswherein the Therapeutic Oligonucleotide is bound to the -C- or -O-; R42is hydrogen, alkyl, alkyl-O-alkyl, or C(O)R43; R43is selected from the group consisting of hydrogen, alkyl, and haloalkyl; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from oxo, alkyl, haloalkyl, alkenyl, haloalkenyl, and halogen; Therapeutic Oligonucleotide is an antisense oligonucleotide, siRNA, shRNA, DNA aptamer, RNA aptamer, miRNA, miRNA mimic, antimiRNA, DNA decoy, RNA decoy, or CpG oligonucleotide; LinkerAand LinkerBare independently selected from:LinkerCis selected from:LinkerDis selected from:R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, -[C(O)-CH2- NR6]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; R22is independently at each occurrence selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and X- is an anionic group.

2. The compound of claim 1, wherein: Cleavable Moiety is a bond,wherein the Therapeutic Oligonucleotide is attached to the -P-; orwherein the Therapeutic Oligonucleotide is bound to the -C-; Base is a heterocycle comprising two, three, or four nitrogen atoms, wherein the heterocycle is substituted with an oxo, amino, or carbamoyl and optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, haloalkyl, and halogen; and R1and R5are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, halogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-cyano, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0- C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3, C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3.

3. The compound of claim 1, wherein R1is hydrogen.

4. The compound of any one of claims 1-3, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-3, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is8. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

9. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

10. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

11. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

12. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

13. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

14. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

15. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

16. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

17. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

18. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

19. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

20. The compound of any one of claims 1-6, wherein the ASGPR Binding Ligand is.

21. The compound of any one of claims 1-20, wherein Base is:.

22. The compound of any one of claims 1-20, wherein Base is:.

23. The compound of any one of claims 1-20, wherein Base is:.

24. The compound of any one of claims 1-20, wherein Base is:

25. The compound of any one of claims 1-20, wherein Cleavable Moiety is bond.

26. The compound of any one of claims 1-20, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

27. The compound of any one of claims 1-20, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

28. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

29. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

30. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

31. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

32. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

33. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is attached to the -P-.

34. The compound of any one of claims 1-24, wherein Cleavable Moiety isorwherein the Therapeutic Oligonucleotide is attached to the -P-.

35. The compound of any one of claims 1-24, wherein Cleavable Moiety iswherein the Therapeutic Oligonucleotide is bound to the -N- or -C-, or Cleavable Moiety iswherein the Therapeutic Oligonucleotide is bound to the -C- or -O-.

36. The compound of any one of claims 26-33, wherein R42is methyl.

37. The compound of any one of claims 1-36, wherein LinkerAis bond.

38. The compound of any one of claims 1-37, wherein LinkerBisLinkerCisandLinkerDis.

39. The compound of claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof; whereinn is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; andR2is40. The compound of claim 39 wherein the compound isor a pharmaceutically acceptable salt thereof.

41. The compound of claim 39 wherein the compound isor a pharmaceutically acceptable salt thereof.

42. The compound of claim 39 wherein the compound isor a pharmaceutically acceptable salt thereof.

43. The compound of claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10.

44. The compound of claim 43 wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

45. The compound of claim 43 wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

46. The compound of claim 43 wherein the compound is of Formulaor a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is48. The compound of claim 1, wherein the compound is selected from the group consisting of:,,,and; or a pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; and R2is49. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide described in Table 1.

50. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 80% identical to a nucleotide described in Table 1.

51. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 85% identical to a nucleotide described in Table 1.

52. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 90% identical to a nucleotide described in Table 1.

53. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 95% identical to a nucleotide described in Table 1.

54. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 96% identical to a nucleotide described in Table 1.

55. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 97% identical to a nucleotide described in Table 1.

56. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotideis a nucleotide that is at least 98% identical to a nucleotide described in Table 1.

57. The compound of any one of claims 1-48, wherein Therapeutic Oligonucleotide is a nucleotide that is at least 99% identical to a nucleotide described in Table 1.

58. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 1.

59. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 2.

60. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 3.

61. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 4.

62. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 5.

63. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 6.

64. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 7.

65. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 8.

66. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 9.

67. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 10.

68. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 11.

69. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 12.

70. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 13.

71. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide isTherapeutic Oligonucleotide 14.

72. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 15.

73. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 16.

74. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 17.

75. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 18.

76. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 19.

77. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 20.

78. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 21.

79. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 22.

80. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 23.

81. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 24.

82. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 25.

83. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 26.

84. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 27.

85. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide is Therapeutic Oligonucleotide 28.

86. The compound of any one of claims 1-57, wherein the Therapeutic Oligonucleotide isTherapeutic Oligonucleotide 29.

87. A compound selected fromor a pharmaceutically acceptable salt thereof.

88. A pharmaceutical composition comprising a compound of any one of claims 1-87 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

89. A method for the treatment of a disorder comprising administering an effective amount of a compound of any one of claims 1-87 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a human patient.

90. The method of claim 89, wherein the disorder responds to treatment with the Therapeutic Oligonucleotide.

91. The method of claim 89 or 90, wherein the disorder is a liver associated disorder.

92. The method of claim 89 or 90, wherein the disorder is selected from acute hepaticporphyria (AHP), hyperoxaluria type 1 (PH1), hypercholesterolemia, hemophilia, a complement mediated disorder, HBV, hypertension, nonalcoholic steatohepatitis (NASH), a cardiovascular disease, hyperoxaluria type 2, hyperoxaluria type 3, β-thalassemia, immunoglobulin A nephropathy (IgAN), angioedema, myelodysplastic disorder, and treatment resistant hypertension.

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