Lysosomal targeting bifunctional molecules for degradation of muscle-specific kinase autoantibodies

Abstract

The present disclosure provides lysosomal targeting bifunctional molecules that target disease causing anti-MuSK autoantibodies for degradation. The lysosomal targeting bifunctional molecules include a ligand moiety that specifically binds to an asialoglycoprotein receptor (ASGPR), and which is linked via a carrier protein to a muscle-specific kinase (MuSK) polypeptide that specifically binds target anti-MuSK autoantibodies.

Description

[0001] LYSOSOMAL TARGETING BIFUNCTIONAL MOLECULES FOR DEGRADATION OF MUSCLE-SPECIFIC KINASE AUTOANTIBODIES CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Numbers 63 / 518,541, filed August 9, 2023, and 63 / 669,664, filed July 10, 2024, each of which is hereby incorporated by reference in its entirety. 1. BACKGROUND Many therapeutics act by binding a functionally important site on a target protein, thereby modulating the activity of that protein, or by recruiting immune effectors, as with many monoclonal antibody drugs, to act upon the target protein. However, there is an untapped reservoir of medically important human proteins that are considered to be “undruggable” because these proteins are not readily amenable to currently available therapeutic targeting approaches. Myasthenia gravis (MG) is a chronic autoimmune, neuromuscular disease of the neuromuscular junction synapse (NMJ) characterized by weakness in the skeletal muscles that worsens with continued muscle work and improves with resting of the involved muscles. MG often results in progressive fatigue, loss of muscle tone and increasing paralysis. MG affects the voluntary muscles of the body, especially those that control the eyes, mouth, throat, and limbs. Most MG patients have circulating antibodies to the NMJ postsynaptic neurotransmitter receptor, nicotinic acetylcholine receptor (AChR). In patients with AChR antibody-positive MG (AChR-MG), antibodies directed against AChR damage the NMJ and deplete AChRs, resulting in impaired synaptic transmission and muscle weakness. Some patients who are AChR Ab- negative have antibodies to muscle specific kinase (MuSK) and are referred to as having MuSK- MG. MuSK-MG is a distinct autoimmune disease from AChR-MG. Although MuSK-MG is an antibody-mediated disease, inflammatory damage to the NMJ does not occur. The majority of anti-MuSK antibodies are of the IgG4 immunoglobulin subclass, which is characterized in part by reduced affinity for effector molecules such as complement and Fc receptors compared to other IgG subclasses. Anti-MuSK antibodies prevent MuSK autophosphorylation and downstream signaling required for clustering of AChRs and proper formation and maintenance of the NMJ. The prevalence of MG in the United States is estimated at approximately 60,000 cases. In approximately 15% of patients with MG, symptoms are confined to the ocular muscles. The remaining patients have MG that affects multiple muscle groups throughout the body, which is typically referred to as generalized MG (gMG). Patients with gMG present with muscle weakness that characteristically becomes more severe with repeated use and recovers with rest. Muscle weakness can be localized to specific muscles, but often progresses to more diffuse muscle weakness. Generalized myasthenia gravis symptoms can become life-threatening when muscle weakness involves the diaphragm and intercostal muscles in the chest wall that are responsible for breathing. The most dangerous complication of gMG, known as myasthenic crisis, requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG will experience a myasthenic crisis within 2 years of diagnosis. Despite treatment, many patients are unable to achieve control of their gMG symptoms and the burden of gMG can be attributed to both the disease and the conventional treatments. The symptom burden associated with gMG means that many patients require support from professional caregivers and family and friends with activities of daily living. Current standard of care (SOC) therapy for gMG includes multiple categories of therapeutics. However, each therapeutic agent or category of therapeutics has their challenges and limitations. LYTACs (lysosomal targeting chimera) are bifunctional molecules for selective protein degradation. The first LYTACs targeted extracellular proteins for degradation via engaging the cation- independent mannose-6-phosphate receptor (CI-M6PR) or the asialoglycoprotein receptor (ASGPR). ASGPR is the transmembrane glycoprotein receptor found primarily in hepatocytes which plays an important role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine (GalNAc) residues. ASGPR cycles between endosomes and the cell surface. Therapies that can target anti-MuSK autoantibodies are of interest for treatment of MG. 2. SUMMARY The present disclosure provides lysosomal targeting bifunctional molecules that target disease causing anti-MuSK autoantibodies for degradation. The lysosomal targeting bifunctional molecules include a ligand moiety that specifically binds to an asialoglycoprotein receptor (ASGPR), and which is linked to a muscle-specific kinase (MuSK) polypeptide that specifically binds target anti-MuSK autoantibodies. The lysosomal targeting bifunctional molecules bind extracellular target anti-MuSK autoantibodies via the MuSK polypeptide and bind cell surface ASGPRs via the ASGPR ligand moiety. Binding of the ligand moiety to ASGPR can trigger internalization of the bifunctional molecule and bound target anti-MuSK autoantibody. The bifunctional molecule described herein can then facilitate transport of anti-MuSK autoantibodies into a cell and can facilitate sequestration and / or degradation of anti-MuSK autoantibodies in the cell’s lysosome. Also provided herein are compositions including such lysosomal targeting bifunctional molecules, methods of using the bifunctional molecules to reduce levels of target anti-MuSK autoantibody, and methods of treating MG in a subject in need thereof using the bifunctional molecules. 3. BRIEF DESCRIPTION OF THE DRAWINGS These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings. FIG.1 illustrates an exemplary mechanism of action of an exemplary bifunctional molecule (e.g., target anti-MuSK autoantibody-binding conjugate to bind a cell internalizing receptor (e.g., ASGPR) on the surface of a cell (e.g., a liver cell), to facilitate transport into the cell, sequestration and degradation of the target anti-MuSK autoantibody in the cell’s lysosome. FIG.2 illustrates an exemplary protein construct comprising a MuSK polypeptide bait derived from the Ig1 + Ig2 domains of the MuSK protein that is fused to human serum albumin (HSA) carrier protein. FIG.3 is a schematic illustrating binding of four patient-derived pathogenic monoclonal antibodies (mAbs) identified from literature. The antibodies are potent MuSK-HSA binders. Monovalent (except MuSK1b) and bivalent versions were generated for in vitro and in vivo studies. FIG.4 shows an exemplary LYTAC (Conjugate 1) molecule that targets pathogenic autoantibodies to the liver for degradation. The protein construct of the molecule includes MuSK residues 22-209, and a (G4S)3 linker to the fused HSA carrier protein. MW = 87.9 kDa and ~150 mg / L tCHO yield. The LPR (also referred to as DAR) loading of an exemplary LYTAC studied was 5.6. A conjugate of ligand ent-1253A(i.e., 1253A enantiomer, non-binder of ASGPR) was used as a negative control in select studies. FIG.5 shows exemplary LYTACs having mono-, di-, or trivalent ASGPR ligand valencies and conjugate loadings (LPR) via two protein conjugation chemistries. FIG.6 shows the structures of exemplary ASGPR ligand structures that can be incorporated into exemplary divalent or trivalent linker constructs to prepare MuSK-HSA conjugate LYTACs of this disclosure. In an initial assessment, a phenyl maleimide chemoselective group was used in the linkers to conjugate a first set of compounds to the MuSK-HSA protein construct. Additional cysteine conjugation optimization studies were conducted to minimize amounts of unconjugated protein (LPR0) in the conjugate product compositions. It is understood that a PFP ester chemoselective group (-C(O)O- pentafluorophenyl) can be installed at the terminal of the exemplary linkers depicted (e.g., as described herein). FIGs.7A-7C shows the analysis of loading (LPR) for Conjugate 1 prepared using lysine conjugation chemistry. LC-MS analysis (FIG.7A), HILIC-HPLC (FIG.7B) and CE-SDS (FIG.7C). FIGs.8A-8C show the results of a 1-week stability study of Conjugate 1. No aggregation or presence of other high molecular weight species observed after 1 week, as demonstrated by aSEC, DLS (data not shown), and CE-SDS. Percent DAR0 remained <1% after 1 week at all pH values, as determined by AUC integration of CE-SDS electropherogram. Intact mass spectra agree with the other assays and confirm the presence of DAR species 0 through 8. Minor species such as NAC addition and glycation (up to 3) were also observed in all spectra. FIG.9 shows results of MuSK-HSA-1253A lysine conjugation site mapping according to ribbon diagrams of the HSA and MuSK domains of the protein construct. FIG.10 shows that Conjugate 1 mediates pathogenic anti-MuSK antibody uptake in Hep G2 cells. FIG.11 shows autoantibody uptake that was observed in HepG2 cells is stereoselective and LYTAC ligand-mediated. FIG.12 shows that Conjugate 1 mediates pathogenic anti-MuSK antibody uptake in primary hepatocytes. FIG.13, panels A-C, show that Conjugate 1 mediates pathogenic anti-MuSK antibody degradation in Hep G2 cells. FIG.14, panels A-C, show that immobilized Conjugate 1 binds to >85% anti-MuSK antibodies from an MG patient sample and restores agrin-mediated AChR clustering in C2C12 myotubes. FIG.15, panels A-E, show that Conjugate 1 depletes pathogenic anti-MuSK antibodies in mouse. FIG.16, panels A-B, show that Conjugate 1 depletes mixtures of pathogenic monovalent and bivalent anti-MuSK antibodies in mouse. FIG.17, panels A-C, show that Conjugate 1 prevents body weight and grip strength loss in a single dose mouse passive immunization model. FIG.18, panels A-C, show that Conjugate 1 prevents body weight and grip strength loss in a multi dose mouse passive immunization model. FIGs.19A-19C shows the cell uptake results for three different labelled test anti-MuSK autoantibodies (13-3B5, MuSK1a, and 13-3B5-KLH). Fluorescence (MFI) values are normalized to that for MuSK-HSA-1254 (FIG.19D). FIG.20 shows robust D1 and D2 autoantibody uptake with MuSK-HSA lysine conjugates. FIG.21 shows that acidic compartment accumulation of D1 autoantibody was observed with multiple high-affinity LYTAC conjugates. FIG.22 shows surface plasmon resonance (SPR) traces for autoantibody binding to MuSK-HSA which show that autoantibody MuSK1a binds exemplary LYTAC molecules with pM affinity. FIGs.23A-23C illustrate LYTAC-mediated bivalent and monovalent autoantibody degradation. FIG.24A-24C illustrate LYTAC-mediated degradation of bivalent and monovalent anti-D1 and - D2 autoantibodies. FIG.25 shows the assessment of MuSK LYTAC to bind MG patient autoantibodies. FIGs.26A-26B illustrate that patient sample treatment with immobilized LYTAC removes pathogenic autoantibodies. FIGs.27A-27B illustrate that patient sample treatment with immobilized LYTAC removes MuSK-binding autoantibodies. FIG.28 illustrate that divalent and trivalent ligand-linker lysine conjugates show lowest exposure with <1% remaining at 24 and 72 hours. FIG.29 shows that subcutaneous (SC) MuSK LYTAC serum exposure is limited. FIG.30 shows that cysteine conjugated MuSK LYTAC depletes autoantibodies in a mouse study. FIG. 31 shows that all MuSK-HSA conjugate LYTACs clear anti-D1 autoantibody in a mouse study. FIG. 32 shows that MuSK-HSA conjugate LYTACs effectively clear D1 autoantibody after subcutaneous (SC) injection in a mouse study. FIG.33 shows antibody clearance (also referred to as autoantibody depletion) of di- and trivalent ASGPR ligand-linker lysine conjugate LYTACs. FIG.34 shows that exemplary MuSK LYTAC clears pathogenic autoantibodies in a dose- dependent manner. FIG.35 shows that multiple IV LYTAC doses cause additional autoantibody clearance (also referred to as autoantibody depletion) in a mouse study. FIG.36 shows that an exemplary MuSK LYTAC clears monovalent antibody and prevents disease onset in a mouse study. 