WO2025199466A1

WO2025199466A1 - Liver-specific asialoglycoprotein receptor targeting ligands, conjugates comprising same, and related compositions and methods of use

Info

Publication number: WO2025199466A1
Application number: PCT/US2025/020963
Authority: WO
Inventors: Philip S. Low; Madduri SRINIVASARAO; Rajeswara Reddy MANNEM
Original assignee: Purdue Research Foundation
Current assignee: Purdue Research Foundation
Priority date: 2024-03-22
Filing date: 2025-03-21
Publication date: 2025-09-25
Anticipated expiration: 2026-09-22
Also published as: WO2025199466A9

Abstract

Conjugates that target an asialoglycoprotein receptor, such as in the liver, and comprise an active agent (e.g., a therapeutic or an imaging agent) and rigid linker components; pharmaceutical compositions; and methods of use in the delivery of conjugates, and the imaging and treating of the liver (e.g., in a subject with NASH) with conjugates.

Description

LIVER-SPECIFIC ASIALOGLYCOPROTEIN RECEPTOR TARGETING LIGANDS, CONJUGATES COMPRISING SAME, AND RELATED COMPOSITIONS AND METHODS OF USE RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No.63/568,748, filed March 22, 2024, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to conjugates that target an asialoglycoprotein receptor, such as in the liver, and pharmaceutical compositions thereof. The conjugates of the present disclosure comprise an active agent, such as a therapeutic agent or an imaging agent. Additionally, the present disclosure relates to methods of using conjugates and pharmaceutical compositions described herein in the delivery of active agents to the liver, and the imaging and treating of the liver, such as in a subject with nonalcoholic fatty liver disease. BACKGROUND Non-alcoholic fatty liver disease (NASH) is a spectrum of liver disease in which fat builds up in the liver of people who drink little or no alcohol. This causes inflammation of the liver and damage to the cells in the liver, which may lead to fibrosis, cirrhosis (scarring of the liver) and liver failure. An ideal drug for NASH would be a drug that targets fat deposition and metabolic disorders. Thyroid hormones (THs) are essential regulatory molecules for normal growth and development and for maintaining metabolic homeostasis. The use of THs derivatives as therapeutic agents for NAFLD have been hampered for a long time by the lack of selectivity and the consequent harmful adverse side effects on organs, such as the heart, and systems, such the skeletal muscles system. N-acetylgalactosamine (GalNAc) is a well-known ligand for the asialoglycoprotein receptor (ASGPR), which is highly over-expressed in the liver hepatocytes. GalNAc conjugate I has been widely used in siRNA and antisense oligonucleotide (ASO) therapies by several pharmaceutical companies. A disadvantage of GalNAc conjugate I, however, is that it clears from the liver within about 10 hours. Triiodothryonine (T3) administration has a therapeutic effect on non-alcoholic steatohepatitis (NASH) and significantly eliminates hepatic steatosis. T3, however, causes heart burn and reduces bone mineral density. Therefore, there is a current need to provide conjugates which provide an advantage over currently available conjugates. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description provided herein. SUMMARY In one aspect, the present disclosure provides a conjugate of formula I: or a pharmaceutically acceptable salt thereof, wherein L¹ is a linker, each L² is independently a linker comprising a rigid component, A is an active agent, and each R is N-acetylgalactosamine (GalNAc), wherein the rigid component of L² comprises a structure of formula Ia: wherein: each X is independently -C(R¹)2- or -NR²- , n is an integer selected from 2-7, each m is independently 0, 1, 2, 3, or 4, provided that if m is 0, then X is -C(R¹)₂-, each R¹ is independently H, OH, or amino, and each R² is independently H or alkyl. In another aspect, the present disclosure provides a conjugate of formula I: formula (I) wherein L1 is a linker, L2 is a linker comprising a rigid component, A is an active agent, and R is a ligand that binds an asialoglycoprotein receptor (ASGPR). The active agent can be a therapeutic agent, such as a therapeutic agent that has a therapeutic effect in the liver. The therapeutic agent can be an imaging agent, such as a fluorescent imaging agent or a radio-imaging agent. Also provided is a pharmaceutical composition comprising an above-described conjugate and a pharmaceutically acceptable carrier. Further provided is a method of delivering an active agent to a liver in a subject. The method comprises administering to the subject an effective amount of a conjugate as described herein, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. The subject can have nonalcoholic fatty liver disease (NASH). Further provided is a method of imaging a liver in a subject. The method comprises administering to the subject a conjugate as described herein (e.g., GalNAc-III-NIR (GalNAc conjugate III-56 containing S0456) or GalNAc-IV-NIR), or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, and imaging the subject. Still further provided is a method of treating a liver in a subject. The method comprises administering to the subject an effective amount of a conjugate as described herein, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. The subject can have nonalcoholic fatty liver disease (NASH), in which case the method can comprise administering to the subject an effective amount of a conjugate as described herein (e.g., GalNAc-III-T3 (GalNAc conjugate III-64) or GalNAc-IV-T3), or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. Even still further provided is a method of improving the residence time in a liver of a mammal of a conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in the mammalian liver. The method comprises modifying/replacing L with a linker having the structure L₁(NH)C(CH₂OL₂R)_x, wherein L₁ is a linker bound to A, L₂ is a linker comprising a rigid component, and x is an integer from 1 to 3. The rigid component of L2 can be an oligoproline. The rigid component of L₂ can be an oligopiperidine. The rigid component of L₂ can be an α-helix. The rigid component of L₂ can be peptidic. The rigid component of L₂ can be the amino acid sequence (EAAAK)3. The rigid component can be selected from: . L2 can comprise an alkyl group, a PEG, a peptide, or a combination of two or more thereof. The residence time in the liver of the mammal is at least three days. In view of the above, also provided is a conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in a liver of a mammal, wherein L has the structure L₁(NH)C(CH₂OL₂R)_x, wherein L1 is a linker bound to A, L2 is a linker comprising a rigid component, and x is an integer from 1 to 3, wherein the rigid component of L2 is an oligoproline, an oligopiperidine, an α-helix, the amino acid sequence (EAAAK)3, or a structure selected from: wherein L2 optionally further comprises an alkyl group, a PEG, a peptide, or a combination of two or more thereof; and wherein the conjugate has a residence time in the liver of the mammal of at least three days. FIGURES Fig.1 shows the structure of GalNAc-III-54 (GalNAc-III-Tris-1), a precursor to a GalNAc conjugate III. Fig.2 shows the structure of comparative GalNAc-I-NIR (GalNAc conjugate I containing S0456). Fig.3 shows the structure of a GalNAc conjugate III, GalNAcIII-NIR (GalNAc conjugate III-56 containing S0456. Fig.4 shows the structure of a GalNAc conjugate III (GalNAc conjugate III-56 without active agent (imaging agent, such as S0456, or therapeutic agent, such as T3)). Figs.5A and 5B show images of Balb/c mice (10 weeks) (Fig.5A) and their excised organs (Fig.5B) 12 hours after being injected in the tail vein with either GalNAc-III-NIR (GalNAc conjugate III-56 containing S0456) alone or in the presence of GalNAc conjugate III-56 without S0456. Figs.6A-6G show biodistribution images of excised organs of mice taken at 6 hours (Fig.6A), 10 hours (Fig.6B), 24 hours (Fig.6C), 48 hours (Fig.6D), 72 hours (Fig.6E), 106 hours (Fig.6F) and 130 hours (Fig.6G) after being injected in the tail vein with either GalNAc-I-NIR (GalNAc conjugate I containing S0456) (“I”) or GalNAc-III-NIR (GalNAc conjugate III containing S0456) (“III”). Fig.7 shows the structure of GalNAc-III-T3, a GalNAc conjugate III containing T3. Fig.8 shows the receptor saturation curve (concentration (nmol) vs. fluorescence intensity) for two mice receiving a concentration of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, or 12 nmol of GalNAc-III-NIR (GalNAc conjugate III-56 containing S0456). The maximum tolerable dose was 10 nmol. Figs.9A and 9B show the pharmacokinetic (PK) stability of GalNAc-III-T3 administered intravenously (Fig.9A) and subcutaneously (Fig.9B). Figs.10A and 10B show the stability of GalNAc-III-T3 (GalNAc-III-64) in human plasma over a period of 8 hours (Fig.10A) and 24 hours (Fig.10B). Fig.11 shows body weight over time for untreated mice and mice treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc-III-T3. Fig.12 shows liver weights of mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc-III-T3. Fig.13 shows liver/body weight ratios for mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc- III-T3. Fig.14 shows aspartate aminotransferase (AST) levels (U/L) for mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc-III-T3. Fig.15 shows alanine transaminase (ALT) levels (U/L) for mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc-III-T3. Fig.16 shows triglyceride levels (mg/dl) for mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc- III-T3. Fig.17 shows cholesterol levels (mg/dl) for mice fed a regular diet or a high fat diet (HFD) and then treated with either 10 nmol/day or 10 nmol/injection twice daily of GalNAc- III-T3. DETAILED DESCRIPTION An object of the present disclosure is based on the discovery that rigid linkers that increase the residence time in the liver of conjugates targeted to aialoglycoprotein receptors (AGPRs). In view of the foregoing, provided is a conjugate of formula I: or a pharmaceutically acceptable salt thereof, wherein: L¹ is a linker, each L² is independently a linker comprising a rigid component, A is an active agent, and each R is N-acetylgalactosamine (GalNAc), wherein the rigid component of L² comprises the structure of formula Ia: wherein: each X is independently -C(R¹)2- or -NR²- , n is an integer selected from 2-7, each m is independently 0, 1, 2, 3, or 4, provided that if m is 0, then X is -C(R¹)₂-, each R¹ is independently H, OH, or amino, and each R² is independently H or alkyl. In view of the foregoing, provided is a conjugate of formula I: formula (I) wherein L1 is a linker, L2 is a linker comprising a rigid component, A is an active agent, and R is a ligand that binds an asialoglycoprotein receptor (ASGPR). ASGPRs are lectins, which bind asialoglycoprotein and glycoproteins from which a sialic acid has been removed to expose a galactose residue. Integral membrane proteins, ASGPRs are locating on hepatocytes in mammals. ASGPRs are weakly expressed by glandular cells of the gallbladder and the stomach and are also expressed on several human carcinoma cell lines. The active agent can be a therapeutic agent, such as a therapeutic agent that has a therapeutic effect in the liver. The therapeutic agent can be a hormone. The therapeutic agent can be a thyroid hormone receptor beta (THRβ) agonist, such as triiodothyronine (T3). The therapeutic agent can be a farnesoid X receptor (FXR) agonist, such as tropifexor (LJN452). The therapeutic agent can be a peroxisome proliferator-activated receptor α agonist or αδ dual agonist; an example of an αδ dual agonist is elafibranor (GFT505). The therapeutic agent can be an angiotensin II receptor blocker, such as telmisartan, candesartan, or losartan. The therapeutic agent can be a patatin-like phospholipase domain-containing protein 3 (PNPLA3) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be a complement component C5 inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be a stearoyl-CoA desaturase-1 (SCD1) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be a diacylglycerol acyltransferase 1 (DGAT1) inhibitor, such as pradigastat (LCQ-908) or T-863. The therapeutic agent can be a δ-aminolevulinate synthase 1 inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be an angiopoietin-like 3 protein (ANGPTL3) inhibitor, such as an an siRNA or an antisense oligonucleotide. The therapeutic agent can be a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be an apolipoprotein C-III (ApoC-III) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be an apolipoprotein B (apoB) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be a glycolate oxidase (GO) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be an α-1 antitrypsin (AAT) inhibitor, such as an siRNA or an antisense oligonucleotide. The therapeutic agent can be a pyruvate kinase L/R (PKLR) inhibitor, such as an inhibitory polynucleotide (see, e.g., US 2020/0190523). The therapeutic agent can be an antiviral small molecule drug, such as an antiviral small molecule drug for hepatitis A virus (HAV), hepatitis B virus (HBV), such as entecavir, tenofovir, lamivudine, adefovir, telbivudine, an A1CF inhibitor (see, e.g., US 2023/0257748), a Shwachman-Bodian-Diamond syndrome (SBDS) ribosome maturation factor inhibitor (see, e.g., US 2023/0193263), a Septin 9 (SEPT9) inhibitor (see, e.g., US 2023/0183692), a COPS signalosome subunit 3 (COPS3) inhibitor (see, e.g., US 2023/0122751), a store-operated calcium entry-associated regulatory factor (SARAF) inhibitor (see, e.g., US 2023/0120063), a secretory carrier membrane protein 3 (SCAMP3) inhibitor (see, e.g., US 2023/0118138), a PAP-associated domain containing 5 (PAPD5) inhibitor and/or a PAP-associated domain containing 7 (PAPD7) inhibitor (see, e.g., US 2019/0216846 and US 2019/0111073), or a far upstream element-binding protein 1 (FUBP1) inhibitor (see, e.g., US 2021/0024934), hepatitis C virus (HCV), such as elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/ledipasvir, or sofosbuvir/velpatasvir, or hepatitis D virus (HDV). The therapeutic agent can be an antiviral siRNA or an antiviral antisense oligonucleotide (see, e.g., US 2022/0378920), such as an antiviral siRNA or an antiviral antisense oligonucleotide for HAV, HBV (see, e.g., US 2023/0357773, US 2023/0295630, US 2023/0119360, US 2021/0395745, US 2020/0171069, and US 2019/0343864), HCV, or HDV (see, e.g., US2021/0403908). The therapeutic agent can be an siRNA or an antisense oligonucleotide (see, e.g., WO 2018/223073 (e.g., APOC3 oligonucleotide); WO 2018/223081 (e.g., PNPLA3 oligonucleotide); and Schmidt et al., Nucl Acids Res 45: 2294 (2017)). The active agent can be an extracellular protein binding ligand for the selective degradation of a target extracellular protein to treat a disorder mediated by the extracellular protein (see, e.g., US 2024/0072809; and US 2023/0097256). The therapeutic agent can be an imaging agent, such as a fluorescent imaging agent (fluorescent dye) or a radio-imaging agent. The fluorescent dye can be carbocyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, merocyanine, polymethine, coumarine, rhodamine, xanthene, fluorescein, borondipyrromethane (BODIPY), CyS, CyS.S, Cy7, VivoTag-680, VivoTag-S680, VivoTag-S7S0, AlexaFluor660, AlexaFluor680, AlexaFluor700, AlexaFluor7S0, 10 AlexaFluor790, Dy677, Dy676, Dy682, Dy7S2, Dy780, DyLightS47, Dylight647, HiLyte Fluor 647, HiLyte Fluor 680, HiLyte Fluor 7S0, IRDye 800CW, IRDye 800RS, IRDye 700DX, ADS780WS, ADS830WS, indocyanine green (ICG), an analog of ICG, or ADS832WS. The fluorescent dye can comprise a structure selected from:

. The fluorescent dye can have a peak emission in NIR-II window (1,000-1,700 nm). The fluorescent dye can be selected from:

The imaging agent can comprise a chelating group, for example an imaging agent selected from DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or a derivative thereof; S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) or derivative thereof; 2-S-(4-isothiocyanatobenzyl)-1,4,7- triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or a derivative thereof; [(R)-2- amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (p-SCN-Bn-CHX-A”-DTPA) or a derivative thereof; TETA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) or a derivative thereof; SarAr (1-N-(4- aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine or a derivative thereof; NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) or a derivative thereof; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl- [1,4,7]triazonan-1-yl) acetic acid or a derivative thereof; TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2- carboxyethyl)phosphinic acid) or a derivative thereof; HBED (N,N0-bis(2-hydroxybenzyl)- ethylenediamine-N,N0-diacetic acid) or a derivative thereof; 2,3-HOPO (3-hydroxypyridin-2- one) or a derivative thereof; PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13- triene-3,6,9,-triacetic acid) or a derivative thereof; DFO (desferrioxamine) or a derivative thereof; DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof; OCTAPA (N,N0- bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N0-diacetic acid) or a derivative thereof; H2-MACROPA (N,N'-bis[(6-carboxy-2-pyridipmethyl]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (1,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and EC20-head comprising β-l-diaminopropionic acid, aspartic acid, and cysteine, wherein the chelating group optionally chelates a metal. The imaging agent can comprise a radioisotope/radionuclide for radio-imaging, radiotherapy, or magnetic resonance imaging (MRI). The radioisotope/radionuclide can be selected from the group consisting of ¹⁷⁷Lu, ⁹⁰Y, ²¹¹At, ²²⁵Ac, ¹⁶¹Tb, ¹⁸F, ³²P, ⁴⁴Sc, ⁴⁷Sc, ⁵²Mn, ⁵⁵Co, ⁶⁴Cu, ⁶7Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Sr, ⁸⁹Zr, ^99mTc, ¹¹¹In, ^114mIn, ^117mSn, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁴⁹Tb, ¹⁵³Sm, ¹⁵²Tb, ¹⁵⁵Tb, ¹⁶⁹Er, ¹⁸⁶Re, ¹⁸⁸Re, ²¹²Pb, ²¹²Bi, ²¹³Bi, ²²³Ra, ²²⁴Ra, ²²⁵Ab, and ²²⁷Th. The radioisotope/radionuclide can be selected from the group consisting of ¹¹C, ¹³C, ¹³N, ¹⁵O, ⁶⁰Co, and ¹²³I. The imaging agent can be or can comprise: wherein each X is independently a radioisotope selected from the group consisting of 18p, ¹²⁴I, ¹²⁵I, ¹³¹I, and ^2llAt; each R and R' is independently selected from -H, -D, -C1-C3 alkyl, benzyls, and substituted benzyls; and each n is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. The imaging agent can be or can comprise a radiolabeled prosthetic group selected from the group consisting of: The imaging agent can comprise a chelating agent selected from:

The imaging agent can comprise a nuclide for positron emission tomography (PET) or single- photon emission computed tomography (SPECT). The nuclide can be selected from the group consisting of ^99mTc, ¹¹¹In,¹⁸F, ⁶⁸Ga, ¹²⁴I, ^125I, ¹³¹I, and ⁶⁴Cu. In some embodiments, the linkers (e.g., L¹ and each of L²) may include a chain of atoms selected from C, N, O, S, Si, and P. The linker may have a wide variety of lengths, such as a range of atoms from about 7 to about 100. The atoms used in forming the linker (e.g., L¹ and each of L²) may be combined in all chemically relevant ways, such as chains of carbon atoms forming alkylene groups, chains of carbon and oxygen atoms forming polyoxyalkylene groups, chains of carbon and nitrogen atoms forming polyamines, and others. In addition, it is to be understood that the bonds connecting atoms in the chain may be either saturated or unsaturated, such that for example, alkanes, alkenes, alkynes, cycloalkanes, arylenes, imides, and the like may be divalent radicals that are included in the linker (e.g., L¹ and each of L²). In addition, it is to be understood that the atoms forming the linker may also be cyclized upon each other to form divalent cyclic radicals in the linker(e.g., L¹ and each of L²). In each of the foregoing and other linkers described herein the chain forming the linker (e.g., L¹ and each of L²) may be substituted with a wide variety of groups. In another embodiment, the linker (e.g., L¹ and each of L²) includes radicals that form one or more spacer linkers and/or releasable linkers that are taken together to form the linkers described herein having certain length, diameter, and/or functional group requirements. It is appreciated that releasable linkers may be used when the drug to be delivered is advantageously liberated from the binding ligand-linker conjugate so that the free therapeutic will have the same or nearly the same effect at the target as it would when administered without the targeting provided by the conjugates described herein. In another embodiment, the linker L is a non-releasable linker. It is appreciated that non-releasable linkers may be used when the active agent is advantageously retained by the conjugate, such as in imaging, diagnosing, uses of the conjugates described herein. It is to be understood that the choice of a releasable linker or a non-releasable linker may be made independently for each application or configuration of the conjugates, without limiting the invention described herein. It is to be further understood that the linkers L described herein comprise various atoms, chains of atoms, functional groups, and combinations of functional groups. Where appropriate in the present disclosure, the linker L may be referred to by the presence of spacer linkers, releasable linkers, and heteroatoms. However, such references are not to be construed as limiting the definition of the linkers L described herein. L¹ can be a non-releasable linker. L¹ can be a slowly releasable linker. L¹ can comprise an alkyl group, a polyethylene glycol (PEG), a peptide, or a combination of two or more thereof. L¹ can be a releasable linker. L¹ can be reductively cleavable. L¹ can be oxidatively cleavable. L¹ can be enzymatically cleavable. L¹ can be acid-cleavable. In some embodiments, L¹ is a releasable linker and comprises a disulfide bond. L¹ can comprise an alkyl group (e.g., ethylene), a polyethylene glycol (PEG), a peptide, an aryl group (e.g., a phenyl or a phenoxy), a heteroaryl group, or a combination of two or more thereof. Each of these groups can be linked together or to the rest of the molecule through various functional groups, including ethers, esters, amines, amides, carbonyls, and others. For example, in some embodiments, L¹ comprises L¹ can comprise a portion having the structure: . In some embodiments, each L² is independently a linker comprising a rigid component. In certain preferred embodiments, each L² comprises a rigid component and preferably each L² comprises the same rigid component. The rigid component of L² can improve residence time of the conjugate in the liver. The rigid component of L² can include at least one heterocyclylene. The prefix “oligo” can refer to 2 to 50 repeating components. For example, an "oligo amino acid," or more precisely an "oligopeptide," can refer to a short chain of amino acids (e.g., between 2 and 20 amino acid residues) joined by peptide (amide) bonds. The rigid component of L² can be an oligoproline. A proline can refer to a substituted or unsubstituted pyrrolidine-2-carboxylic acid (e.g., unsubstituted proline, hydroxy-proline, amino-proline, or methyl-proline). The rigid component of L² can be an oligopiperidine. A piperidine can refer to a substituted or unsubstituted piperidine-carboxylic acid (e.g., piperidine-2-carboxylic acid, piperidine -3-carboxylic acid, or piperidine -4-carboxylic acid). The rigid component of L² can be an α-helix. The rigid component of L² can be peptidic. For example, a peptidic rigid component of L² can comprise 2 to 50 amino acids (e.g., 2 to 7 amino acids). The rigid component of L² can be the amino acid sequence (EAAAK)3. The rigid component can be selected from: . The rigid component of L² can comprise the structure of formula Ia: wherein: each X is independently -C(R¹)₂- or -NR²- , n is an integer selected from 2-7, each m is independently 0, 1, 2, 3, or 4, provided that if m is 0, then X is -C(R¹)₂-, each R¹ is independently H, OH, or amino, and each R² is independently H or alkyl. In some embodiments of formula Ia, X is -C(R¹)2- (e.g., -CH2-). In some embodiments, X is -NR²- (e.g., -NH-). In some embodiments of formula Ia, n is 2, 3, 4, or 5. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2, 3, or 4. In some embodiments of formula Ia, each m is independently 1 or 2. In some embodiments, each m is 1. In some embodiments, each m is 2. In some embodiments of formula Ia, each R¹ is independently H, OH, or amino (e.g., NH2). In some embodiments, each R¹ is independently H or OH. In some embodiments, one R¹ is H and the other is OH. In some embodiments, each R¹ is H. In some embodiments of formula Ia, each R² is independently H or alkyl (e.g., C1-C6 alkyl, such as methyl). In some embodiments, R² is H. Formula Ia can be selected from: Formula Ia can be selected from: Formula Ia can be selected from: . Formula Ia can be selected from: In some embodiments, L² comprises a compound of formula wherein R, m, n, and X are as defined herein, A is a carbonyl, C₁-C₆ alkylene, C₁-C₆ alkylene-C(O)-, preferably is a carbonyl (e.g., to form an amide with the nitrogen-containing ring), wherein C₁-C₆ alkyl is optionally substituted, (i) is an integer selected from 0 to 6, preferably is 2 or 3, (ii) is an integer selected from 0 to 6, preferably is 2 or 3, and B is amide (e.g., -NHC(O)-C1-C6 alkylene- such as -NHC(O)-ethylene-). L² can comprise an alkyl group, a PEG, a peptide, or a combination of two or more thereof. Each of these groups can be linked together or to the rest of the molecule through various functional groups, including ethers, esters, amines, amides, carbonyls, and others. The alkyl group, a PEG, a peptide, or a combination can be present between R and the rigid component, between the rigid component and , in some embodiments, L² comprises , , . conjugate can have a residence time in the liver of at least three days. The conjugate can have a binding affinity (K_D) to asialoglycoprotein receptor of about 0.1 nM to about 100 nM. R can be a carbohydrate. R can be a monosaccharide. R can be selected from galactose, glucose, fucose, mannose, galactosamine, rhamnose, rhamnitol, N- acetylgalactosamine (GalNAc), mannosamine, glucosamine, N-acetyl-glucosamine (GluNAc), fucosamine and rhamnosamine. In some embodiments, R is N- acetylgalactosamine (GalNAc). Each R-L² can independently comprise the structure: , wherein X, n, and m are as described in formula Ia, and p is an integer of 1-12 (e.g., and integer of 1-8, such as 2, 3, 4, 5, or 6). Each R-L² can independently comprise the structure: , wherein X, n, and m are as described in formula Ia. Each R-L² can independently comprise the structure: , wherein n is as described in formula Ia. Each R-L² can independently have the structure: H H , wherein n is as described in formula Ia. Each R-L² can independently have the structure: . The conjugate of formula I have the structure: , or a pharmaceutically acceptable salt thereof. The conjugate of formula I (e.g., a GalNAc conjugate III) can have the structure: , or a pharmaceutically acceptable salt thereof. The conjugate of formula I (e.g., a GalNAc conjugate IV) can have the structure: , or a pharmaceutically acceptable salt thereof. The conjugate can have the structure: , or a pharmaceutically acceptable salt thereof. The conjugate can have the structure: H HO or a pharmaceutically acceptable salt thereof. The conjugate can have the structure: , or a pharmaceutically acceptable salt thereof. The conjugate can have the structure:

, or a pharmaceutically acceptable salt thereof. A comparative conjugate without a rigid component, such as a GalNAc conjugate I, can have the structure: H H . A conjugate of formula I (e.g., GalNAc conjugate III, such as GalNAc-III-NIR and GalNAc-III-T3), which has a rigid linker, shows a retention time in the liver of more than four days. By comparison, a GalNAc conjugate I, which does not have a rigid linker, clears from the liver within ten hours. The conjugates of the present disclosure (e.g., GalNAc conjugate III, such as GalNAc-III-T3) enable the delivery of an agent to hepatocytes, such as delivery of T3, while minimizing/avoiding off-target toxicities. The conjugates can contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the conjugates are contemplated. When the conjugates described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. Further, it is understood that replacement of one or more hydrogen atoms with deuterium can significantly lower the rate of metabolism of a drug and, therefore, increase its half-life. The term “substituted” as used herein refers to a functional group in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, azides, hydroxylamines, cyano, nitro groups, N-oxides, hydrazides, and enamines; and other heteroatoms in various other groups. The term “optionally substituted,” or “optional substituents,” as used herein, means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. When using the terms “independently,” “independently are,” and “independently selected from” mean that the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other. The term “amino acid” refers to an organic compound that contain both amino and carboxylic acid functional groups. Amino acids can be classified according to the locations of the core structural functional groups (alpha- (α-), beta- (β-), gamma- (γ-) amino acids, etc.). Alpha amino acids can be classified according to stereocenter of the alpha carbon, for example, in an L configuration or a D configuration. An amino acid can refer to one of the 22 proteinogenic amino acids (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, selenocysteine and pyrrolysine), or a non-proteinogenic amino acids (e.g., hydroxyproline, piperidine-carboxylic acid). "Oxo" refers to the =O radical. "Alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). "Alkyl" is intended to include independent recitations of a saturated "alkyl, " unless otherwise stated. An alkyl can comprise one to thirteen carbon atoms (e.g., C1-C13 alkyl). An alkyl can comprise one to eight carbon atoms (e.g., C1-C8 alkyl). An alkyl can comprise one to five carbon atoms (e.g., C₁-C₅ alkyl). An alkyl can comprise one to four carbon atoms (e.g., C1-C4 alkyl). An alkyl can comprise one to three carbon atoms (e.g., C1- C₃ alkyl). An alkyl can comprise one to two carbon atoms (e.g., C₁-C₂ alkyl). An alkyl can comprise one carbon atom (e.g., C1 alkyl). An alkyl can comprise five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). An alkyl can comprise five to eight carbon atoms (e.g., C₅-C₈ alkyl). An alkyl can comprise two to five carbon atoms (e.g., C2-C5 alkyl). An alkyl can comprise three to five carbon atoms (e.g., C₃-C₅ alkyl). In various embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. The term “amide”, as used herein, refers to a group wherein R⁹ and R¹⁰ each independently represent a hydrogen or hydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R⁹, R¹⁰, and R¹⁰, each independently represent a hydrogen or a hydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. Examples of amino groups include, but are not limited to, -NH₂, -NH(alkyl), -N(alkyl)_2. The term “carbonyl” is art-recognized and refers to a group -C(O)- where a double bond exists between the carbon and oxygen. The term “ester,” as used herein, refers to a group —C(O)OR⁹ wherein R⁹ represents a hydrocarbyl group. The term “ether,” as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may be either symmetrical or unsymmetrical. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O- alkyl. "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like. "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indane, indene, tetralin and naphthalene. "Aralkyl" or "aryl-alkyl" refers to a radical of the formula -R^c-aryl, where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. A carbocyclyl can comprise three to ten carbon atoms. A carbocyclyl can comprise five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. "Carbocyclylalkyl" refers to a radical of the formula –R^c-carbocyclyl, where R^c is an alkylene chain as defined above. “Carboxy” or “carboxylic acid group”, as used herein, refers to a group represented by the formula —CO₂H. "Halo" or "halogen" refers to a bromo, chloro, fluoro or iodo substituent. "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The term "heteroalkyl" refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies – for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. -S-, -S(=O)-, or -S(=O)2-). A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. A heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. A heteroalkyl is a C1-C18 heteroalkyl. A heteroalkyl is a C₁-C₁₂ heteroalkyl. A heteroalkyl is a C₁-C₆ heteroalkyl. A heteroalkyl is a C₁-C₄ heteroalkyl. Heteroalkyl can include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. "Heteroalkylene" refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that can comprise two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes aromatic, fused, and/or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. The heterocyclyl radical is partially or fully saturated. "Heterocyclyl" is intended to include independent recitations of heterocyclyl comprising aromatic and non-aromatic ring structures, unless otherwise stated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, indolinyl, isoindolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. "Heterocyclylene" refers to a divalent heterocyclyl group defined above which links one part of the molecule to another part of the molecule. "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Examples of such N-heterocyclyl radicals include, but are not limited to, 1- morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that can comprise two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a ═O or ═S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a ═O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. The compounds and conjugates can be presented as a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to those salts whose counter ions can be used in pharmaceuticals. In various embodiments, such salts include, but are not limited to 1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or 2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are well-known to those skilled in the art, and any such pharmaceutically acceptable salt is contemplated in connection with the embodiments described herein. Pharmaceutically acceptable salts can be synthesized from the parent conjugate/compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is hereby incorporated by reference. In certain embodiments, it can be desired to modify the conjugate and/or composition synthesis process to optimize yield at production (e.g., when the conjugate is optionally bound to a metal suitable for radio-imaging, radiotherapy, or magnetic resonance imaging). For example, a multiple step process can be utilized to facilitate stability of the conjugate at the pH required for radiolabeling. In various embodiments, suitable acid addition salts are formed from acids which form non-toxic salts. Illustrative examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. In various embodiments, suitable base salts are formed from bases which form non- toxic salts. Illustrative examples include the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases also can be formed, for example, hemisulphate and hemicalcium salts. In each embodiment hereof, it will be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds and conjugates, but also include any and all hydrates of the compound formulae or salts thereof where appropriate. The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a “hydrate.” Certain functional groups, such as the hydroxy, amino, and like, can form complexes and/or coordination conjugates with water and/or various solvents. Accordingly, the formulae are to be understood to include and represent those various hydrates and/or solvates. Non- hydrates and/or non-solvates of the compounds and conjugates are also included. The ligands and conjugates can be synthesized in accordance with methods known in the art and exemplified herein. See, e.g., Examples 1-13. Also provided is a pharmaceutical composition comprising an above-described conjugate and a pharmaceutically acceptable carrier. The term "composition" generally refers to any product comprising more than one ingredient, including the conjugate. The compositions can be prepared from isolated conjugates or from salts, solutions, hydrates, solvates, and other forms of the conjugates. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carrier can be an excipient. The choice of carrier can depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. For example, the carrier can be suitable for parenteral administration. Pharmaceutical compositions suitable for the delivery of compounds as described herein and methods for their preparation may be found, for example, in Remington: The Science & Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005). Pharmaceutically acceptable carriers can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Examples of such carriers (or excipients) include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Liquids within which the conjugate can be dispersed include a carrier liquid or an in vivo liquid. By the conjugate being "dispersed" throughout or in a liquid is meant that the conjugate presents as a dispersed phase within the liquid which itself, relative to the conjugate, presents as a continuous liquid medium or phase. The term "liquid" in the context of a liquid carrier is intended to mean a vehicle in which the conjugate is dispersed and which is in a liquid state at least at the temperature of intended use. A liquid carrier can be made up of one or more different liquids. Suitable pharmacologically acceptable liquid carriers are described in Martin, Remington's Pharmaceutical Sciences, 18^th Ed., Mack Publishing Co., Easton, PA, (1990), and include, but are not limited to, liquids that are sterilized, such as water and oils, including those of petroleum, animal, vegetable, mineral or synthetic origin, such as peanut oil, soya bean oil, mineral oil, sesame oil, and the like. Other liquid carriers include methylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, ethanol, isopropyl alcohol, and benzyl alcohol. Water or soluble saline solutions and aqueous dextrose and glycerol solutions can be employed as liquid carriers, particularly for injectable solutions. In practice, the conjugate can be taken up by a subject in vivo, for example, when the conjugate is administered orally or parenterally. In that case, a liquid carrier originally carrying the conjugate can become so dilute in vivo that the surrounding liquid environment throughout which the conjugate is dispersed becomes more representative of an in vivo liquid (i.e., a biological liquid/fluid within the subject) than the original liquid carrier. For example, once administered parenterally, the conjugate might more aptly be described as being dispersed throughout blood rather than an original liquid carrier. Under those circumstances, it can be convenient to refer to the conjugate as being dispersed throughout an in vivo liquid carrier (i.e., a biological liquid/fluid within the subject). The components of the compositions also can be commingled with the conjugate, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The composition can comprise cremophor, polysorbate, nanoparticles, a polymer, or a hydrogel, for example. In certain embodiments, the pharmaceutical composition comprises a plurality of conjugates and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and combinations thereof, that are physiologically compatible. One or more other active agents also can be incorporated into a pharmaceutical composition. In certain embodiments, a pharmaceutical composition further comprises at least one additional pharmaceutically active agent. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of a cancer. In certain embodiments, the at least one additional pharmaceutically active agent can be an agent useful for radiotherapy. In certain embodiments, the at least one additional pharmaceutically active agent can be an agent useful for imaging (e.g., diagnostic imaging). Pharmaceutical compositions can be prepared by combining one or more conjugates with a pharmaceutically acceptable carrier and, optionally, one or more additional ingredients (e.g., pharmaceutically active ingredients). The formulations can be administered in pharmaceutically acceptable solutions, which can routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. Compositions can comprise one or more pharmacologically acceptable additives known to those in the art. For example, the liquid carrier may comprise one or more additives such as wetting agents, de-foaming agents, surfactants, buffers, electrolytes, preservatives, colourings, flavourings, and sweeteners. The particular nature of a liquid carrier and any additive (if present) can, in part, depend upon the intended application of the composition. A suitable liquid carrier and additive (if present) can be selected for the intended application of the composition. The composition is suitable for administration to a subject for diagnostic, mapping, and/or therapeutic applications. By "suitable" for administration is meant that administration of the conjugate/composition to a subject will not result in unacceptable toxicity, including allergenic responses and disease states. For use in therapy or treatment, an effective amount of the conjugate or composition can be administered to a subject by any mode that delivers the conjugate(s) as desired. Administering a composition can be accomplished by any means known to the skilled artisan. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection, mucosal (e.g., topical to eye), inhalation, and topical. Colorants and/or flavoring agents can be included. For example, the conjugate can be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. Illustrative formats for oral administration include, but are not limited to, tablets, capsules, elixirs, syrups, and the like. In certain embodiments, a conjugate and/or composition can be administered directly into the blood stream, into muscle, or into an internal organ. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular, intranasal, and subcutaneous. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. Where it is desirable to deliver the compound(s) and/or compositions systemically, the compound(s) and/or composition can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Parenteral formulations are typically aqueous or non-aqueous isotonic sterile solutions that can contain carriers or excipients, such as salts, carbohydrates, anti-oxidants, bactericide, solute and/or buffering agents (preferably at a pH of 3–9) which renders the composition isotonic with the blood of the intended subject, but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle, such as sterile, pyrogen-free water. Such compositions can be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials. A liquid formulation can be adapted for parenteral administration of a conjugate or composition as described herein. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization under sterile conditions, can readily be accomplished using standard pharmaceutical techniques well-known to those skilled in the art. The solubility of a conjugate can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration can be formulated for immediate and/or modified release. A conjugate can be administered in a time-release formulation, for example in a composition which includes a slow-release polymer. The conjugate can be prepared with a carrier that will protect it against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PGLA). Methods for the preparation of such formulations are generally known to those skilled in the art. Sterile injectable solutions can be prepared by incorporating the conjugate(s), alone or in further combination with one or more other active agents, in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the conjugate(s) into a sterile vehicle, which contains a dispersion medium and any additional ingredients of those described above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying, which yield a powder of the active ingredients plus any additional desired ingredient from a previously sterile-filtered solution thereof, or the ingredients can be sterile- filtered together. The pharmaceutical composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. A conjugate, or a pharmaceutical composition comprising a conjugate, can be continuously administered, where appropriate. Further provided is a method of imaging a liver in a subject. The method comprises administering to the subject an above-described conjugate (e.g., GalNAc conjugate III-56 containing S0456), or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, and imaging the subject. “Subject” means a human or a non-human animal, such as a mammal. The term "subject" does not denote a particular age. Thus, adult, juvenile and newborn subjects are covered. The terms "subject, " "individual" and "patient" may be used interchangeably herein. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. The imaging can be performed after administering the conjugate(s), or pharmaceutically acceptable salt, hydrate or solvate thereof, or pharmaceutical composition comprising same. The imaging can be performed by any suitable means, such as fluorescent imaging or radio-imaging. When the subject has been treated for cancer and the tumor site (e.g., tumor microenvironment) in the subject is imaged, the method can further comprise assessing or monitoring the efficacy of treatment. For example, the conjugates and/or compositions can be used to monitor tumor or lesion growth and proliferation quantitatively in vivo. In certain embodiments, a method of monitoring a progression of a cancer in a subject is provided, comprising administering a conjugate, a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a pharmaceutical composition comprising the conjugate or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof to a subject. Such method can further comprise imaging the cancer of the subject. The subject can be imaged periodically over the course of a therapeutic treatment, and a practitioner can then compare the images and/or otherwise quantify lesion or cancer growth to determine therapeutic efficacy (e.g., if there is a differential killing effect of the cancer cells over the course of the therapeutic treatment, or a relative increase in lesion size or cancer growth). Accordingly, a method is provided for determining a likelihood of success of a therapeutic treatment in a subject. In certain embodiments, the method further comprises assessing or monitoring efficacy of a treatment administered to the subject. When the conjugates, pharmaceutically acceptable salts, hydrates, or solvates thereof, and/or pharmaceutical compositions comprising the conjugate(s) are administered for imaging, the conjugate(s) pharmaceutically acceptable salts, hydrates, or solvates thereof, and/or compositions can be administered by any suitable route including, for example, intravenously, intraperitoneally, subcutaneously, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intracerebrally, and intranasally. Typically, the conjugate(s), pharmaceutically acceptable salts, hydrates, or solvates thereof, and/or compositions are administered intravenously or orally. The conjugates and compositions are administered orally for gastrointestinal scans. The conjugate(s), pharmaceutically acceptable salts, hydrates, or solvates thereof, and/or compositions comprising them can be administered intratumorally or peritumorally. The amount of conjugate(s), pharmaceutically acceptable salts, hydrates, or solvates thereof, and/or compositions administered can, in certain embodiments, be the smallest amount sufficient to generate a clinically useful image. Amounts of currently available contrast agents can be used as a guide in determining the amounts of the conjugate(s), pharmaceutically acceptable salts or hydrates thereof, and/or compositions to be used. In certain embodiment, the methods hereof further comprise treating the subject, or having the subject treated, for cancer. For example, the method can further comprise administering an effective amount of a treatment for cancer (e.g., a second anti-cancer therapy) at a site where the conjugate accumulates. The treatment can be any suitable treatment, such as surgery, radiotherapy, brachytherapy, photodynamic therapy, photothermal therapy, focal ablation therapy including cryoablation, focal laser ablation and high-frequency ultrasound ablation, chemotherapy, and immunotherapy. As for treatment, the therapeutic regimen for the treatment of a disease state (e.g., cancer, fibrosis, an inflammatory disease or disorder, etc.) can be determined by a person skilled in the art and will typically depend on factors including, but not limited to, the type, size, stage and receptor status of a tumor (e.g., with cancer) in addition to the age, weight and general health of the subject. Another determinative factor can be the risk of developing recurrent disease. For instance, for a subject identified as being at high risk or higher risk or developing recurrent disease, a more aggressive therapeutic regimen can be prescribed as compared to a subject who is deemed at a low or lower risk of developing recurrent disease. Similarly, for a subject identified as having a more advanced stage of cancer, for example, stage III or IV disease, a more aggressive therapeutic regimen can be prescribed as compared to a subject that has a less advanced stage of cancer. Still further provided is a method of treating a liver in a subject. The method comprises administering to the subject an effective amount of an above-described conjugate, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. The subject can have nonalcoholic fatty liver disease (NASH), in which case the method can comprise administering to the subject an effective amount of GalNAc-III-T3 (GalNAc conjugate III-64), or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. The terms "treat," "treatment," and "treating" refer to any and all uses which remedy a condition or symptom, or otherwise prevent, hinder, retard, abrogate or reverse the onset or progression of cancer or other undesirable symptoms in any way whatsoever. Thus, the term "treating," and the like, is to be considered in its broadest possible context. For example, treatment does not necessarily imply that a subject is treated until total recovery or cure. In conditions that display or are characterized by multiple signs or symptoms, the treatment need not necessarily remedy, prevent, hinder, retard, abrogate or reverse all signs or symptoms, but can remedy, prevent, hinder, retard, abrogate or reverse one or more signs or symptoms. The expression "therapeutically effective amount" means the amount of conjugate when administered to a mammal, in particular a human, in need of such treatment, is sufficient to treat cancer. The precise amount of conjugate to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the subject. "Administration" of the conjugate(s), pharmaceutically acceptable salt, hydrate, or solvate thereof, and/or composition to a subject is meant that the conjugate(s), pharmaceutically acceptable salt, hydrate, or solvate thereof, or composition is presented such that the conjugate(s) and/or pharmaceutically acceptable salts, hydrates, or solvates thereof can be transferred to the subject. There is no particular limitation on the mode of administration, but this will generally be by way of oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intracerebrally, intranasally, intrathecal, and intraspinal), inhalation (including nebulization), topical, rectal and vaginal modes. The conjugate(s), pharmaceutically acceptable salt, hydrate, or solvate thereof, and/or composition can also be administered directly into a tumor and/or into tissue adjacent one or more segments of a tumor or administered directly into blood vessels. The conjugate(s), pharmaceutically acceptable salt, hydrate, or solvate thereof, and/or composition can be administered in, as appropriate, a treatment or diagnostic effective amount. A treatment or diagnostic effective amount includes an amount which, when administered according to the desired dosing regimen, achieves a desired therapeutic or diagnostic effect, including one or more of: alleviating the symptoms of, preventing or delaying the onset of, inhibiting or slowing the progression of, diagnosing, or halting or reversing altogether the onset or progression of a particular condition being treated and/or assessed. As used herein, “effective amount” means and encompasses both therapeutically effective amount and treatment or diagnostic effective amount. Suitable dosage amounts and dosing regimens to achieve this can be determined by the attending physician and can depend on the particular condition being treated or diagnosed, the severity of the condition as well the general age, health and weight of the subject. Depending upon the route of administration, a wide range of permissible dosages are contemplated. The dosing can occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages of the particulate material per se can lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage can be in the range of 1 µg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage can be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage can be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage. Conjugate(s), pharmaceutically acceptable salt, hydrate, or solvate thereof, and/or compositions hereof can be administered in a single dose or a series of doses. For example, dosages may be single or divided and may be administered according to a wide variety of protocols, including q.d. (once a day), b.i.d. (twice a day), t.i.d. (three times a day), or even every other day, once a week, once a month, once a quarter, and the like. In each of these cases it is understood that the effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, month, or quarterly dose, as determined by the dosing protocol. In addition to the illustrative dosages and dosing protocols described herein, an effective amount of any one or a mixture of the compounds described herein can be determined by the attending diagnostician or physician by the use of known techniques and/or by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician or physician, including, but not limited to the species of mammal, including human, its size, age, and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances. In certain embodiments, a use of a conjugate, a pharmaceutically acceptable salt, hydrate, or solvate of the conjugate, or a composition hereof in the manufacture of a medicament for the treatment of a disease in a subject is provided. The conjugate can be any compound or conjugate hereof. The disease in the subject can be cancer. The disease in the subject can be fibrosis. The disease in the subject can be an inflammatory disease or disorder. Any of the conjugates and/or compositions hereof can be for use in the treatment of a subject experiencing and/or having a disease state described herein. The disease state, for example, can be cancer, fibrosis, or an inflammatory disease or disorder. Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. The implementations should not be limited to the particular limitations described. Other implementations may be possible. While the conjugates and pharmaceutical compositions are illustrated and described in detail in the foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only certain embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected. Various techniques and mechanisms will sometimes describe a connection or link between two components. Words such as attached, linked, coupled, connected, and similar terms with their inflectional morphemes are used interchangeably, unless the difference is noted or made otherwise clear from the context. These words and expressions do not necessarily signify direct connections but include connections through mediate components. It should be noted that a connection between two components does not necessarily mean a direct, unimpeded connection, as a variety of other components may reside between the two components of note. Consequently, a connection does not necessarily mean a direct, unimpeded connection unless otherwise noted. Even still further provided is a method of improving the residence time in a liver of a mammal of a conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in the mammalian liver. The method comprises modifying/replacing L with a linker having the structure L₁(NH)C(CH₂OL₂R)_x, wherein L₁ is a linker bound to A, L₂ is a linker comprising a rigid component, and x is an integer from 1 to 3. The rigid component of L2 can be an oligoproline. The rigid component of L₂ can be an oligopiperidine. The rigid component of L₂ can be an α-helix. The rigid component of L₂ can be peptidic. The rigid component of L₂ can be the amino acid sequence (EAAAK)3. The rigid component can be selected from: . L2 can comprise an alkyl group, a PEG, a peptide, or a combination of two or more thereof. The residence time in the liver of the mammal is at least three days. In view of the above, also provided is a conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in a liver of a mammal, wherein L has the structure L₁(NH)C(CH₂OL₂R)_x, wherein L1 is a linker bound to A, L2 is a linker comprising a rigid component, and x is an integer from 1 to 3, wherein the rigid component of L2 is an oligoproline, an oligopiperidine, an α-helix, the amino acid sequence (EAAAK)3, or a structure selected from: wherein L2 optionally further comprises an alkyl group, a PEG, a peptide, or a combination of two or more thereof; and wherein the conjugate has a residence time in the liver of the mammal of at least three days. ALTERNATIVE EMBODIMENTS 1. A conjugate of formula I: formula (I) wherein L₁ is a linker, L₂ is a linker comprising a rigid component, A is an active agent, and R is a ligand that binds an asialoglycoprotein receptor (ASGPR). 2. The conjugate of clause 1, wherein the active agent is a therapeutic agent. 3. The conjugate of clause 2, wherein the therapeutic agent has a therapeutic effect in the liver. 4. The conjugate of clause 2 or 3, wherein the therapeutic agent is a hormone. 5. The conjugate of clause 2, wherein the therapeutic agent is a thyroid hormone receptor beta (THRβ) agonist. 6. The conjugate of clause 5, wherein the THRβ agonist is triiodothyronine (T3). 7. The conjugate of clause 2, wherein the therapeutic agent is a farnesoid X receptor (FXR) agonist. 9. The conjugate of clause 7, wherein the FXR agonist is tropifexor (LJN452). 10. The conjugate of clause 2, wherein the therapeutic agent is a peroxisome proliferator-activated receptor α agonist or αδ dual agonist. 11. The conjugate of clause 10, wherein the αδ dual agonist is elafibranor (GFT505). 12. The conjugate of clause 2, wherein the therapeutic agent is an angiotensin II receptor blocker. 13. The conjugate of clause 12, wherein the angiotensin II receptor blocker is telmisartan, candesartan, or losartan. 14. The conjugate of clause 2, wherein the therapeutic agent is a patatin-like phospholipase domain-containing protein 3 (PNPLA3) inhibitor. 15. The conjugate of clause 14, wherein the PNPLA3 inhibitor is an siRNA or an antisense oligonucleotide. 16. The conjugate of clause 2, wherein the therapeutic agent is a complement component C5 inhibitor. 17. The conjugate of clause 16, wherein the complement component C5 inhibitor is an siRNA or an antisense oligonucleotide. 18. The conjugate of clause 2, wherein the therapeutic agent is a stearoyl-CoA desaturase-1 (SCD1) inhibitor. 19. The conjugate of clause 18, wherein the SCD1 inhibitor is an siRNA or an antisense oligonucleotide. 20. The conjugate of clause 2, wherein the therapeutic agent is a diacylglycerol acyltransferase 1 (DGAT1) inhibitor. 21. The conjugate of clause 20, wherein the DGAT1 inhibitor is pradigastat (LCQ- 908) or T-863. 22. The conjugate of clause 2, wherein the therapeutic agent is a δ-aminolevulinate synthase 1 inhibitor. 23. The conjugate of clause 22, wherein the δ-aminolevulinate synthase 1 inhibitor is an siRNA or an antisense oligonucleotide. 24. The conjugate of clause 2, wherein the therapeutic agent is an angiopoietin-like 3 protein (ANGPTL3) inhibitor. 25. The conjugate of clause 24, wherein the ANGPTL3 inhibitor is an siRNA or an antisense oligonucleotide. 26. The conjugate of clause 2, wherein the therapeutic agent is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. 27. The conjugate of clause 26, wherein the PCSK9 inhibitor is an siRNA or an antisense oligonucleotide. 28. The conjugate of clause 2, wherein the therapeutic agent is an apolipoprotein C- III (ApoC-III) inhibitor. 29. The conjugate of clause 28, wherein the ApoC-III inhibitor is an siRNA or an antisense oligonucleotide. 30. The conjugate of clause 2, wherein the therapeutic agent is an apolipoprotein B (apoB) inhibitor. 31. The conjugate of clause 30, wherein the apoB inhibitor is an siRNA or an antisense oligonucleotide. 32. The conjugate of clause 2, wherein the therapeutic agent is a glycolate oxidase (GO) inhibitor. 33. The conjugate of clause 32, wherein the GO inhibitor is an siRNA or an antisense oligonucleotide. 34. The conjugate of clause 2, wherein the therapeutic agent is an α-1 antitrypsin (AAT) inhibitor. 35. The conjugate of clause 34, wherein the AAT inhibitor is an siRNA or an antisense oligonucleotide. 36. The conjugate of clause 2, wherein the therapeutic agent is an antiviral small molecule drug. 37. The conjugate of clause 36, wherein the antiviral small molecule drug is an antiviral small molecule drugs for hepatitis A virus (HAV), hepatitis B virus (HBV), or hepatitis C virus (HCV). 38. The conjugate of clause 37, wherein the antiviral small molecule drug for HBV is entecavir, tenofovir, lamivudine, adefovir, or telbivudine. 39. The conjugate of clause 37, wherein the antiviral small molecule drug for HCV is elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/ledipasvir, or sofosbuvir/velpatasvir. 40. The conjugate of clause 2, wherein the therapeutic agent is an antiviral siRNA or an antiviral antisense oligonucleotide. 41. The conjugate of clause 40, wherein the antiviral siRNA or the antiviral antisense oligonucleotide is an antiviral siRNA or an antiviral antisense oligonucleotide for HAV, HBV, or HCV. 42. The conjugate of clause 2, wherein the therapeutic agent is an siRNA or an antisense oligonucleotide. 43. The conjugate of clause 2, wherein the active agent is an imaging agent. 44. The conjugate of clause 43, wherein the imaging agent is fluorescent. 45. The conjugate of clause 43, wherein the imaging agent is a radio-imaging agent. 46. The conjugate of clause 1, wherein L1 is a non-releasable linker. 47. The conjugate of clause 1, wherein L1 is a slowly releasable linker. 48. The conjugate of clause 1, wherein L1 comprises an alkyl group, a polyethylene glycol (PEG), a peptide, or a combination of two or more thereof. 49. The conjugate of clause 1, wherein L1 is a releasable linker. 50. The conjugate of clause 49, wherein L1 is reductively cleavable. 51. The conjugate of clause 49, wherein L1 is oxidatively cleavable. 52. The conjugate of clause 49, wherein L1 is enzymatically cleavable. 53. The conjugate of clause 49, wherein L1 is acid-cleavable. 54. The conjugate of clause 1, wherein L1 is: . 55. The conjugate of clause 1, wherein the rigid component of L2 improves residence time of the conjugate in the liver. 56. The conjugate of clause 1, wherein the rigid component of L2 is an oligoproline. 57. The conjugate of clause 1, wherein the rigid component of L2 is an oligopiperidine. 58. The conjugate of clause 1, wherein the rigid component of L2 is an α-helix. 59. The conjugate of clause 58, wherein the rigid component of L2 is peptidic. 60. The conjugate of clause 1, wherein the rigid component of L2 is the amino acid sequence (EAAAK)3. 61. The conjugate of clause 1, wherein the rigid component is selected from: . 62. The conjugate of clause 1, wherein L2 comprises an alkyl group, a PEG, a peptide, or a combination of two or more thereof. 63. The conjugate of clause 1, which has a residence time in the liver of at least three days. 64. The conjugate of clause 1, which has a binding affinity (kd) of about 0.1 nM to about 100 nM. 65. The conjugate of clause 1, wherein R is a carbohydrate. 66. The conjugate of clause 1, wherein R is a monosaccharide. 67. The conjugate of clause 1, wherein R is selected from galactose, glucose, fucose, mannose, galactosamine, rhamnose, rhamnitol, N-acetylgalactosamine (GalNAc), mannosamine, glucosamine, N-acetyl-glucosamine (GluNAc), fucosamine and rhamnosamine. 68. The conjugate of clause 1, which has the structure: . 69. The conjugate of clause 1, which has the structure: 70. A pharmaceutical composition comprising a conjugate of any one of clauses 1-69 and a pharmaceutically acceptable carrier. 71. A method of imaging a liver in a subject, which method comprises administering to the subject a conjugate of any one of clauses 43-45 and 68, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, and imaging the subject. 72. A method of treating a liver in a subject, which method comprises administering to the subject an effective amount of a conjugate of any one of clauses 1-42, 46-67, and 69, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, whereupon the liver in the subject is treated. 73. The method of clause 72, wherein the subject has nonalcoholic fatty liver disease (NASH). 74. The method of clause 73, wherein the method comprises administering to the subject an effective amount of the conjugate of clause 69 or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. 75. A method of improving the residence time in a liver of a mammal of a conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in the mammalian liver, which method comprises modifying/replacing L with a linker having the structure L1(NH)C(CH2OL2R)x, wherein L₁ is a linker bound to A, L₂ is a linker comprising a rigid component, and x is an integer from 1 to 3. 76. The method of clause 75, wherein the rigid component of L₂ is an oligoproline. 77. The method of clause 75, wherein the rigid component of L2 is an oligopiperidine. 78. The method of clause 75, wherein the rigid component of L2 is an α-helix. 79. The method of clause 75, wherein the rigid component of L2 is peptidic. 80. The method of clause 75, wherein the rigid component of L2 is the amino acid sequence (EAAAK)3. 81. The method of clause 75, wherein the rigid component is selected from: . 82. The method of clause 75, wherein L2 comprises an alkyl group, a PEG, a peptide, or a combination of two or more thereof. 83. The method of clause 75, wherein the residence time in the liver of the mammal is at least three days. 84. A conjugate comprising an active agent A linked via a linker L to at least one ligand R that binds an asialoglycoprotein receptor (ASGPR) on a hepatocyte in a liver of a mammal, wherein L has the structure L₁(NH)C(CH₂OL₂R)_x, wherein L₁ is a linker bound to A, L2 is a linker comprising a rigid component, and x is an integer from 1 to 3, wherein the rigid component of L2 is an oligoproline, an oligopiperidine, an α-helix, the amino acid sequence (EAAAK)3, or a structure selected from:

, wherein L2 optionally further comprises an alkyl group, a PEG, a peptide, or a combination of two or more thereof; and wherein the conjugate has a residence time in the liver of the mammal of at least three days. EXAMPLES The examples and preparations provided below further illustrate and exemplify particular aspects of embodiments of the disclosure. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples. Example 1 Synthesis of Gal-3 (5-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid) Step 1: Synthesis of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a- tetrahydro-5H-pyrano[3,2-d]oxazole-6,7-diyl diacetate (Gal-1) Commercially available galactosamine pentaacetate (8.0 g, 20.5 mmol, 1.0 eq.) was dissolved in anhydrous dichloroethane (50 mL) at room temperature, and TMSOTf (5.98 mL, 32.9 mmol, 1.6 eq.) was added to the reaction mixture. The reaction was stirred at 60 ^oC for 90 minutes, allowed to come to room temperature, and stirred for another 12 hours. The reaction was diluted with sat. NaHCO3 solution, and the product was extracted with dichloroethane. The combined organic layer was washed with water followed by brine solution and dried over Na2SO4. The solvents were removed under reduced pressure, and the residue was dried under high vacuum overnight to yield Gal-1(6.5 g) as dark brown-colored gum. LCMS m/z calc’d for C14H20NO8 (M + H)⁺ 330.11; found 330.10. Step 2: Synthesis of Gal-2 Freshly prepared Gal-1 (1.5 g, 1.0 eq.) was dissolved in anhydrous 1,2-dichloroethane (8 vol) at room temperature, 4 Å molecular sieve powder (1.0 eq, wt/wt) was added to the reaction, and the reaction was allowed to stir for 5 min at room temperature. 5-hexen-1-ol (1.2 eq.) was added under N2 atmosphere and allowed to stir for another 30 min. Finally, TMSOTf was added slowly, and stirring continued for 2 hours at room temperature. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with sat. NaHCO3 solution and filtered to remove the molecular sieves. The filtrate was extracted with dichloromethane, washed with NaHCO3 and water, and dried over Na2SO4. Solvents were removed, and the residue was dried under high vacuum overnight to provide a dark brown- colored gum, which was triturated with hexanes to get Gal-2 as a light brown-colored solid in quantitative yield. LCMS m/z calc’d for C₂₀H₃₂NO₉ (M + H)⁺ 430.47; found 430.2. Step 3: Synthesis of Gal-3 Freshly prepared Gal-2 (7.0 g, 1.0 eq.) was dissolved in dichloroethane (3 vol) and acetonitrile (3 vol) at room temperature. To the resultant clear solution, sodium metaperiodate (13.96 g.4.0 eq) was added, and the mixture was allowed to stir for 5 min at room temperature. RuCl3.H2O (0.14 g, 0.05 eq.) was added to the reaction mixture, and the mixture was allowed to stir at 30 ^oC (highly exothermic, cold-water bath) for another hour. To the resultant reaction mixture, another 1.0 eq. of NaIO4 was added, and the mixture was allowed to stir for another 3 hours at room temperature. Reaction progress was monitored by LCMS. The reaction mixture was diluted with water, and the pH of the resultant solution was adjusted to 7.5 with solid NaHCO3 and filtered to remove the undissolved particles. The filtrate was washed with dichloromethane. The organic layer was discarded, and the aqueous layer was acidified to pH 2.0 with citric acid and saturated with NaCl. The resultant solution was extracted with EtOAc (3 x 500 mL). The resultant organic layer was dried over Na₂SO₄, and solvents were concentrated under reduced pressure. The resultant crude was purified by combi-flash (MeOH:CH₂Cl₂, 1:9) to get Gal-3as a colorless solid. LCMS m/z calc’d for C₁₉H₃₀NO₁₁ (M + H)⁺ 448.44; found 448.2. Example 2 Synthesis of GalNAc-Tris-4 Step 1: Synthesis of Tris-1 A round-bottomed flask containing tris(hydroxymethyl)aminomethane (15.0 g) and potassium hydroxide (3.0 g, 53 mmol, 3.0 eq.) was added dioxane (150 mL). After 10 min, to that colorless suspension, 3.5 equivalent of acrylonitrile was added dropwise slowly. After stirring for another 24 hours at room temperature, the reaction was diluted by adding a copious amount of chloroform, washing with water, drying the organic solution over anhydrous Na₂SO₄, and concentrating the solvents to achieve a crude product as yellow- colored liquid. The crude product was purified by combi-flash using DCM:MeOH (9:1) to get a final yellow liquid of Tris-1 in 74.3%. Step 2: Synthesis of Tris-2 Tris-1 was dissolved in EtOH^.HCl (3.3 M, 10 mL/1.0 g) and allowed to stir at reflux temperature (80 ^oC an internal temperature). After completing the reaction (monitored by LCMS, usually 6 hours), the resulting solution was concentrated, and the resultant crude was diluted with DCM and washed with Sat. NaHCO₃ (expected to be exothermic) solution, followed by brine, and dried over Na2SO4. The crude compound was purified by flash chromatography (DCM:MeOH, 9:1) (Tris-2). LCMS m/z calc’d for C₁₉H₃₆NO₉ (M + H)⁺ 422.23; found 422.3. Step 3: Synthesis of Tris-3 To a stirred solution of Tris-2 (7.0 g,16.62 mmol) in dioxane was added Na₂CO₃ (2.642 g, 24.93 mmol) followed by water (24 mL). To this solution was added Cbz-Cl (2.44 mL, 18.33 mmol), and the reaction was allowed to continue for 12 hours. The solvent was removed under reduced pressure, and the resulting oil was purified by flash chromatography (Hexanes: EtOAc, 1:1) to yield compound Tris-3 as a colorless liquid. LCMS m/z calc’d for C27H42NO11 (M + H)⁺ 556.27; found 556.3. Step 4: Synthesis of Tris-4 To a stirred solution of Tris-3 (2.2 g, 3.96 mmol) in MeOH (30 mL) was added LiOH^.H2O (1,42 g, 59.4 mmol) followed by water: THF (30 mL, 1:1). The resulting solution was allowed to stir for 1 hour at room temperature. After completion of reaction, pH was acidified to 2 with concentrated HCl. The volatile solvents were removed under reduced pressure using rotavapor, the resulting oil was diluted with EtOAc, and the organic layer was washed with water and dried over Na2SO4. The solvents were concentrated under reduced pressure, and the resultant crude was used without any further purification for next step. LCMS m/z calc’d for C21H30NO11 (M + H)⁺ 472.17; found 472.3. Step 5: Synthesis of Tris-5 To Tris-4 (1.5 g, 3.18 mmol) in DMF (20 mL) was added HBTU (5.42 g, 14.31 mmol), HOBt (1.93 g, 14.31, 4.5 eq.) and DIPEA (5.52 mL, 31.8 mmol, 10.0 eq.), and the resulting solution was allowed to stir for 15 min. To the resulting solution, N-Boc-1,3-propanediamine (3.33 mL, 19.08 mmol) was added at room temperature and allowed to stir for 12 hours. After reaction completion, as monitored by LCMS, the reaction mixture was diluted with 1 M phosphoric acid and extracted with DCM. The resultant organic layer was concentrated and purified by combi-flash using CH₂Cl₂ and MeOH (9:1) mixture as eluant to get the compound Tris-5. LCMS m/z calcd for C44H76N7O13 (M + H)⁺ 910.54; found 910.5. Step 6: Synthesis of Tris-6 To Tris-5 in DCM (10 vol) was added trifluoroacetic acid (3 vol), and the reaction mixture was allowed to stir at room temperature for 30 min. Boc deprotection was confirmed by LCMS, and the resulting solution was concentrated and co-distilled with toluene. The resultant compound was used for the next step without any further purification. Step 7: Synthesis of GalNAc-Tris-1 To Gal-3 (2.31 g, 5.17 mmol) in DMF (20 mL) was added HBTU (2.52 g, 6.66 mmol), HOBt (0.89 g, 6.66 mmol, 4.5 eq.) and DIPEA (2.57 mL, 14.8 mmol, 10.0 eq.), and the resulting solution was allowed to stir for 15 min. To the resulting solution, Tris-6 (0.95 g, 1.48 mmol, 1.0 eq.) in DMF (6 mL) was added at room temperature and allowed to stir for 12 hours. After reaction completion, as monitored by TLC, the reaction mixture was diluted with 1 M phosphoric acid and extracted with DCM. The resultant organic layer was concentrated and purified by combi-flash using CH2Cl2 and MeOH (4:1) mixture as eluant to get the compound GalNAc-Tris-1. LCMS m/z calc’d for C₈₇H₁₃₅N₁₀O₃₈ (M + H)⁺ 1926.89; found 1926.97. Step 8: Synthesis of GalNAc-Tris-2 To GalNAc-Tris-1 (0.760 g) in MeOH (10 mL) was added 10% Pd on carbon (0.08 g, 10% wt/wt), and the reaction mixture was allowed to stir at room temperature for 2 hours under hydrogen atmosphere (balloon pressure). Cbz deprotection was confirmed by TLC, and the reaction mixture was filtered through a celite pad. The resulting filtrate was concentrated under reduced pressure and co-distilled with toluene. The resultant compound GalNAc-Tris-2 was used for next step without any further purification. Step-9: Synthesis of GalNAc-Tris-3 To N-Cbz hexanoic acid (0.288 g, 1.087 mmol) in DMF was added HATU (0.413 g, 1.087 mmol) 2.0 eq.) and DIPEA (1.3 mL, 7.25 mmol, 10.0 eq.), and the resulting solution was allowed to stir for 15 min. To the resulting solution, GalNAc-Tris-2 (1.3 g, 0.725 mmol) in DMF was added at room temperature and allowed to stir for 3 hours. After reaction completion, as monitored by TLC, the reaction mixture was diluted with 1 M phosphoric acid and extracted with DCM. The resulted organic layer was concentrated and purified by combi-flash using CH₂Cl₂ and MeOH (4:1) mixture as eluant to get the compound GalNAc-Tris-3. LCMS m/z calc’d for C93H146N11O39 (M + H)⁺ 2039.97; found 2040.17. Step-10: Synthesis of GalNAc-Tris-4

GalNAc-Tris-3 (0.4 g) in MeOH (5 mL) was added 10% Pd on carbon (0.040 g, 10% wt/wt), and the reaction mixture was allowed to stir at room temperature for 2 hours under hydrogen atmosphere (balloon pressure). Cbz deprotection was confirmed by LCMS, and the reaction mixture was filtered through the celite pad. The resulting filtrate was concentrated under reduced pressure and co-distilled with toluene. The resultant compound was used for the next step without any further purification. LCMS m/z calc’d for C₈₅H₁₄₀N₁₁O₃₇ (M + H)⁺ 1905.97; found 1906.17. K Step-1: Synthesis of NIR-acid Potassium salt of 3-(4-hydroxy phenyl) propionic acid (0.5 g, 2.4 mmol) in DMSO was added sodium 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-5-sulfonato-1-(4- sulfonatobutyl)indolin-2-ylidene)ethylidene)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(4- sulfonatobutyl)-3H-indol-1-ium-5-sulfonate (Cl-S0456) (2.3 g, 2.4 mmol) was allowed to stir for 1 hour. The resultant product was purified by HPLC to yield NIR-acid as a green solid. LCMS m/z calcd for C₄₇H₅₈N₂O₁₅S₄ (M + H)⁺ 1017.26 found 1017.31. Ac Ac Step-2: To NIR-acid (0.020 g, 0.02 mmol) in dry DMSO was added HATU (0.033 g, 0.09 mmol, 4.5 eq.), and DIPEA (0.04, 0.2 mmol, 10.0 eq.). The resulting solution was allowed for stirring for 15 min. To the solution, GalNAc-Tris-4 (0.04 g, 0.013 mmol) was added at rt and allowed to stir for 1h. After reaction completion, monitored by LCMS, the mixture was diluted with water. The product was purified by HPLC to get GalNAc-I-NIR-1. LCMS m/z calcd for C₁₃₂H₁₉₅N₁₃O₅₁S₄ (M + H)⁺ 2905.19 found 2905.27. Step-3: To GalNAc-I-NIR-1 (0.005 g, 0.02 mmol) was added 10 % aq. NH3 (0.5 mL) and allowed to stir for 30 min. The product formation was monitored by LCMS and was purified by UPLC using a gradient mobile phase of A = 20 mM ammonium acetate buffer (pH = 7) and B = acetonitrile; solvent gradient 0% B to 35% B over 60 mins (column: Waters xTerra C18, 10 μm; 19 x 250 mm). Elution of the conjugates were monitored at λ = 254 nm, the identities of the eluted compounds were analyzed by LC-MS. LCMS m/z calcd for C114H177N13O42S4 (M + H)⁺ 2527.09 found 2527.12. Example 4 Step 1: Synthesis of Gal-1 Commercially available galactosamine pentaacetate (8.0 g, 20.5 mmol, 1.0 eq.) was dissolved in anhydrous dichloroethane (50 mL) at room temperature, and TMSOTf (5.98 mL, 32.9 mmol, 1.6 eq.) was added to the reaction mixture. The reaction was stirred at 60 ^oC for 90 minutes, allowed to come to room temperature, and stirred for another 12 hours. The reaction was diluted with sat. NaHCO3 solution, and the product was extracted with dichloroethane. The combined organic layer was washed with water followed by brine solution and dried over Na₂SO₄. The solvents were removed under reduced pressure, and the residue was dried under high vacuum overnight to yield Gal-1 (6.5 g) as dark brown-colored gum. LCMS m/z calc’d for C₁₄H₂₀NO₈ (M + H)⁺ 330.11; found 330.10. Step 2: Synthesis of Gal-2 Freshly prepared Gal-1 (1.5 g, 1.0 eq.) was dissolved in anhydrous 1,2-dichloroethane (8 vol) at room temperature, 4 Å molecular sieve powder (1.0 eq, wt/wt) was added to the reaction, and the reaction was allowed to stir for 5 min at room temperature. 3-buten-1-ol (1.2 eq.) was added under N₂ atmosphere and allowed to stir for another 30 min. Finally, TMSOTf was added slowly, and stirring continued for 2 hours at room temperature. After the reaction was completed (monitored by LCMS), the reaction mixture was quenched with sat. NaHCO3 solution and filtered to remove the molecular sieves. The filtrate was extracted with dichloromethane, washed with NaHCO₃ and water, and dried over Na₂SO₄. Solvents were removed, and the residue was dried under high vacuum overnight to provide a dark brown- colored gum, which was triturated with hexanes to get Gal-2 as a light yellow liquid in quantitative yield. Step 3: Synthesis of GalNAc-III-8 Freshly prepared Gal-2 (7.0 g, 1.0 eq.) was dissolved in dichloroethane (3 vol) and acetonitrile (3 vol) at room temperature. To the resultant clear solution, sodium metaperiodate (13.96 g.4.0 eq) was added, and the mixture was allowed to stir for 5 min at room temperature. RuCl3.H2O (0.14 g, 0.05 eq.) was added to the reaction mixture, and the mixture was allowed to stir at 30 ^oC (highly exothermic, cold-water bath) for another hour. To the resultant reaction mixture, another 1.0 eq. of NaIO4 was added, and the mixture was allowed to stir for another 3 hours at room temperature. Reaction progress was monitored by LCMS. The reaction mixture was diluted with water, and the pH of the resultant solution was adjusted to 7.5 with solid NaHCO₃ and filtered to remove the undissolved particles. The filtrate was washed with dichloromethane. The organic layer was discarded, and the aqueous layer was acidified to pH 2.0 with citric acid and saturated with NaCl. The resultant solution was extracted with EtOAc (3 x 500 mL). The resultant organic layer was dried over Na2SO4, and solvents were concentrated under reduced pressure. The resultant crude was purified by combi-flash (MeOH:CH2Cl2, 1:9) to get GalNAc-III-8 (Gal-8) as a colorless viscous liquid. LCMS m/z calc’d for C18H31N4O7 (M + H)⁺ 431.21; found 431.4. Example 5 Synthesis of Tris-10 Step-1: Synthesis of diethyl 3,3'-((2-((tert-butoxycarbonyl)amino)-2-((3-ethoxy-3- oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionate (Tris-7)