4. DETAILED DESCRIPTION 4.1 Lysosomal targeting bifunctional molecules As summarized above, this disclosure provides lysosomal targeting bifunctional molecules (also referred to as LYTACs) that target disease causing anti-MuSK autoantibodies for degradation. The lysosomal targeting bifunctional molecules include a ligand moiety that specifically binds to an asialoglycoprotein receptor (ASGPR), and which is linked to a muscle-specific kinase (MuSK) polypeptide that specifically binds target anti-MuSK autoantibodies. In some embodiments, a LYTAC binds pathogenic anti-MuSK antibodies in circulation and forms a ternary complex with a liver-specific internalizing receptor, ASGPR. After clathrin-mediated endocytosis, the protein complex progresses through the endocytic pathway whereby ASGPR dissociates due to decreasing pH and Ca2+levels and is recycled to the cell surface. A LYTAC and the pathogenic antibody continue to the lysosome where they are degraded by lysosomal proteases. The bifunctional molecules (e.g., conjugates) of this disclosure having a particular configuration of ASGPR binding moieties (X) with a linker of desired valency and / or length can specifically bind with high affinity to both the ASGPR receptor and a target anti-MuSK antibody simultaneously and exhibit high uptake activity of the target autoantibody. The conjugates of this disclosure can provide for sequestering and degrading of a target anti-MuSK autoantibody in the cell’s lysosome. This disclosure includes anti-MuSK autoantibody degrading bifunctional molecules of formula (I): or a pharmaceutically acceptable salt thereof, wherein: B is a muscle-specific kinase (MuSK) polypeptide that specifically binds anti-MuSK autoantibody; X is an asialoglycoprotein receptor (ASGPR) ligand moiety (e.g., as described herein); Y is an optional carrier polypeptide connected to B; n is 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 10, or 1 to 6, such as 1, 2, or 3); L is a linker connected to Y-B; and m is the average number of (Xn-L) moieties connected to Y-B, wherein m is in the range from 1 to 80. In some embodiments of formula (I), m is from 1 to 20, 1 to 10, 1 to 8, 2 to 8, 3 to 6, or 4 to 5, or m is from 1 to 3, such as 1, 2 or 3. In some embodiments of formula (I), the bifunctional molecule is a conjugate of formula (Ia): wherein: Z is residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; the linker L is comprised of optional linking moieties L1, L2and L3that together provide a linear or branched linker between X and Y-B, wherein L1and L3are independently a linear linking moiety, and L2is a branched linking moiety, wherein a, b and c are independently 0 or 1; n is 1, 2, or 3, wherein: when n is 1, b is 0 and at least one of a and c is 1; and when n is 2 or 3, a, b and c are each 1; and m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is in the range from about 1 to about 80 (e.g., m is 1 to 20, 1 to 10, 1 to 8, 2 to 8, 3 to 6, or 4 to 5, or m is from 1 to 3, such as 1, 2 or 3). In certain embodiments of formula (Ia), Z is a residual moiety resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y-B; or Z is a residual moiety resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y-B. In some embodiments, the bifunctional molecule is a conjugate of formula (Ia’): or a pharmaceutically acceptable salt thereof, wherein: B is a muscle-specific kinase (MuSK) polypeptide that specifically binds anti-MuSK autoantibody; X is an asialoglycoprotein receptor (ASGPR) ligand moiety (e.g., as described herein); Y is an optional carrier polypeptide connected to B; n is 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 10, or 1 to 6, such as 1, 2, or 3); m is the average number of (Xn-L) moieties connected to Y-B, wherein m is in the range from 1 to 80. In some embodiments of formula (I), m is from 1 to 20, 1 to 10, 1 to 8, 2 to 8, 3 to 6, or 4 to 5, or m is from 1 to 3, such as 1, 2 or 3. each L1to L6is independently a linking moiety which together provide a linear or branched linker between each X and Y-B; and a, b, c, d, and e are each independently 1, 2, 3, 4, or 5. In some embodiments, L6comprises a residual moiety resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y-B; or L6is a residual moiety resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y-B. In certain embodiments of formula (I)-(Ia’), Y is absent and the linker is connected directly to polypeptide B. In certain embodiments of formula (I)-(Ia’), a carrier polypeptide Y is present and the linker is connected directly to Y and / or polypeptide B (i.e., Y-B). In certain embodiments of formula (I)-(Ia’), Y-B is a chimeric fusion protein including a carrier polypeptide and a polypeptide that specifically binds the target anti-MuSK autoantibody. Each of the components of the lysosomal targeting bifunctional molecules, preferred configurations of such molecules, and methods of using the same, are now described in greater detail. 4.1.1 ASGPR Ligand Moieties An asialoglycoprotein receptor (ASGPR) ligand moiety is a moiety that binds to ASGPR (i.e., also referred to as an ASGPR binding moiety) and, via the ASGPR, facilitates internalization of the bifunctional molecule of which it is a part, plus any bound target autoantibody. The ASGPR ligand moieties of this disclosure can be connected via a linker to a polypeptide construct without impacting the specific binding to, or function of, the cell surface ASGPR. The lysosomal targeting bifunctional molecules of this disclosure which include one or more linked ASGPR ligand moieties can utilize the functions of cell surface ASGPRs in a biological system, e.g., for internalization and / or sequestration of anti-MuSK autoantibody to the lysosome of a cell, and subsequent lysosomal degradation, e.g., in the methods of this disclosure. ASGPR, also known as the Ashwell Morell receptor, is a transmembrane glycoprotein receptor found primarily in hepatocytes which mediates the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine (GalNAc) residues. ASGPR cycles between intracellular endosomes and the cell surface. In some embodiments, the ASGPR is Homo sapiens asialoglycoprotein receptor 1 (ASGR1) (see, e.g., NCBI Reference Sequence: NM_001197216). In some embodiments, the ASGPR binding moiety (X) includes an amino sugar ring analog of galactose (e.g., N-acetylgalactosamine, or analogs thereof) that is connected to a linker scaffold via an optional linking moiety at the 1-, 2- or 6-position of the sugar ring analog. In some embodiments, the linking moiety includes an oxygen, sulfur, nitrogen or carbon atom connected at the 1-position of the ring. In some embodiments, the linking moiety includes an oxygen, sulfur, nitrogen or carbon atom connected at the 2-position of the ring. In some embodiments, the linking moiety includes an oxygen, sulfur, nitrogen or carbon atom connected at the 1-position of the ring. In certain embodiments, the linking moiety connected at the 1-, 2-, or 6-position of the ring includes an optionally substituted aryl or heteroaryl group. In certain embodiments, the amino sugar ring analog of galactose has a bicyclic structure. ASGPR ligand moieties which can be adapted for use in the conjugates of this disclosure are described in International Publication WO2023 / 288033 or WO2022 / 142377, the disclosure of which are herein incorporated by reference in its entirety. Exemplary ASGPR ligand moieties of interest are described below. In some embodiments, the ASGPR ligand moieties (e.g., (X-L)nof formula (I)) of the bifunctional molecule specifically bind to ASGPR with an affinity (Kd) of 300 nM or less, such as 100 nM or less, 30 nM or less, 10 nM or less, 3 nM or less, or 1 nM or less. The terms “binds,” “binds to,” “specifically binds” or “specifically binds to” in this context are used interchangeably. In some embodiments of the lysosomal targeting bifunctional molecules of this disclosure, X is an asialoglycoprotein receptor (ASGPR) binding moiety of formula (II): wherein: R1is selected from -Z1-*, -H, -OH, optionally substituted (C1-C6)alkyl, -OCH3,-OCH2CH=CH, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, and optionally substituted -S-heteroaryl; R2is selected from -Z1-*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, -NHR, and optionally substituted triazole; R6is selected from -Z1-*, -OH, -OR, optionally substituted (C1-C6)alkyl, -OC(O)R, -C(O)NHR, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, and -NRCOR; each R is independently optionally substituted (C1-C6)alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rxxand Ryyare independently H, optionally substituted (C1-C6)alkyl, or Rxxand Ryycan cyclize to form an optionally substituted heterocyclyl; wherein one of R1, R2, and R6is -Z1-*, and “ * ” represents a point of connection of Z1to the linker (L); R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H, or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, R2is: In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-1: wherein: R1is -H, -OH, optionally substituted (C1-C6)alkyl, or -OCH3, and R11is hydrogen; or R1and R11together with the carbon atoms to which each is attached form a bridging moiety; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-2: ∗ wherein: R1is -H, -OH, optionally substituted (C1-C6)alkyl, or -OCH3, and R11is hydrogen; or R1and R11together with the carbon atoms to which each is attached form a bridging moiety; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-1A: . In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-2A: ∗ In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula a-IIc-1, a-IIc-2, a-IIc-1A, or a-IIc-2A: The lysosomal targeting bifunctional molecules of this disclosure (e.g., of formula (I)-(Ia’)) can include an ASGPR ligand moiety of formula (II): wherein: R1is selected from –Z1–*, –H, –OH, –CH3, –OCH3, and –OCH2CH=CH; R2is selected from –Z1–*, –NHCOCH3, –NHCOCF3, –NHCOCH2CF3, –OH, and optionally substituted triazole; R6is selected from –Z1–*, –OH, –OC(O)R, -C(O)NHR, and optionally substituted triazole, where R is optionally substituted (C1-C6)alkyl or optionally substituted aryl; wherein one of R1, R2, and R6is –Z1–*, and “ * ” represents a point of connection of Z1to the linker (L); R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H, or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-, -A2-, -NR21CO-, - CONR21-, -NR21SO2-, -SO2NR21-, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In some embodiments of formula (II): 16) when n is 3, R6is OH, R2is –NHCOCH3,R3-R4are H, and R1is Z1, then Z1is not O; ii) when n is 2 or 3, R6is OAc, R2is –NHCOCH3,R3-R4are Ac, and R1is Z1, then Z1is not O; iii) when n is 2 or 3, R6is OBz, BR2is –NHCOCH3,R3-R4are Bz, and R1is Z1, then Z1is not O; iv) when n is 3, R6is OH, R2is –NHCOCH3,R3-R4are H, and R1is Z1, and Z11is O, then L comprises a backbone of at least 16 consecutive atoms to a branching point; v) when n is 3, R6is Z1, where Z1is O, and R3-R4are H, then R1is not -CH3–OCH3,or –OCH2CH=CH; and vi) when R11is a group of the formula -CH2O- that forms a bridge (i.e., is cyclically linked) to the 1-position carbon atom on the sugar ring, R2is –NHCOCH3,R3-R4are H, then R1and R3are not Z1. In some embodiments, X is represented by Formula a-II: In some embodiments, R1is -Z1-*, -H, or (C1-C6)alkyl. In some embodiments, R1is -Z1-*, -H, or n-propyl. In some embodiments, R2is -Z1-* or -NHCOCH3. In some embodiments, R3and R4are each -H. In some embodiments, L comprises of 10 to 60 consecutive branched or linear chain atoms. In some embodiments, L is of Formula: wherein: n is 1, 2, or 3; each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** represents the point of attachment of X via Z1to L1; and *** represents the point of attachment to Y-B. In some embodiments, each L1to L5independently comprises one or more linking moieties independently selected from -C1-20-alkylene-, -NHC(O)-C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NHC1-6-alkylene-, -NHC(O)NH-C1-6-alkylene-, -NHC(S)NH-C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C(O)NH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; L6is a linking group comprising one or more linking moieties independently selected from -C1-20-alkylene-, -NR16C(O)-C1-6-alkylene-, -C(O)NR16-C1-6-alkylene-, -NR16-C1-6-alkylene-, -NR16C(O)NR16-C1-6-alkylene-, -NR16C(S)NR16-C1-6-alkylene-, -C1-6-alkylene-NR16C(O)-, -C1-6-alkylene- C(O)NR16-, -C1-6-alkylene-NR16-, -C1-6-alkylene-NR16C(O)N R16-, -C1-6-alkylene-NR16C(S)NR16-, -O(CH2)p-, -(OCH2CH2)p-, -NR16C(O)-, -C(O)NR16-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or -NR16-; and each R16is independently -H, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted monocyclic heteroaryl or monocyclic heteroaryl. In some embodiments, each L1to L5is independently selected from -C1-20-alkylene-, -NHC(O)- C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NH-C1-6-alkylene-, -NHC(O)NH-C1-6-alkylene-, -NHC(S)NH- C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C( )NH-, -C1-6-alkylene-NH-, -C1-6-alkylene- NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and ,