To a stirred solution of diethyl 3,3'-((2-amino-2-((3-ethoxy-3- oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionate (Tris-2) (5.6 g, 13.3 mmol), prepared according to the methods described in Example 2, in dioxane (60 mL) was added (Boc)2O (7.24 g, 33.25 mmol) followed by Sat. NaHCO3 (60 mL). The reaction was allowed to stir for 12 hours and was diluted with CH₂Cl₂. The organic layer was washed with water and brine solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by flash chromatography to get Tris-7. LCMS m/z calc’d for C24H44NO11 (M + H)⁺ 522.28; found 522.34. Step-2: Synthesis of 3,3'-((2-((tert-butoxycarbonyl)amino)-2-((2- carboxyethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionic acid (Tris-8) To a stirred solution of Tris-7 (3.0 g, 5.7 mmol) in MeOH (30 mL) was added LiOH^.H₂O (1.38 g, 57 mmol, 10.0 eq.)) followed by water: THF (30 mL, 1:1). The resulting solution was allowed to stir for 1 hour at room temperature. After completion of reaction, pH was acidified to pH=2 with concentration HCl. The volatile solvents were removed under reduced pressure, the resulting oil was diluted with EtOAc, and the organic layer was washed with water and dried over Na2SO4. The solvents were concentrated under reduced pressure, and the resultant crude was used without any further purification for the next step. Synthesis of Tris-9 Step-3: To Tris-8 (6.3 g, 14.4 mmol) in dry DMF (100 mL) were added HATU (24.68 g, 64.8 mmol, 4.5 eq.) and DIPEA (15.02 mL, 86.4 mL, 6.0 eq.), and the resulting solution was allowed to stir for 15 min. To the solution, NFmoc-1,2-ethylenediamine (24.68 g, 64.8 mmol) was added at room temperature, and the resulting solution was allowed to stir for 2 hours. After reaction completion, as monitored by LCMS, the mixture was diluted with DCM and washed with water. The resultant organic layer was concentrated and purified by combi-flash using CH2Cl2 and MeOH mixture as eluant. LCMS m/z calc’d for C64H72N7O12 (M + H)⁺ 1230.52; found 1230.87. Step-4: Synthesis of Tris-9 To the product of step 3 (3.2 g) in DCM (30 mL) was added trifluoroacetic acid (10 mL), and the reaction mixture was stirred at room temperature for 30 min. Boc deprotection was confirmed by LCMS, and the resulting solution was concentrated and co-distilled with toluene. The resultant compound was used for the next step without any further purification. LCMS m/z calc’d for C64H72N7O12 (M + H)⁺ 1130.52; found 1130.87. Synthesis of Tris-10

Step-5: To Tris-9 (1.0 g, 0.884 mmol) in dry DMF (10 mL) were added PyBOP (0.919 g, 1.769 mmol) and DIPEA (0.307 mL, 1.769 mmol), and the resulting solution was allowed to stir for 15 min.4-(tert-butoxy)-4-oxobutanoic acid (0.310 g, 1.769 mmol) was added at room temperature, and the solution was stirred for two hours. After reaction completion, as monitored by LCMS, the mixture was diluted with DCM and washed with water. The resultant organic layer was concentrated and purified by combi-flash using a mixture of CH2Cl2 and MeOH as eluant. LCMS m/z calc’d for C₇₂H₈₄N7O₁₅ (M + H)⁺ 1286.59; found 1287.12. Step-6: Synthesis of Tris-10 To the product of step 5 (3.0 g) in DCM (30 mL) was added trifluoroacetic acid (10 mL), and the reaction mixture was allowed to stir at room temperature for two hours. Tertiary butyl deprotection was confirmed by LCMS, and the resulting solution was concentrated and co-distilled with toluene. The resultant compound was used for the next step without any further purification. LCMS m/z calc’d for C68H76N7O15 (M + H)⁺ 1230.53; found 1230.67. Example 6 Synthesis of GalNAc-III-Tris-1 (GalNAc-III-54)