[0002] . 1-linked ASGPR ligand moieties In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Iia): wherein R2, R3, R4, R6and Z1are as defined herein. In some embodiments of formula (Iia), R6is selected from –OH, –OC(O)R, and -C(O)NHR; and R2is selected from –NHCOCH3, –NHCOCF3, and –NHCOCH2CF3. In some embodiments of formula (II), Z1is in a beta configuration, and can be described by formula (Iia-1): In some embodiments of formula (II), Z1is in an alpha configuration, and can be described by formula (Iia-2) In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is -Z11-A1-, wherein A1- is optionally substituted arylene or optionally substituted heteroarylene. In certain embodiments, A1is an optionally substituted heteroarylene. In certain embodiments, the heteroarylene is a 5 or 6-membered heteroarylene. In certain embodiments, the heteroarylene is a 5-membered heteroarylene. In certain embodiments, the 5-membered heteroarylene is a triazole. In certain embodiments, the triazole is a 1,2,3- triazole moiety. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (IIIa) or (IIIb): wherein: -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2-, where each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl, and R21is H or optionally substituted (C1-C6)alkyl; and -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In some embodiments, -A1- is arylene or heteroarylene; wherein each is independently optionally substituted with one to three halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments of formula (IIIa) or (IIIb), Z11is -S-. In some embodiments, Z11is -C(R22)2-. In some embodiments, Z11is -CH2-. In certain embodiments, Z11is -C(R22)2, where at least one R22is H. In certain cases, both R22are H. In certain embodiments Z11is -O-. In certain embodiments, Z11is -S-. In certain embodiments cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In certain embodiments, -A1- is triazole. * In certain embodiments, Z1is -C(R22)2-triazole-. In certain embodiments, Z1is: . * In certain embodiments, Z1is: . In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is Z11. In certain cases, Z11is - C(R22)2. In certain cases, at least one R22is H. In certain cases, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain cases, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is monocyclic 5 or 6-membered heteroaryl or aryl. In certain cases, certain cases, Z1is . In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is selected from -O-, -S-, -C(R22)2-, - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z1is optionally substituted (C1-C6)alkyl. In some cases of Z1the alkyl is methyl. In some cases of Z1, the alkyl is ethyl. In some cases of Z1, the alkyl is propyl. In some cases of Z1, the alkyl is butyl. In some cases of Z1, the alkyl is pentyl. In some cases of Z1, the alkyl is hexyl. In certain embodiments, the ASGPR binding moiety (X) of formula (Iia-1) is selected from one of the following structures: HH, H H In some embodiments of formula (Iia-2), Z1is in a beta configuration and X is of formula (IIIb- 2): (IIIb-2) wherein: -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In some embodiments of formula (IIIb-2), A1is a triazole. In some embodiments of formula (IIIb- 2), X is of formula (XA-4). In some embodiments of formula (Iia-1), Z1is in a beta configuration at the 1-position carbon of the galactosamine ring. In some embodiments of formula (Iia-1), Z1is S, and each X is of formula (XA-1). In some embodiments of formula (Iia-1), each X is of formula (XA-2). In some embodiments of formula (Iia-1), each X is of formula (XA-3). In some embodiments of formula (Iia-1), each X is of formula (XA- 4). In some embodiments of formula (Iia-1), each X is of formula (XA-5). In certain embodiments, the compound of formula (Iia-2) is selected from one of the following structures:

[0003] . In some embodiments of formula (Iia-2), each X is of formula (XB-1). In some embodiments of formula (Iia-2), each X is of formula (XB-2). In some embodiments of formula (Iia-2), each X is of formula (XB-3). In some embodiments of formula (Iia-2), each X is of formula (XB-4). In some embodiments of formula (Iia-2), Z1is in an alpha configuration and X is of formula (IIIb- 1): wherein -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In certain embodiments of formula (IIIb-1), A1is an optionally substituted heteroarylene. In certain cases, the heteroarylene is a 5 or 6-membered heteroarylene. In certain cases, the heteroarylene is a 5-membered heteroarylene. In certain cases, the 5-membered heteroarylene is a triazole. In certain cases, the triazole is a 1,2,3-triazole moiety. In certain embodiments, the X of formula (IIIb-1) is selected from one of the following structures: (XC-1), and (XC-2). In some embodiments of formula (IIa): R6is -OH, R2is -NHC(O)CH3, R3is H or -C(O)CH(CH3)2, R4is H, and Z1is -O-, -S-, -CH2-, -NH-, or a 1,2,3-triazolyl. In some embodiments of formula (IIIb-1), each X is of formula (XC-1). In some embodiments of formula (IIIb-1), each X is of formula (XC-2). Exemplary ligand moieties that bind ASGPR, and synthons thereof, which can be utilized in the compounds of this disclosure are shown in Tables 1-5. In certain embodiments, the compound of formula (Iia) is a compound shown in Table 1:

[0004] In some embodiments of any one of X1-X5.1, Z1is in the alpha configuration such that the ASGPR binding moiety X1-X5.1 is derived from formula (Iia-2): 2-linked ASGPR ligand moieties In some embodiments, the ASGPR binding moiety (X) is linked via the 2-postion of the sugar analog. In some embodiments, the ASGPR binding moiety (X) has a reduced ring carbon at the 1- position relative to a galactosamine derived sugar. In some embodiments, the ASGPR binding moiety (X) of the bifunctional molecules of this disclosure is described by formula (Iib): wherein R1, R3, R4, R6, R11, and Z1are as defined herein. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure are described by formula (Iib’):

[0005] wherein R3-R4, R6, and Z1are as defined herein. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure are described by formula (Iva): wherein R1, R11, and Z1are as defined herein. In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1is selected from optionally substituted –(C(R22)2)q-heteroarylene, wherein t is 0 or 1. In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1is optionally substituted –(C(R22)2)q- triazole wherein q is 0 or 1. In some embodiments of formulae (Iib), some embodiments, Z1i . In some embodiments of formulae (Iib), , wherein R23is H,or C(1-3)-alkyl. In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1is -NR23CO-, wherein R23is H or C(1-3)- alkyl. In certain embodiments of formula of formulae (Iib), (Iib’) or (Iva), Z1is selected from optionally substituted –(C(R22)2)q-heteroaryl, wherein q is 0 or 1. In certain embodiments of formula of formulae (Iib), (Iib’) or (Iva), Z1is optionally substituted – (C(R22)2)q-triazole wherein q is 0 or 1. In certain cases, . In certain cases of formulae (Iib), , wherein R23is H, orC(1-3)-alkyl. In certain cases of formulae (Iib), (Iib’) or (Iva), Z1is -NR23CO-, wherein R23is H or C(1-3)-alkyl. In certain embodiments of formula of formulae (Iib), - membered heteroarylene or arylene. In certain embodiments, In certain embodiments of formula of formulae (Iib), (Iib’) or (Iva), Z1is selected from -O-, -S-, - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In certain embodiments, the compound of formula of formulae (Iib), (Iib’) or (Iva) is selected from one of the following structures: , , wherein R1Ais independently H or (C1-3)alkyl. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ivb) or (Ivc): (Ivb) (Ivc), wherein: -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In some embodiments of formula (Ivb) or (Ivc), R1is H. In certain embodiments of formula (Iib), R11is H and the compound is of Table 2:

[0006] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ivb-1) or (Ivc-1): (Ivb-1) (Ivc-1), wherein R11is the bridging moiety that connects the 5-position carbon to the 1-position carbon. , In some embodiments of formulae (Ivb), or (Ivb-1), Z11is -C(R22)2. In certain cases, at least one R22is H. In certain cases, both R22are H. In certain cases, Z11is -O-. In certain cases, Z11is -S-. In certain cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In certain embodiments of formulae (Ivb), (Ivc), (Ivb-1) or (Ivc-1), -A1- and -A2- are each independently an optionally substituted heteroarylene. In certain cases, the heteroarylene is a 5 or 6- membered heteroarylene. In certain cases, the heteroarylene is a 5-membered heteroarylene. In certain cases, the heteroarylene is a 6-membered heteroarylene. In some embodiments of formulae (Ivb), or (Ivb-1), the A1ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In certain cases, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain cases, the A1ring is triazole. In certain cases, the A1ring is pyridine. In certain cases, the A1ring is pyrimidine. In certain cases, the A1ring is thiadiazole. In certain cases, the A1ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of any one of formulae (Ivc), or (Ivc-1), the A2ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole,oxadiazole, and furan. In certain cases, the A2ring is a 6-membered heteroarylene selected from pyridine,pyrimidine, pyridazine, pyrazine, and triazine. In certain cases, the A2ring is triazole. In certain cases, the A2ring is pyridine. In certain cases, the A2ring is pyrimidine. In certain cases, the A2ring is thiadiazole. In certain cases, the A2ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In certain embodiments of formulae (Ivb) or (Ivb-1), -Z11-A1- is a monocyclic 5 or 6-memebered heteroarylene of one of the following structures:

[0007] . In certain embodiments of formulae (Ivc) or (Ivc-1), -A2- is a monocyclic 5 or 6-membered heteroarylene of the following structure: I wherein each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments, - It is understood that a variety of substituents can be utilized to connect a particular -Z11-A1- group to an adjacent linker. In certain embodiments of formulae (Ivb) or (Ivb-1), -Z11-A1- is a monocyclic 5 or 6-membered heteroarylene that is attached to a linking moiety as shown in one of the following structures: , In certain embodiments of formulae (Ivc) or (Ivc-1), -Z11-A1- is a monocyclic 5 or 6-membered heteroarylene that is attached to a linking moiety as shown in one of the following structures: . In some embodiments of the compound of formula of formulae (Iib), or (Iva)-(Ivc)R1is H, such that the compound of formula of formulae (Iib), or (Iva)-(Ivc) has no non-hydrogen substituents at the 1- position of the sugar ring. In some embodiments, the compound of formula (Iib) is of any one of formulae (Ivd)-(Ivg): (Ivf), and (Ivg), wherein the A1and A2rings, R6, R4, R3, R11, and R21are as defined herein. In some embodiments of any one of formulae (Ivd)-(Ivg), the A1ring is a 5 or 6-membered arylene or heteroarylene. In certain cases, the A1ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In certain cases, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain cases, the A1ring is triazole. In certain cases, the A1ring is pyridine. In certain cases, the A1ring is pyrimidine. In certain cases, the A1ring is thiadiazole. In certain cases, the A1ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of any one of formulae (Ivd)-(Ivg), the A2ring is a 5 or 6-membered arylene or heteroarylene. In certain cases, the A2ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In certain cases, the A2ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain cases, the A2ring is triazole. In certain cases, the A2ring is pyridine. In certain cases, the A2ring is pyrimidine. In certain cases, the A2ring is thiadiazole. In certain cases, the A2ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of any one of formulae (Ivd)-(Ivg),the A1or A2ring is absent. In some embodiments of any one of formulae (Ivd)-(Ivg),the A1or A2ring is phenylene or substituted phenylene. In some embodiments of formula (Ivd), the A2ring is a 5 or 6-membered heteroarylene. In certain cases of formula (Ivd), the A2ring is a 5-membered heteroarylene. In certain embodiments of formula (Ivd), the A2ring is triazole. In certain embodiments of (Ivd), the A2ring is absent. In some embodiments of formula (Ive), the A1ring is a 5 or 6-membered heteroarylene and R21is H. In certain embodiments of formula (Ive), the A ring is triazole. In certain cases of formula (Ive), the A1ring is pyridine. In certain cases of formula (Ive), the A1ring is pyrimidine. In certain cases of formula (Ive), the A1ring is thiadiazole. In some embodiments of formula (Ive), the A1ring is absent and R21is H or optionally substituted acyl. In some cases, R21is -COCH3. In some cases, R21is H. In some embodiments of formula (Ivf), the A1ring is a 5 or 6-membered heteroarylene. In certain cases of formula (Ivf), the A1ring is a 5-membered heteroarylene. In certain embodiments of formula (Ivf), the A1ring is triazole. In certain embodiments of (Ivf), the A1ring is absent. In some embodiments of formula (Ivg), the A2ring is a 5 or 6-membered heteroarylene. In certain cases of formula (Ivg), the A2ring is a 5-membered heteroarylene. In certain embodiments of formula (Ivg), the A2ring is triazole. In certain embodiments of (Ivg), the A2ring is absent. In some cases, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by any one of formulae (Ivh)-(Ivk): wherein: R6, R4, R3, and R21are as defined herein; Y1-Y3are each independently N or CR25; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments of formula (Ivi) at least one of Y1to Y3is N. In some cases, at least two of Y1to Y3are N. In certain cases, Y1and Y3are N and Y2is CR25. In certain cases, Y1and Y2are N and Y3is CR25. In certain cases, Y1and Y2are CR25and Y3is N. In certain embodiments of any one of formulae (Ivd)-(Ivk) R6is H. In some embodiments of any one of formulae (Ivd)-(Ivk), R4and R3are each H. In certain cases, at least one of R4-R3is a promoiety. In certain embodiments, R4and R3are cyclically linked to form a promoiety (e.g., as described herein). In some embodiments, the compound of formula (Ivi) is of formula (Ivi-1):

[0008] wherein R24and R25are independently selected from H, halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of formula (Ivi)-(Ivi-1), R25is H. In certain cases, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments of formula (Ivi) or (Ivi-1), R24is H. In certain cases, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, the compound of formula (Ivi-1) is of formula (XD1): In some embodiments, X is of Formula XD2: In some embodiments, the compound of formula (Ivk-1) is of formula (XE):

[0009] In some embodiments, X is of formula (IVl-1): wherein: R6, R4, R3, and R21are as defined herein; Y1-Y4are each independently N or CR25; Y5is S, O, or NH; and each R25is independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments, each R25is H. In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures: H . In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures: . In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures: * * * H * In certain embodiments of formula (Iib), R1R3, R4, and R11are H, and R6is OH: wherein Z1is -NH-, -CH2-, -S- or -O-. In certain embodiments of formula (Iib’), R3, R4are H, and R6is OH: wherein Z1is -NH-, -CH2-, -S-, -O-, triazole, . In some embodiments, the -Z1-L1- comprises a group selected from: wherein R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen; and each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl. In some embodiments, R21is H. In some embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, -Z1-L1- is . It is understood that a variety of substituents and chemistries can be utilized to connect a particular X ligand moiety (e.g., as described herein) to an adjacent linker. In some embodiments, a linking moiety of the linker comprises a triazole that derives from a Click chemistry conjugation. In some embodiments, the ASGPR ligand moiety (X) is attached to a linking moiety as shown in one of the following structures: ,

[0010] , In some embodiments, R1R3, R4, and R11are H, and R6is OH: wherein Z1is triazole, -NH-heteroaryl (e.g., -NH- attached to pyridine or pyrimidine), -NH-, -O-, or -CH2- , and / or Z1is attached to a linking moiety as shown in one of the following structures: ,

[0011] , In some embodiments, of Formula Iib, R1R3, R4, and R11are H, and R6is OH: wherein Z1is attached to a linking moiety as shown in one of the following structures: . 6-linked ASGPR ligand moieties In some embodiments, the ASGPR binding moiety (X) is linked via the 6-postion of the sugar analog. In some embodiments, the ASGPR binding moiety (X) has a reduced ring carbon at the 1- position relative to a galactosamine derived sugar. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Iic): * wherein R1-R4and Z1are as defined herein. In certain embodiments of formula (Iic), Z1is selected from -O-, -S-, -CONR21-, and optionally substituted –(C(R22)2)q- heteroarylene, wherein q is 0 or 1. In certain cases, Z1is -O-. In certain other cases, Z1is optionally substituted –(C(R22)2)q-triazole wherein q is 0 or 1. In certain cases, Z1is . In certain embodiments of formula (Iic), Z1is -Z11-A1-, wherein -A1- is or optionally substituted - A1- or optionally substituted arylene. In certain cases, -A1- is an optionally substituted heteroarylene. In certain cases, the heteroarylene is a 5 or 6-membered heteroarylene. In certain cases, the heteroarylene is a 5-membered heteroarylene. In certain cases, the 5-membered heteroarylene is a triazole. In certain cases, the triazole is a 1,2,3-triazole moiety. In certain cases, Z11is -C(R22)2. In certain cases, at least one R22is H. In certain cases, both R22are H. In certain cases Z11is -O-. In certain cases, Z11is -S-. In certain other cases, Z11is3)alkyl. In certain cases, Z1is -C(R22)2-triazole- . In certain cases, Z1is: In certain embodiments of formula (Iic), Z1is Z11. In certain cases, Z11is -C(R22)2. In certain cases, at least one R22is H. In certain cases, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain cases, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In certain embodiments of formula (Iic), Z1is monocyclic 5 or 6-membered heteroarylene or arylene. In certain cases, In certain embodiments of formula (Iic), Z1is selected from -O-, -S-, -C(R22)2-, -N(R21) - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In certain embodiments, the compound of formula (Iic) is the following structure: .In certain embodiments, the compound of formula (Iic) is the following structure: . In certain embodiments of formula (Iic), R11is H and the compound is of Table 3:

[0012] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Iid): wherein: R6, R4, R3and Z1are as defined herein; Y6and Y5are each independently selected from -O-, -S-, NR21-, and -C(R22)2; R21is selected from H, optionally substituted (C1-C6)alkyl, and -C(O)R22; each R22is independently selected from H, halogen and optionally substituted (C1-C6)alkyl; and ring B is a 5 or 6-membered optionally substituted cyclic group. In some embodiments of formula (Iid), Y5is connected to the sugar ring via an alpha configuration. In some embodiments of formula (Iid), Y5is connected to the sugar ring via a beta configuration. In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Iid’):

[0013] wherein: R6, R4, R3and Z1are as defined herein; Y5and Y6are each independently selected from -O-, -S-, NR21-, and -C(R22)2; R21is selected from H, optionally substituted (C1-C6)alkyl, and -C(O)R22; each R22is independently selected from H, halogen and optionally substituted (C1-C6)alkyl; and ring B is a 5 or 6-membered optionally substituted cyclic group. In some embodiments of formula (Iid)-(Iid’) Y5is O. In certain cases, Y5is S. In certain cases, Y5is -NR21-. In certain cases, Y5is -C(R22)2and each R22is H. In some embodiments of formula (Iid)-(Iid’) Y6is -NR21- where R21is H. In certain cases, Y6is - NR21- where R21is -C(O)R22. In some cases, R22is methyl. In some embodiments of formula (Iid)-(Iid’) the B ring is a 5 or 6-membered heterocycle. In some cases, the B ring is a 5-membered heterocycle. In some cases, the B ring is a 6-membered heterocycle. In some embodiments of formula (Iid)-(Iid’) Z1is Z11, where Z11is selected from -O-, -S-, NR21-, and -C(R22)2. In some cases, Z1is -O-. In some cases, Z1is -S-. In some cases, Z1is NR21where R21is H. In some cases, Z1is -C(R22)2where each R22is H. In some embodiments of formula (Iid)-(Iid’) Z1is optionally substituted Z11-heteroarylene or optionally substituted Z11-arylene. In some embodiments, Z1is CH2-heteroarylene or CH2-arylene. In some embodiments of formula (Iid)-(Iid’) Z1is optionally substituted amide. In some embodiments of formula (Iid)-(Iid’) Z1is optionally substituted sulfonamide. In some embodiments of formula (Iid)-(Iid’) Z1is optionally substituted urea or optionally substituted thiourea. In some embodiments, the compound of formula (Iid)-(Iid’) has one of the following structures: In certain embodiments of any one of formulae (Iia), (Iib) or (Iid), R6is OH. In certain other cases, R6is -OC(O)R. In certain cases, R6is -C(O)NHR, where R is an optionally substituted alkyl. In certain cases, R terminates in an alkenyl or an alkynyl group. In certain other cases R6is optionally substituted triazole. In certain cases, the triazole is of the following structure: . In certain embodiments of (Iia), and (Iic), R2is -NHCOCH3. In certain other embodiments, R2is –NHCOCF3. In certain other embodiments, R2is –NHCOCH2CF3. In certain cases, R2is –OH. In certain other cases, R2is an optionally substituted triazole. In certain cases, the triazole in of the following structure: .In certain embodiments when R6or R2is a substituted triazole, the triazole is a 1,2,3-trizole, and the substituent is at the 4 or 5-position. In certain cases, the substituent on the triazole moiety includes but is not limited to, an optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkaryl, and an optionally substituted alkyheteroaryl. It will be understood that any convenient substituent can be included in the triazole moiety, see, e.g., triazole moieties disclosed in Mamidayala et al, J. Am. Chem. Soc.2012, 134, 1978-1981. It is understood that the Z1, Z11, and Z11-Ar linking moieties can be considered part of the X group of formula (I). In the ASGPR binding moieties (X) as described herein, -Z1- can be linked to an -L1- moiety (e.g., of the linker as described herein) via a variety of bonds and linking moieties, depending on the method of preparation. In some embodiments, the subject compounds comprise a -Z1-L1- moiety selected from:

[0014] wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; and o, p, q, r, s, t, u, v, w, x, y, z and z1 are each independently 1 to 6. In certain embodiments, the Z1-L1- group is , and o is 1 or 2. In certain embodiments, the Z1-L1- group , each R22is H, and p is 1 or 2. In certain embodiments, the Z1-L1- group . In certain embodiments, the Z1-L1- group is , where r is 1-3. In certain embodiments, the Z1-L1- group is , where r is 1-3. In certain embodiments, the Z1-L1- group is , where s and t are each independently 1-3. In certain embodiments, the Z1-L1- group is , where u is 1-3. In certain embodiments, the Z1-L1- group is , where v and w are each independently is 1-3. In certain embodiments, the Z1-L1- group is , where x is 0-3. In certain embodiments, the Z1-L1- group is , where y is 1-3. R21In certain embodiments, the Z1-L1- group is , where R21is H, and z is 1-4. R21In certain embodiments, the Z1-L1- group is , where R21is H, and z1 is 1-4. In certain embodiments, the Z1-L1- group is , where each R22is H, and q is 1-3. In certain embodiments, the Z1-L1- group is , where q is 1-3. In certain embodiments, the subject compounds comprise a -Z1-L- group selected from: In certain embodiments, the Z1-L1- group is , where q is 1-3. In certain cases, q is 1. In certain cases, q is 2. In certain cases, q is 3. In certain embodiments, the Z1-L1- group is . In certain embodiments, the Z1-L1- group is . In certain embodiments, the Z1-L1- group is . In certain embodiments, -Z1-L1- comprises an optionally substituted -NH-heteroarylene-. In certain embodiments the heteroarylene is a triazole. In certain cases, the heteroarylene is pyridine. In certain cases, the heteroarylene is pyrimidine. In certain cases, the heteroarylene is thiadiazole. In some embodiments, the -Z1-L1- comprises a group selected from: , wherein each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In certain embodiments, the -Z1-L1- comprises a group selected from: wherein R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen; and each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl. In certain cases, R21is H. In certain cases, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In certain cases, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, -Z1-L1- is . It is understood that a variety of substituents and chemistries can be utilized to connect a particular X ligand moiety (e.g., as described herein) to an adjacent linker. In some embodiments, a linking moiety of the linker comprises a triazole that derives from a Click chemistry conjugation. In certain embodiments, the ASGPR ligand moiety (X) is attached to a linking moiety as shown in one of the following structures:

[0015] H H , H In certain embodiments of formula (Iib), R1R3, R4, and R11are H, and R6is OH: wherein Z1is triazole, -NH-heteroaryl (e.g., -NH- attached to pyridine or pyrimidine) , -NH-, -O-, or - CH2- , and / or Z1is attached to a linking moiety as shown in one of the following structures:

[0016] , Aspects of this disclosure include prodrugs of any of the ASGPR ligand moieties described herein that are incorporated into the linker compounds and conjugates of this disclosure. The term “prodrug” refers to an agent which is converted into the drug in vivo by some physiological or chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Prodrugs forms of any of the ASGPR ligand moieties described herein can be useful because, for example, can lead to particular therapeutic benefits as a consequence of an extension of the half-life of the resulting compound or conjugate in the body or a reduction in the active dose required. Prodrugs can also be useful in some situations, as they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A prodrug derivative of a ASGPR ligand moiety generally includes a labile promoiety substituent at a suitable site of the moiety. The promoiety refers to the group that is removed by enzymatic or chemical reactions, when a prodrug is converted to the drug in vivo. In some embodiments, the promoiety is a group, such as an optionally substituted alkanoyl, attached via an ester linkage to a hydroxyl group of the moiety. In some embodiments, a prodrug derivative of one or more of the hydroxyl groups of the sugar ring of the ASGPR ligand moiety may be incorporated into the compounds. For example, an ester promoiety can be incorporated at one or more of the hydroxyl groups at the 3 and / or 4 positions of the core sugar ring (e.g., as described in Formula (II)). In some embodiments, the hydroxyl groups at the 3 and 4 positions of the core sugar ring are cyclically linked to form a promoiety (e.g., as described herein). Aspects of the disclosure include prodrugs of the ASGPR binding moiety (X) as described herein, where at least one group of X is modified to include a promoiety. In some embodiments, the X moiety is a prodrug of (Iia-1), e.g., that includes a promoiety (e.g., as described herein). In some embodiments, the promoiety is the part of an ester group attached to a hydroxyl of X (-O-), such as -COCH3, -COCH(CH3)2or -COC(CH3)3. In certain embodiments, the promoiety is -CH2OCOC(CH3)3. In some embodiments, e.g., of formula (Iia), a promoiety cyclically links two adjacent hydroxyl groups via a carbonate linkage, i.e., a cyclic carbonate. In some embodiments, the X moiety is a prodrug of (Iia-2), e.g., that includes a promoiety (e.g., as described herein). In some embodiments, the X is a prodrug including one or more promoieties selected from -COCH3, -COCH(CH3)2, -COC(CH3)3and -CH2OCOC(CH3).4.1.3 Linker The ASGPR ligand moieties (X) can be used in a monovalent or multivalent configuration with respect to the binding to ASGPR of the “n” X groups that are displayed on the linker scaffold. A monovalent configuration includes a single ASGPR ligand moiety (X) per linker of the bifunctional molecule, where it is understood that one or more linkers may be connected to the protein construct Y-B. A multivalent configuration includes two or more such ASGPR ligand moieties per linker (e.g., bivalent or trivalent or of higher valency linker). This disclosure provides particular linker scaffolds and linker valencies that display preferred ASGPR ligand moieties in the bifunctional molecules of this disclosure. In some embodiments, the linked ASGPR ligand moiety (X) of the bifunctional molecule is monovalent (e.g., in Formula (I), n is 1), such that a linker covalently links a single ASGPR ligand moiety (X) via a linking moiety at the 1, 6, or 2-position of the sugar ring analog to a protein construct (Y-B) including a muscle-specific kinase (MuSK) polypeptide (B) and a carrier protein (Y). In certain embodiments of formula (I), n is 1, and L comprises a linear linker having a backbone of 20 or more consecutive atoms (e.g., 25 or more) covalently linking the ASGPR ligand X to Y-B via a linking moiety at any of the 1-, 2- or 6-positions of X. In certain cases, the linker L includes a backbone of 20 to 100 consecutive atoms linking the ASGPR ligand (X) to Y-B, such as 25 to 80, 25 to 60, or 25 to 50 consecutive atoms. In some embodiments, the bifunctional molecule is multivalent with respect to X, where in Formula (I), n is 2 or more, such that the conjugate includes two or more ASGPR ligand binding moieties (X) per multivalent linker which connects to the protein construct (Y-B). In such cases, the multivalent linker (L) is a branched linker or a dendrimer linker. In certain cases, the bifunctional molecule has one or more divalent linkers (e.g., n is 2 in Formula (I)). In certain cases, the bifunctional molecule has one or more trivalent linkers (e.g., n is 3 in Formula (I)). In certain embodiments, each branch of a branched linker includes a linear linker portion covalently connecting each X moiety (via the linking moiety described herein) to a branching point in the branched linker or dendrimer linker. In certain embodiments, each branch of the linker includes a linear linker portion having a backbone of 8 or more consecutive atoms, such as 10 or more, 12 or more, 14 or more, 16 or more, 18 or more or 20 or more consecutive atoms between the X ligand moiety and the branching point in the linker. In certain embodiments, each branch of the linker includes a linear linker portion having a backbone of 8 to 50 consecutive atoms, such as 10 to 50, 12 to 50, 14 to 50, or 14 to 40, 14 to 30, or 14 to 20 consecutive atoms. The terms “linker”, “linking moiety” and “linking group” are used interchangeably and refer to a linking moiety that covalently connects two or more moieties, compounds or other biomolecules, such as ligands and proteins of interest. In some cases, the linker is divalent and connects two moieties. In certain cases, the linker is a branched linking group that is trivalent or of a higher multivalency. In some cases, the linker that connects the two or more moieties has a linear or branched backbone of 500 atoms or less (such as 400 atoms or less, 300 atoms or less, 200 atoms or less, 100 atoms or less, 80 atoms or less, 60 atoms or less, 50 atoms or less, 40 atoms or less, 30 atoms or less, or even 20 atoms or less) in length, e.g., as measured between the two or more moieties. A linking moiety may be a covalent bond that connects two groups or a linear or branched chain of between 1 and 500 atoms in length, for example of about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 carbon atoms in length, where the linker may be linear, branched, cyclic or a single atom. In certain cases, one, two, three, four, five or more, ten or more, or even more carbon atoms of a linker backbone may be optionally substituted with heteroatoms, e.g., sulfur, nitrogen or oxygen heteroatom. In certain instances, when the linker includes an ethylene glycol, or longer polyethylene glycol (PEG) linking group, e.g., where every third atom of that segment of the linker backbone is substituted with an oxygen. The bonds between backbone atoms of a linker may be saturated or unsaturated, usually not more than one, two, or three unsaturated bonds will be present in a linker backbone. The linker may include one or more substituent groups, for example an alkyl, aryl or alkenyl group. A linker may include, without limitations, one or more of the following: oligo(ethylene glycol) (also referred to as PEG), ether, thioether, disulfide, amide, carbonate, carbamate, tertiary amine, alkyl which may be straight or branched, e.g., methyl, ethyl, n- propyl, 1-methylethyl (iso-propyl), n¬butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. The linker backbone may include a cyclic group, for example, an aryl, a heterocycle, a cycloalkyl group or a heterocycle group, where 2 or more atoms, e.g., 2, 3 or 4 atoms, of the cyclic group are included in the backbone. In some embodiments, a “linker” or linking moiety is derived from a molecule with a reactive terminus, e.g., suitable for conjugation to a protein of interest. In some instances, the reactive terminus of the linker precursor includes a chemoselective ligation group capable of conjugating to amino acid residue(s) of a polypeptide. In certain instances, the chemoselective ligation group conjugates to a cysteine thiol group, or a lysine sidechain amine group of the polypeptide that is accessible. A variety of conjugation chemistries can be utilized in the conjugates of this disclosure (e.g., as described herein). In some embodiments, the chemoselective ligation group is a thiol-reactive group such as maleimide or dibromomaleimide. In some embodiments, the chemoselective ligation group is an amine-reactive group such as an active ester, e.g., perfluorophenyl ester or tetrafluorophenyl ester, or N-hydroxysuccinimidyl ester (NHS) or sulfo-NHS, or as defined herein. In certain embodiments of