Commercially available 1,2-diaminoethane trityl resin (1.0 g, 0.98 mmol) was swollen with dichloromethane (20 mL) for 20 mins followed by dimethyl formamide (2 × 15 mL) for 15 mins each. Then, a solution of Tris-10 (2.41 g, 1.96 mmol), Cl-HOBt (0.331 g, 1.96 mmol), tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.02 g, 1.96 mmol), and N, N- Diisopropylethylamine (DIPEA) (5.1 mL, 30 mmol) in DMF (30 mL) was added. After bubbling under argon for three hours, the resin was washed with DMF (2 × 20 mL) for 10 mins each. Then, a Kaiser test was performed and showed negative result. After swelling the resin in DMF, 20% piperidine in DMF (3 × 20 mL) was added to the resin and bubbled under nitrogen for 15 mins each time to deprotect the Fmoc group. The resin was then washed with DMF. After that, a solution of Fmoc-Pro-OH (2.0 g, 5.88 mmol), PyBOP (3.05 g, 5.88 mmol), Cl- HOBt (1.0 g, 5.88 mmol), and DIPEA (1.0 mL, 5.88 mmol) in DMF (20 mL) was added to the resin and bubbled under argon for four hours. Then, the resin was again washed with DMF (2 × 20 mL) for 10 mins and tested by a Kaiser test. After confirming the coupling of proline on the resin by LCMS, 20% piperidine in DMF (3 × 20 mL) was added to the resin. Then, the resin was washed with DMF. The above procedure was repeated to add three proline units. After, successful addition of three proline units was confirmed by LCMS. The Fmoc group was deprotected by 20% piperidine in DMF (3 × 20 mL). Then, the resin was washed with DMF. After that, a solution of Gal-8 (2.47 g, 5.88 mmol), PyBOP (3.05 g, 5.88 mmol), Cl- HOBt (1.0 g, 5.88 mmol), and DIPEA (1.0 mL, 5.88 mmol) in DMF (30 mL) was added to the resin and bubbled under argon for 12 hours. GalNAc-III-Tris-1 was cleaved from the resin using the cocktail solution DCM: TFA: triisopropylsilane (TIPS) (55:40:5) (3 × 20 mL) for 20 min each time. The compound was concentrated under vacuum. Excess TFA was evaporated under rotavapor. Then, the crude product was precipitated in cold diethyl ether solution and centrifuged at 2,000 rpm for 10 mins. The supernatant was removed. The product was dissolved in dimethyl sulfoxide (DMSO) and purified using preparative reverse-phase high performance liquid chromatography (RPHPLC) using a gradient mobile phase of A = 20 mM ammonium acetate buffer (pH = 7) and B = acetonitrile; solvent gradient 0% B to 55% B over 40 mins (column: Waters xTerra C18, 10 μm; 19 x 250 mm). Elution of the conjugates was monitored at λ = 210 nm, and the identities of the eluted compounds were analyzed by LC-MS. LCMS m/z calc’d for C121H184N21O47 (M + H)⁺ 2683.26; found 2683.75. Example 7

Step-1: Synthesis of GalNAc-III-NIR-1 To NIR-acid (0.009 g, 0.008195 mmol), in dry DMSO were added HATU (0.012 g, 0.02983 mmol) and DIPEA (0.0129 mL, 0.0745 mmol), and the resulting solution was stirred for 15 min. To the solution, GalNAc-III-Tris-1 (0.02 g, 0.00745 mmol) was added at room temperature and allowed to stir for one hour. After reaction completion, as monitored by LCMS, the mixture was diluted with water. The product was purified by HPLC. LCMS m/z calc’d for C169H240N23O61S4 (M + H)⁺ 3682.51; found 3682.76. Step-2: Synthesis of GalNAc-III-NIR (GalNAc conjugate-III-56 containing S0456) To GalNAc-III-NIR-1 (0.005 g, 0.02 mmol) was added 10 % aq. NH3 (0.5 mL), and the mixture was stirred for 30 min. The product formation was monitored by LCMS and was purified by UPLC using a gradient mobile phase of A = 20 mM ammonium acetate buffer (pH = 7) and B = acetonitrile; solvent gradient 0% B to 35% B over 60 mins (column: Waters xTerra C18, 10 μm; 19 x 250 mm). Elution of the conjugates was monitored at λ = 254 nm, and the identities of the eluted compounds were analyzed by LC-MS. LCMS m/z calc’d for C150H221N23O52 (M + H)⁺ 3304.42; found 3304.73. Example 8 Synthesis of GalNAc-III-Tris-3 Step-1: Synthesis of GalNAc-III-Tris-2 To the solution of GalNAc-III-Tris-1 (0.055 g, 0.0205 mmol) in DMF were added NHS ester (0.090 g, 0.206 mmol), and DIPEA (0.035 mL, 0.206 mmol), and the resulting solution was allowed to stir for 1 hour. The reaction completion was observed by LCMS, and the product was purified by HPLC using 5-55 acetonitrile. LCMS m/z calc’d for C₁₄₃H₂₀₂N₂₁O₄₈S (M + H)⁺ 3013.37; found 3013.67. Step-2: Synthesis of GalNAc-III-Tris-3 To the solution of GalNAc-III-Tris-2 (90 mg) in DCM (1 mL), a solution of trifluoracetic acid: triisopropylsilane (95:5, 0.5 mL) was added, and the mixture was stirred for one hour. The volatiles in the reaction were concentrated under rotavapor. Then, the crude product was precipitated in cold diethyl ether solution and centrifuged at 2,000 rpm for 10 mins. The supernatant was removed to get GalNAc-III-Tris-3 as a colorless solid. LCMS m/z calc’d for C₁₂₄H₁₈₈N₂₁O₄₈S (M + H)⁺ 2771.26; found 2771.72. Example 9 Synthesis of 2-amino-3-(3,5-diiodo-4-(3-iodo-4-(((2-(pyridin-2- yldisulfaneyl)ethoxy)carbonyl)oxy)phenoxy)phenyl)propanoic acid (T3-MC) Step 1: To a solution of methoxycarbonylsulfenyl chloride (3.1 mL, 34.25 mmol) in CH₃CN (30.0 mL) at 0 °C, 2-mercaptoethanol (2.4 ml, 34.25 mmol) in CH₃CN (1.0 ml) was added drop wise, and the reaction mixture was allowed to stir at -10 °C for 30 min. A solution of 2-thiopyridine (3.46 g, 31.13 mmol) in CH₃CN (18.0 mL) was added to the reaction mixture and refluxed for 2 h. The reaction mixture was then stirred at 10 °C for 1 h and filtered. The solid was washed with CH₃CN and dried under vacuum at r. t. to yield the 2-(pyridine-2-yl- disulfanyl) ethanol as a colorless solid (4.0 g, 57.5%) Step 2: To a solution of 2-(pyridine-2-yl-disulfanyl) ethanol (2.0, 8.94 mmol), and TEA (1.25 mL, 8.94 mmol) in dry DCM (35 mL) at -780 °C, triphosgene (1.74 g, 5.98 mmol) in DCM (15 mL) was added dropwise and the reaction mixture was stirred at the same temperature for 2 h. Then, a solution of HOBT (1.58 g, 11.71 mmol) in DCM (15 mL) was added dropwise. Next, the reaction mixture was slowly transferred to room temperature and stirred for 16 h. Then, the reaction mixture was diluted with DCM and washed twice with DI water followed by brine. Then, the organic solvent was dried over Na2SO4, and the solvent was evaporated under vacuum. The crude compound was purified using flash column chromatography (silica gel, Hexane/EtOAc, 0-100% over 50 mins) to yield the pure magic carbonate product as a pale white solid (3.49 g, 96%). Step 3: To a solution of magic carbonate (500 mg, 1.44 mmol) and DIPEA (1 mL, 5.76 mmol) in dry DMSO (5 mL) at 0 °C, triiodothyronine (938 mg, 1.44 mmol) was added. The reaction mixture was allowed to stir at 0 °C for 15 min and 1 h r. t. The completion of the reaction was confirmed by LCMS. Then, the compound was purified using reverse-phase flash column chromatography using a C18 column to obtain the T3-MC compound as a white solid (809 mg, 65%). LCMS m/z calc’d for C₂₃H₁₉I₃N₂O₆S₂ (M + H)⁺ 864.79; found 864.7. Example 10 Synthesis of GalNAc-III-T3

Step-1: To the magic carbonate activated (T3-MC, 0.012 g, 0.013 mmol) in DMSO (0.5 mL) was added DMAP (0.004 g, 0.026 mmol), and the mixture was stirred for 10 minutes under oxygen-free conditions. To the reaction mixture, GalNAc-III-Tris-3 (0.036 g, 0.013 mmol) in DMSO was added in 3 portions with each 20 minutes interval. After complete addition of GalNAc-III-T3-1, the reaction mixture was stirred for 30 minutes, and the completion of the starting material was confirmed by LCMS. The product was purified by HPLC using 5-55. LCMS m/z calc’d for C₁₄₂H₂₀₂I₃N₂₂O₅₄S₂ (M + H)⁺ 3524.02; found 3524.37. Step-2: To GalNAc-III-T3-1 (20 mg) was added 10 % aq. NH3 (0.5 mL) and allowed to stir for 1 h. The product formation was monitored by LCMS and was purified by HPLC using a gradient mobile phase of A = 20 mM ammonium acetate buffer (pH = 7) and B = acetonitrile; solvent gradient 5% B to 55% B over 40 mins (column: Waters xTerra C18, 10 μm; 19 x 250 mm). Elution of the conjugates were monitored at λ = 220, 254 nm, the identities of the eluted compounds were analyzed by LC-MS. LCMS m/z calcd for C₁₂₄H₁₈₄1₃N₂₂O₄₅S₂ (M + H)+ 3145.93 found 3146. Example 11

Commercially available 1,2-diaminoethane trityl resin (0.8-1.2 meq/g, 200-400 mesh) (1.0 g, 0.98 mmol) was swollen with dichloromethane (DCM, 20 mL) for 20 minutes, followed by dimethylformamide (DMF, 2 × 15 mL) for 15 minutes each. Then, a solution of Tris-10 (2.41 g, 1.96 mmol), Cl-HOBt (0.331 g, 1.96 mmol), tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.02 g, 1.96 mmol), and N, N-Diisopropylethylamine (DIPEA) (5.1 mL, 30 mmol) in DMF (30 mL) was added. After bubbling under argon for three hours, the resin was washed with DMF (2 × 20 mL) for 10 mins each. Then, a Kaiser test was performed and showed a negative result. After swelling the resin in DMF, 20% piperidine in DMF (3 × 20 mL) was added to the resin and bubbled under nitrogen for 15 minutes each time to deprotect the Fmoc group. The resin was then washed with DMF. After that, a solution of Fmoc-isonipecotic acid (2.07 g, 5.88 mmol), PyBOP (3.05 g, 5.88 mmol), Cl- HOBt (1.0 g, 5.88 mmol), and DIPEA (1.0 mL, 5.88 mmol) in DMF (20 mL) was added to the resin and bubbled under argon for four hours. Then, the resin was washed again with DMF (2 × 20 mL) for 10 minutes and tested using a Kaiser test. After confirming the coupling of piperidine-4-carboxylic acid on the resin by LCMS, 20% piperidine in DMF (3 × 20 mL) was added to the resin. Then, the resin was washed with DMF. The above procedure was repeated to add three piperidine-4-carboxylic acid units. Afterward, LCMS confirmed the successful addition of three piperidine-4-carboxylic acid units. The Fmoc group was deprotected by 20% piperidine in DMF (3 × 20 mL). Then, the resin was washed with DMF. After that, a solution of Gal-8 (2.47 g, 5.88 mmol), PyBOP (3.05 g, 5.88 mmol), Cl-HOBt (1.0 g, 5.88 mmol), and DIPEA (1.0 mL, 5.88 mmol) in DMF (30 mL) was added to the resin and bubbled under argon for 12 hours. GalNAc-IV-Tris-1 was cleaved from the resin using a cocktail solution of DCM: TFA: triisopropylsilane (TIPS) (55:40:5) (3 × 20 mL) for 20 minutes each time. The compound was concentrated under vacuum. Excess TFA was evaporated under rotavapor. Then, the crude product was precipitated in cold diethyl ether solution and centrifuged at 2,000 rpm for 10 mins. The supernatant was removed. The product was dissolved in minimum DMF and purified using reverse-phase flash chromatography (RP-Combi Flash) using a gradient mobile phase of A = 20 mM ammonium acetate buffer (pH = 7) and B = acetonitrile; solvent gradient 0% B to 55% B over 50 mins (column: RediSep^®Rf 150g HP C18). The elution of the conjugates was monitored at λ = 210 nm, and the identities of the eluted compounds were confirmed by LC-MS. LCMS m/z calc’d for C130H202N21O47 (M + H)⁺ 2810.41; found 2810.2. Example 12 GalNAc-IV-NIR will be synthesized via the reaction between GalNAc-IV-Tris 1 compound and NIR-acid compound, followed by the O-deacetylation reaction. Example 13 Step-1: Synthesis of GalNAc conjugate IV-Tris-2 To the solution of GalNAc-IV-Tris-1 (0.055 g, 0.0205 mmol) in DMF, propanoic acid, 3-[(triphenylmethyl)thio]-, 2,5-dioxo-1-pyrrolidinyl ester (NHS ester) (0.090 g, 0.206 mmol) and DIPEA (0.035 mL, 0.206 mmol) were added, and the resulting solution was stirred for 1 hour. The reaction completion was confirmed by LCMS, and the product was purified by HPLC using a gradient of 5-55% acetonitrile. LCMS m/z calc’d for C152H220N21O48S (M + H)⁺ 3141.59; found 3141.4. Step-2: Synthesis of GalNAc conjugate IV-Tris-3 To the solution of GalNAc-IV-Tris-2 (90 mg) in DCM (1 mL), a solution of trifluoracetic acid: triisopropylsilane (TFA:TIPS, 95:5, 0.5 mL) was added, and the mixture was stirred for one hour. The volatiles in the reaction were concentrated under rotavapor. Then, the crude product was precipitated in cold diethyl ether solution and centrifuged at 2,000 rpm for 10 mins. The supernatant was removed to get GalNAc-IV-Tris-3 as a colorless solid. LCMS m/z calc’d for C133H206N21O48S (M + H)⁺ 2899.27; found 2899.4. Step-3: Synthesis of GalNAc IV-T3 GalNAc-IV-T3 will be synthesized via the reaction between GalNAc-IV-Tris 3 and magic carbonate activated T3 (T3-MC) followed by O-deacetylation reaction. Example 14 In vivo imaging with GalNAc-I-NIR and GalNAc-III-NIR All animal procedures were performed according to procedures approved by the Ethic Commission of the Purdue University. Animal experiments and procedures were approved by the local ethics committee and by the American Ministry of Health, complied with national ethical guidelines for animal experimentation, and were conducted in accordance with the guidelines of the local ethics committee for in vivo experimentation. Mice were acclimatized for a week before starting each experiment. GalNAc-III-NIR or competitive ligand conjugate alone was administrated intravenously to mice once at 10 nmol. Mice were exposed to the near-infrared fluorescent light 4 hours after administration of the imaging agent. Mice were anesthetized before exposure to the near infrared red light at 725-810 nm for a maximum of 30 seconds. Mice were euthanized to assess the biodistribution of the imaging agent as shown in Fig.5B. To compare a rigid linker and a flexible linker, GalNAc-III-NIR and GalNAc-I-NIR were used to measure retention time. Each compound (1 nmol) was injected into two mice at different time points up to four days. The results are shown in Figs.6A-6G. Example 15 Plasma Stability A plasma stability experiment was performed to determine the stability of GalNAc-III- T3 (GalNAc-III-64) in human plasma. GalNAc-III-T3 was tested in human plasma over a period of 8 hours (Fig.10A) and 24 hours (Fig.10B). The half-life (t_1/2) of GalNAc-III-T3 in human plasma was determined to be 60 minutes. Example 16 Receptor Saturation A saturation binding experiment was performed for two mice receiving a concentration of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, or 12 nmol of GalNAc-III-NIR (GalNAc conjugate III-56 containing S0456). The maximum tolerable dose was 10 nmol. The results are shown in Fig. 8. Example 17 Pharmacokinetic (PK) Stability A pharmacokinetic stability experiment was performed to determine the half-life (t1/2) of GalNAc-III-T3 administered intravenously (IV) (Fig.9A) and subcutaneously (SC) (Fig. 9B). The half-life of GalNAc-III-T3 administered intravenously was 20 minutes, and the half- life of GalNAc-III-T3 administered subcutaneously was 45 minutes. Example 18 Treatment of NASH with GalNAc-III-T3 Five-week-old C57BL/6 male mice were purchased from Charles River, Italy. The mice were housed for a week at 22 ^oC with free access to basal rodent diet (Mucedola s.r.l., Settimo Milanese, Italy) and drinking water with a 12-hour light/dark daily cycle before starting the experiments. Twelve mice were fed ad libitum a high fat diet (HFD, containing 21.1% fat, 41% sucrose, and 1.25% cholesterol by weight; Teklad diets, TD.120528, Invigo) for 18 weeks. Animals were then split in three groups: group 1 (n = 4) was maintained on HFD for a further three weeks; group 2 (n = 4) was fed a HFD plus a daily dose of GalNAc-III-T3 (0.786 mg/kg) through subcutaneous injection for three weeks; and group 3 (n = 4) was fed a HFD plus twice daily doses of GalNAc-III-T3 (0.786 mg/kg) through subcutaneous injection for three weeks. An additional control group of mice (n = 4) received a regular diet (Mucedola srl) all throughout the experimental time. All animals were sacrificed under isoflurane anesthesia 21 weeks after the beginning of HFD or regular diet administration. Blood and tissues, including liver, intestine, heart, and kidney, were collected. Before sacrifice, blood samples were collected from a heart puncture, placed for 30 min on ice, and then centrifuged (10,000 g, 10 min, 4°C). The serum was collected for triglycerides (TG), total cholesterol (TC), aspartate aminotransferase (AST), and alanine transaminase (ALT) tests. All assays were performed following the manufacturer’s instructions using Cyman colorimetric activity assay kits. The results are shown in Figs.11-17. Immediately after sacrifice, liver samples were weighted, and sections were fixed in 10% buffered formalin and processed for histological analysis (H&E) or Oil O Red. The remaining tissues were snap-frozen in melting isobutyl alcohol or in liquid nitrogen and stored at −80 ^◦C until use. To visualize the hepatic neutral lipid content, isobutyl alcohol-frozen liver sections were stained with Oil Red O (ORO, Sigma Aldrich, St. Louis, MO, USA) for 15 min, rinsed with 60% isopropanol, and stained with Mayer hematoxylin (Sigma Aldrich). The ORO staining positive area for each sample was quantified by using ImageJ analysis software. Quantitative analysis performed on ORO-stained sections revealed a more than 50% reduction in the liver fat content in mice given 10 nmol of GalNAc-III-T3 every day, compared to untreated HFD-fed mice. Moreover, H&E-stained liver sections revealed the presence of macro-vesicular steatosis, and inflammation in the livers of untreated HFD-fed mice was drastically reduced (on average, more than 50%) after daily treatment with 10 nmol of GalNAc- III-T3. The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range. Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings and subheadings is solely for ease of reference and is not intended to limit any disclosure made in one section to that section only; rather, any disclosure made under one section heading or subheading is intended to constitute a disclosure under each and every other section heading or subheading. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims. The terms and expressions, which have been employed, are used as terms of description and not of limitation. In this regard, where certain terms are defined and are described or discussed elsewhere, the definitions and all descriptions and discussions are intended to be attributed to such terms. There also is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. Further, all publications and patents mentioned herein are incorporated by reference in their entireties for all purposes. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

Claims

WHAT IS CLAIMED IS: 1. A conjugate of formula I: or a pharmaceutically acceptable salt thereof, wherein: L¹ is a linker, each L² is independently a linker comprising a rigid component, A is an active agent, and each R is N-acetylgalactosamine (GalNAc), wherein the rigid component of L² comprises the structure of formula Ia: wherein: each X is independently -C(R¹)2- or -NR²- , n is an integer selected from 2-7, each m is independently 0, 1, 2, 3, or 4, provided that if m is 0, then X is -C(R¹)2-, each R¹ is independently H, OH, or amino, and each R² is independently H or alkyl. 2. The conjugate of claim 1, wherein each m is independently 1 or 2. 3. The conjugate of claim 1 or claim 2, wherein each X is -C(R¹)2- (e.g., CH2). 4. The conjugate of any one of claims 1-3, wherein formula Ia is selected from: 5. The conjugate of any one of the preceding claims, wherein n is 2, 3, 4, or 5 (e.g., 3). 6. The conjugate of any one of the preceding claims, wherein formula Ia is selected from: 7. The conjugate of any one of the preceding claims, wherein the rigid component of each L² is an oligoproline. 8. The conjugate of any one of claims 1 to 6, wherein the rigid component of each L² is an oligopiperidine. 9. The conjugate of claim 1 or claim 2, wherein each X is independently -NR²- (e.g., NH). 10. The conjugate of any one of the preceding claims, wherein L² further comprises an alkylene (e.g., ethylene), an amide, a polyethylene glycol (PEG), a peptide, or any combination thereof. 11. The conjugate of claim 1, wherein each R-L² independently comprises a portion having the structure:

. 12. The conjugate of claim 1, wherein each R-L² independently comprises the structure: H H . 13. The conjugate of claim 1, wherein each R-L² independently comprises the structure: . 14. The conjugate of any one of the preceding claims, wherein L¹ comprises an alkylene, a polyethylene glycol (PEG), a peptide, or any combination thereof. 15. The conjugate of any one of the preceding claims, wherein L¹ comprises a portion having the structure: 16. The conjugate of any one of the preceding claims, wherein L¹ is a releasable linker (e.g., a slowly releasable linker). 17. The conjugate of any one of the preceding claims, wherein L¹ is reductively cleavable, oxidatively cleavable, enzymatically cleavable, acid-cleavable, or any combination thereof. 18. The conjugate of any one of the preceding claims, wherein L¹ is: . 19. The conjugate of any one of claims 1-15, wherein L¹ is a non-releasable linker. 20. The conjugate of any one of claims 1-15, or 19, wherein L¹ is: . 21. The conjugate of any one of the preceding claims, wherein the active agent is a hormone. 22. The conjugate of claim 21, wherein the active agent is a thyroid hormone receptor beta (THRβ) agonist). 23. The conjugate of claim 22, wherein the THRβ agonist is triiodothyronine (T3). 24. The conjugate of any one of claims 1 to 20, wherein the active agent is a farnesoid X receptor (FXR) agonist (e.g., tropifexor (LJN452)). 25. The conjugate of any one of claims 1 to 20, wherein the active agent is a peroxisome proliferator-activated receptor α agonist or αδ dual agonist (e.g., elafibranor (GFT505)). 26. The conjugate of any one of claims 1 to 20, wherein the active agent is an angiotensin II receptor blocker (e.g., telmisartan, candesartan, or losartan). 27. The conjugate of any one of claims 1 to 20, wherein the active agent is a diacylglycerol acyltransferase 1 (DGAT1) inhibitor (e.g., pradigastat (LCQ-908) or T-863). 28. The conjugate of any one of claims 1 to 20, wherein the active agent is selected from the group consisting of a patatin-like phospholipase domain-containing protein 3 (PNPLA3) inhibitor, a complement component C5 inhibitor, a stearoyl-CoA desaturase-1 (SCD1) inhibitor, a δ-aminolevulinate synthase 1 inhibitor, an angiopoietin-like 3 protein (ANGPTL3) inhibitor, a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, an apolipoprotein C-III (ApoC-III) inhibitor, an apolipoprotein B (apoB) inhibitor, a glycolate oxidase (GO) inhibitor, and an α-1 antitrypsin (AAT) inhibitor. 29. The conjugate of any one of claims 1-20 or claim 28, wherein the active agent is an siRNA or an antisense oligonucleotide (e.g., an antiviral siRNA or an antiviral antisense oligonucleotide, such as an antiviral siRNA or an antiviral antisense oligonucleotide for hepatitis A virus (HAV), hepatitis B virus (HBV), or hepatitis C virus (HCV)). 30. The conjugate of any one of claims 1-20, wherein the active agent is an antiviral small molecule drug. 31. The conjugate of claim 30, wherein the antiviral small molecule drug is an antiviral small molecule drug for hepatitis A virus (HAV), hepatitis B virus (HBV) (e.g., entecavir, tenofovir, lamivudine, adefovir, or telbivudine), or hepatitis C virus (HCV) (e.g., elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/ledipasvir, or sofosbuvir/velpatasvir). 32. The conjugate of any one of claims 1-20, wherein the active agent is an imaging agent. 33. The conjugate of claim 32, wherein the imaging agent is fluorescent. 34. The conjugate of claim 32 or claim 33, wherein the imaging agent is a near-infrared (NIR) imaging agent. 35. The conjugate of claim 32, wherein the imaging agent is a radio-imaging agent. 36. The conjugate of any one of the preceding claims, wherein the conjugate has a residence time in the liver of at least three days. 37. The conjugate of any one of the preceding claims, wherein the conjugate has a binding affinity (K_D) to asialoglycoprotein receptor of about 0.1 nM to about 100 nM. 38. The conjugate of claim 1, comprising the structure

, or a pharmaceutically acceptable salt thereof. 39. The conjugate of claim 1, which has the structure: , or a pharmaceutically acceptable salt thereof. 40. The conjugate of claim 1, which has the structure: or a pharmaceutically acceptable salt thereof. 41. The conjugate of claim 1, which has the structure: or a pharmaceutically acceptable salt thereof. 42. The conjugate of claim 1, which has the structure:

, or a pharmaceutically acceptable salt thereof. 43. A pharmaceutical composition comprising a conjugate of any one of claims 1-42 and a pharmaceutically acceptable carrier. 44. A method of delivering an active agent to a liver in a subject, the method comprising administering to the subject an effective amount of the conjugate according to any one of claims 1-42, or a pharmaceutical composition according to claim 43. 45. The method of claim 44, wherein the subject has nonalcoholic fatty liver disease (NASH). 46. The method of claim 44 or claim 45, wherein the method comprises administering to the subject an effective amount of the conjugate of claim 39 or claim 40, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier. 47. A method of imaging a liver in a subject, the method comprising administering to the subject a conjugate of claim 39 or claim 41, or a pharmaceutical composition comprising same and a pharmaceutically acceptable carrier, and imaging the subject.