the formula described herein, the linker L includes one or more straight or branched-chain carbon moieties and / or polyether (e.g., ethylene glycol) moieties (e.g., repeating units of -CH2CH2O-), and combinations thereof. In certain embodiments, these linkers optionally have amide linkages, urea or thiourea linkages, carbamate linkages, ester linkages, amino linkages, ether linkages, thioether linkages, sulfhydryl linkages, heteroaryl linkages, or other hetero functional linkages. In certain embodiments, the linker backbone includes one or more of carbon atoms, nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. In certain embodiments, the linker includes one or more of an ether bond, thioether bond, amine bond, amide bond, carbon-carbon bond, carbon-nitrogen bond, carbon-oxygen bond, carbon-sulfur bond, and combinations thereof. In certain embodiments, the linker includes a linear structure. In certain embodiments, the linker includes a branched structure. In certain embodiments, the linker includes a cyclic structure. In certain cases, the linker includes one or more heteroaryl cyclic structures, e.g., a triazole, such as a 1,2,3-traizole. In certain embodiments, L is a linker between about 5 Å and about 500 Å. In certain embodiments, L is between about 10 Å and about 400 Å. In certain embodiments, L is between about 10 Å and about 300 Å. In certain embodiments, L is between about 10 Å and about 200 Å. In certain embodiments, L is between about 10 Å and about 100 Å. In certain embodiments, linker L separates X (or Z1) and Y-B by a chain of 10 to 100 consecutive atoms. In certain embodiments, linker L separates X (or Z1) and Y-B by a chain of 10 to 60 consecutive atoms, by a chain of 12 to 60 consecutive atoms, by a chain of 16 to 50 consecutive atoms, by a chain of 20 to 50 consecutive atoms, by a chain of 30 to 50 consecutive atoms, by a chain of 40 to 50 consecutive atoms. In some embodiments, linker L (e.g., L1-L6) separates X and the Y-B complex by a chain of 4 to 500 consecutive atoms. In some embodiments, linker L (e.g., L1-L6) separates X and the Y-B complex by a chain of 4 to 50 consecutive atoms. In some embodiments, linker separates X and the Y-B complex by a chain of 6 to 50 consecutive atoms, by a chain of 11 to 50 consecutive atoms, by a chain of 16 to 50 consecutive atoms, by a chain of 21 to 50 consecutive atoms, by a chain of 26 to 50 consecutive atoms, by a chain of 31 to 50 consecutive atoms, by a chain of 36 to 50 consecutive atoms, by a chain of 41 to 50 consecutive atoms, or by a chain of 46 to 50 consecutive atoms. It is understood that the linker may be considered as connecting directly to a Z1group of a ASGPR ligand moiety (X) (e.g., as described herein). In some embodiments of formula II (or any formulae described herein for the ASGPR ligand moiety (X)), the linker may be considered as connecting directly to the Z1group. Alternatively, the -Z1-L1- group (e.g., as described herein) can be considered part of a linking moiety that connects L to Y-B. The disclosure is meant to include all such configurations of ASGPR ligand moiety (X) and linker (L). In some embodiments of formula (I), L is a linker of formula (XI): wherein each L1and L3are independently a linear linking moiety, and L2is a branched linking moiety, wherein L1to L3together provide a linear or branched linker between X and Y-B; a, b and c are independently 0 or 1; * represents the point of attachment of L1to X via Z1; and ** represents the point of conjugation of the linker L to Y-B; wherein: when n is 1, b is 0 and at least one of a and c is 1; and when n is 2 or 3, a, b and c are each 1. In some embodiments of the linker of formula (XI), n is 1, a is 1, b is 0, and c is 1, such that the linker L is of formula (Xia): * In some embodiments of the linker of formula (XI), n is 1, a is 1, b is 0, and c is 0, such that the linker L is of formula: * .In certain embodiments, the linear linker of formula (Xia) has a backbone of 10 or more consecutive atoms covalently linking X to Y-B via Z1, such as a backbone of 12 or more consecutive atoms, 14 or more consecutive atoms, or 16 or more consecutive atoms, and in some cases, up to 100 consecutive atoms. In certain embodiments of formula (Xia), the linear linker separates X (or Z1) and Y- B by a chain of 20 to 50 consecutive atoms. In certain embodiments of formula (Xa), the linear linker separates X (or Z1) and Y-B by a chain of 30 to 60 consecutive atoms. In some embodiments of the linker of formula (XI), n is 2, a is 1, b is 1, and c is 1, such that the linker L is of formula (Xib): * In some embodiments of the linker of formula (XI), n is 3, a is 1, b is 1, and c is 1, such that the linker L is of formula (Xic): In some embodiments of the linker of any one of formulae (XI) or (Xia)-(Xic), each L1is of formula (XII): ) wherein: L10is a linking moiety, and * represents the point of attachment of L1to X via Z1; and L11to L19are independently absent or a linking moiety, wherein: L10to L19of each L1are each independently selected from –C1-6-alkylene–, –C1-12-alkylene–, –C1-20-alkylene–,–NHCO-C1-6-alkylene–, –CONH-C1-6-alkylene–, –NH-C1-6-alkylene–, –NHCONH-C1-6- alkylene–, – NHCSNH-C1-6-alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene– NH-, –C1-6-alkylene–NHCONH-, –C1-6-alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, – CONH–, –NHSO2–, –SO2NH–, –NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5- dione, 1,2,3-triazole, –NH–, –N(C1-6-alkyl)–, and –N(CH3)–, wherein each p is independently 1 to 50, such as 1 to 20, 1 to 12, 1 to 10, 1 to 8, or 1 to 6, e.g., 1, 2, 3, 4, 5 or 6. In certain embodiments of formula (XII), the linking moiety L1includes a linear backbone of 6 to 40 consecutive atoms, such as 10 to 40, 10 to 30, 16 to 30, or 20 to 30 consecutive atoms. In certain embodiments of formula (XII), the linking moiety L1includes a linear backbone of each L1comprises a linear backbone of 6 to 20 consecutive atoms, such as 6 to 16 consecutive atoms, such as 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive atoms. In certain embodiments, the linking moiety of formula (XII) includes one or repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In certain cases, the linking moiety of formula (XII) includes 1 to 10 ethylene glycol moieties, such as 1, 2, 3, 4, 5 or 6 ethylene glycol moieties. In certain embodiments, the linking moiety of formula (XII) includes one or more triazole (e.g., 1,2,3-triazole) containing linking moieties. It is understood that the triazole may be derived from an azido-alkyne click chemistry and thus have two possible orientations depending on the method of synthesis: In certain embodiments, the triazole containing linking moiety is : wherein w1 and u1 are independently 0 to 12, such as 0, 1, 2, 3, 4, 5 or 6. In some embodiments of the linker of formula (XI), b is 1 and L2is of the formula (XIIIa) or (XIIIb): (XIIIa) (XIIIb) wherein: L20is a branched linking moiety including one or more linking moieties independently selected from amino acid residue (e.g., a residue such as Gly, Ala, beta-Al , Glu, Ser, Cys, or a derivative thereof), –NH-CH[(CH2)q]2O– or –NH-C[(CH2)q]3O–, -alkylene–, –NHCO-, –CONH–, –NHSO2–, –SO2NH–, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, –NH–, and –Nme–, –NHC(=O)NH–, – NHC(=S)NH–, –O(CH2)p–, and –(OCH2CH2)p–; wherein each p is independently 1 to 50, and q is 1-6. In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L2is selected from one of (L2A)-(L2D): wherein: each Z2and Z3is independently absent or selected from –NHCO-, –CONH–, –CO–, –O–, –NH–, and –Nme–; x is 1 to 12 (e.g., 1 to 6, or 1 to 3); and y is 0 to 12 (e.g., 1 to 6, or 1 to 3). In some embodiments of any one of L2A-L2D, Z2is –NHCO-. In some embodiments of any one of L2A-L2D, Z2is –CONH–. In some embodiments of any one of L2A-L2D, Z2is –CO–. In some embodiments of any one of L2A-L2D, Z2is –O–. In some embodiments of any one of L2A-L2D, Z2is – NH–. In some embodiments of any one of L2A-L2D, Z2is –Nme–. In some embodiments of any one of L2A-L2D, Z2is absent. In some embodiments of any one of L2A-L2D, Z3is –NHCO-. In some embodiments of any one of L2A-L2D, Z3is –CONH–. In some embodiments of any one of L2A-L2D, Z3is –CO–. In some embodiments of any one of L2A-L2D, Z3is –O–. In some embodiments of any one of L2A-L2D, Z3is – NH–. In some embodiments of any one of L2A-L2D, Z3is –Nme–. In some embodiments of any one of L2A-L2D, Z3is absent. In some embodiments of L2A, Z2is –O–, y is 0 and the linking moiety is of the structure L2Ai: In some embodiments of L2B, Z2is –O– or –CO–, and the linking moiety is of the structure L2Bi or L2Bii: .In some embodiments of L2C, Z2is –O–, –CO–, –NHCO-, or –NH–, and the linking moiety is of the structure L2Ci, L2Cii, L2Ciii, or L2Civ:

[0017] ( In some embodiments of L2D, Z2is absent and the linking moiety is of the structure L2Di: In some embodiments, of any one of formulae L2A-L2Di, x is 1 to 6. In some cases, x is 1 to 3. In some cases, x is 1. In some cases, x is 2. In some cases, x is 3. In some embodiments of any one of formulae L2A-L2Di, y is 0 to 6. In some cases, y is 0 to 3. In some cases, y is 0. In some cases, y is 1. In some cases, y is 2. In some cases, y is 3. In certain embodiments of formula (XI), b is 1 and the linking moiety L2is selected from: , . In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L2is of the formula (XIV): wherein: r is 1 or 2; and when n is 2, r is 1, when n is 3, r is 2. In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L2is of the formula (Xva) or (XVb): wherein: r is 1 or 2; and when n is 2, r is 1, when n is 3, r is 2. In some embodiments L2is of formula (XIIIa) or (XIIIb) and L2includes two 2 or more amino acid residues (e.g., 3 or more, or 4 or more amino acid residues, linear or dendrimer). In some embodiments, L2includes 4 or more amino acid residues that are branched linking moieties selected from Lys, Orn, Asp, Glu, Ser, and Cys (e.g., where the sidechain, amino and carboxylic acid are each linked to an adjacent moiety). In some embodiments of the linker of any one of formulae (XI) or (Xa)-(Xc), each L3is of the formulae (XVI): wherein: L30to L39are independently absent or a linking moiety; and Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; wherein L30to L39are each independently selected from –C1-20-alkylene–, –NHCO-C1-6-alkylene– , –CONH-C1-6-alkylene–, –NH C1-6-alkylene–, –NHCONH-C1-6-alkylene–, – NHCSNH-C1-6-alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHCONH-, –C1-6- alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, –CONH–, –NHSO2–, –SO2NH–, – NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, –NH–, and – N(CH3)–, wherein each p is independently 1 to 50. In certain embodiments, the linking moiety of formula (XVI) includes a linear backbone of 6 to 40 consecutive atoms, such as 10 to 40, 10 to 30, or 20 to 30 consecutive atoms. In certain embodiments, the linking moiety of formula (XVI) includes repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In certain cases, the linking moiety of formula (XVI) includes 2 to 20 ethylene glycol moieties, such as 2 to 15, 2 to 10, 3 to 20, 3 to 15, 3 to 10, 4 to 15, 5 to 15 or 5 to 10 ethylene glycol moieties. In some instances, the linking moiety of formula (XVI) includes 2 or more ethylene glycol moieties, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or even more ethylene glycol moieties. In certain embodiments, the linking moiety of formula (XVI) includes one or more triazole linking moieties. In some instances, the linker includes one or more 1,2,3-triazole linking moieties. In certain cases, the one or more 1,2,3-triazoel moieties is selected from one of the following structures: , , wherein w1, u1 and q1 are independently 1 to 25 (e.g., 1 to 12, such as 1 to 6). In certain embodiments, the linking moiety L3includes (C10-C20-alkylene (e.g., C12-alkylene), or – (OCH2CH2)p–, where p is 1 to 25, such as 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25 or 20 to 24. In some embodiments, the linker L is of formula XVII: wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (e.g., 1, 2, or 3); Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group (e.g., as described herein) of a linker precursor to a compatible group of Y-B. In some embodiments of the formula XVII, Z is a residual moiety resulting from the covalent linkage (e.g., via a thioether bond) of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y-B. In some embodiments, the thiol-reactive chemoselective ligation group includes maleimide, bromomaleimide, haloacetamide, vinyl sulfone, or thiolactone. In some embodiments, the thiol-reactive group is selected from one of the following structures: wherein: u is 1 to 11 (e.g., 1 to 5); v is 1 to 11 (e.g., 1 to 5); and X is H or Br. In some embodiments of formula XVII, Z is a residual moiety resulting from the covalent linkage (e.g., via an amide bond) of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y-B. In some embodiments, the amine-reactive chemoselective ligation group includes an active ester (e.g., N-hydroxysuccinimidyl (NHS) ester, sulfo-NHS ester, pentafluorophenyl (PFP) ester, tetrafluorophenyl (TFP) ester, or the like). In some embodiments, the linker L includes one of (XVIIIa)-(XVIIIc): wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2 to 6, such as 2 to 3. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4. In some embodiments, a is 5. In some embodiments a is 6. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), b is 1 to 4, such as 1 to 3. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), c is 1 to 4, such as 1 to 3. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), r is 1. In some embodiments, r is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), d is 1 to 4, such as 1 to 3. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), e is 1 to 5, such as 1 to 3. In some embodiments, e is 1. In some embodiments, e is 2. In some embodiments, e is 3. In some embodiments, e is 4. In some embodiments, e is 5. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), f is 1 to 4, such as 1 to 3. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 1-4; b is 1-4; c is 1-3; r is 2; d is 1-3; e is 1-6; and f is 1-3. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 4; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 4; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 2; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 2; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 0; b is 3; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 4; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), a is 2; b is 4; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, the linker L includes LA: wherein: Z4is selected from -NHC(O)NH-, -NHC(O)-, -C(O)NH-, -O-, -NH-; a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments of LA, Z4is -NHC(O)NH-. In some cases, Z4is -NHC(O)-. In some cases, Z4is -C(O)NH-. In some cases, Z4is -O-. In some cases, Z4is -NH-. In some embodiments of LA, a is 1-4; b is 1-4; c is 1-3; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 4; b is 1; c is 2; d is 2; e is 5; and f is 2. In some embodiments, Z4is -NHC(O)NH- and a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, Z4is -NHC(O)- and a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1- 6; and f is 1-3. In some embodiments, the linker L includes LB: , wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments of LB, a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 4; b is 1; c is 2; r is 1; d is 2; e is 5; and f is 2. In some embodiments, a is 2; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 4; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 1; b is 2; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 0; b is 3; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments of LB, a is 1-4; b is 1-4; c is 1-3; r is 2; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 4; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 1; b is 2; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 0; b is 3; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, the linker L includes LC: , wherein: a is 0 to 12 (e.g., 1 to 6, 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1 to 4, such as 1, 2, or 3); c is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3). In some embodiments of Lc, a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 4; c is 2; r is 1; d is 2; e is 5; and f is 2. In some embodiments of Lc, a is 1-4; b is 1-4; c is 1-3; r is 2; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 4; c is 2; r is 2; d is 2; e is 5; and f is 2. In certain embodiments of the ASGPR binding moiety (X) as described herein, -Z1- is linked to an -L1- moiety (e.g., of the linker as described herein). In some embodiments, the subject compounds comprise a -Z1-L1- moiety comprising a linking moiety selected from: , wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; and o, p, q, r, s, t, u, v, w, x, y, z and z1 are each independently 1 to 6. In certain embodiments, the Z1-L1- group is , and o is 1 or 2. In certain embodiments, the Z1-L1- group , each R22is H, and p is 1 or 2. In certain embodiments, the Z1-L1- group . In certain embodiments, the Z1-L1- group is , where r is 1-3. In certain embodiments, the Z1-L1- group is , where r is 1-3. In certain embodiments, the Z1-L1- group t are each independently 1-3. In certain embodiments, the Z1-L1- group is , where u is 1-3. In certain embodiments, the Z1-L1- group are each independently is 1-3. In certain embodiments, the Z1-L1- group is , where x is 0-3. In certain embodiments, the Z1-L1- group . R21In certain embodiments, the Z1-L1- group is , where R21is H, and z is 1-4. R21In certain embodiments, the Z1-L1- group is , where R21is H, and z1 is 1-4. In certain embodiments, the Z1-L1- group is , where each R22is H, and q is 1-3. In certain embodiments, the Z1-L1- group is , where q is 1-3.In certain embodiments, the subject compounds comprise a -Z1-L- group comprising a linking moiety selected from: , where R21is independently selected from H, and optionally substituted (C1-C6)alkyl (e.g., methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl (e.g., methyl). In certain embodiments, R21is H. In certain embodiments, each R22is H. In certain embodiments, the -Z1-L1- group is , where q is 1-3. In certain cases, q is 1. In certain cases, q is 2. In certain cases, q is 3. O In certain embodiments, the -Z1-L1- group is . In certain embodiments, -Z1-L1- includes an optionally substituted -NH-heteroarylene-. In certain embodiments, the heteroarylene is a triazole. In certain cases, the heteroarylene is pyridine. In certain cases, the heteroarylene is pyrimidine. In certain cases, the heteroarylene is thiadiazole. In certain embodiments, the -Z1-L1- includes a group selected from: wherein R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen; and each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted alkanoyl. In certain cases, R21is H. In certain cases, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In certain cases, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, the linker includes a polypeptide scaffold where some or all of the sidechain groups of the amino acid residues of such a polypeptide scaffold have been modified to attach a X binding moiety (e.g., as described herein). It is understood that X binding moieties (e.g., as described herein) can be conjugated to amino acid residues, such as Asp, Lys, Orn, Glu, and Ser, of a polypeptide containing linker via a convenient conjugation chemistry. In some embodiments, the linker contains a polylysine polypeptide. In some embodiments, the linker contains a polyornithine polypeptide. In some embodiments, the linker contains a polyserine polypeptide. In some embodiments, the linker contains a polyaspartate polypeptide. The polypeptide backbone of such a linker can be a randomly polymerized polymer having an average length, or a polymer of defined length prepared e.g., in a controlled stepwise fashion. In some cases, the polypeptide linker has a length of 10-100 amino acid residues, such as 20-90, or 20-50 amino acid residues. In some embodiments, the N-terminal or C-terminal of the polypeptide linker is modified to include a linking moiety to an additional X binding moiety (e.g., as described herein). In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified with one or more linking moieties (e.g., as described herein) suitable for attachment to a protein construct (Y-B) including a MuSK polypeptide that specifically binds anti- MuSK autoantibody. In some embodiments of the linker of formula (II), L1to L3each independently comprise one or more linking moieties independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH-C1-6- alkylene-, -NH C1-6-alkylene-, -NHCONH-C1-6-alkylene-, - NHCSNH-C1-6-alkylene-, -C1-6-alkylene- NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene- NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3- linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (naturally or non- naturally occurring amino acid residue), -NH-, and -NCH3-, wherein each p is independently1 to 50. In some embodiments of the linker of formula (II), any of L1-L3comprises repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In some embodiments, the linker of formula (II) comprises 1 to 25 ethylene glycol moieties, such as 3 to 25, 5 to 25, 7 to 25, 10 to 25, 15 to 25, 17 to 25, 20 to 25, or 22 to 25 ethylene glycol moieties. In some instances, the linker of formulae (II) comprises 3 or more ethylene glycol moieties, such as 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, or even more ethylene glycol moieties. In some embodiments of the linker of formula (II), any of L1-L3comprises one or more triazole linking moieties. In some instances, the linker comprises one or more 1,2,3-triazole linking moieties. In some embodiments, the one or more 1,2,3-triazole moieties is selected from one of the following structures: , a , wherein w1, u1 and q1 are independently 1 to 25 (e.g., 1 to 12, such as 1 to 6). In some embodiments, the linker of the Formulas described herein is of formula (L-II): wherein: n is 1, 2, or 3; each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** represents the point of attachment of X via Z1to L1; and *** represents the point of attachment to Y-B, optionally via Z. In some embodiments, each L1to L5independently comprises one or more linking moieties independently selected from -C1-20-alkylene-, -NHC(O)-C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NHC1-6-alkylene-, -NHC(O)NH-C1-6-alkylene-, -NHC(S)NH-C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C(O)NH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; L6is a linking group comprising one or more linking moieties independently selected from -C1-20-alkylene-, -NR16C(O)-C1-6-alkylene-, -C(O)NR16-C1-6-alkylene-, -NR16-C1-6-alkylene-, -NR16C(O)NR16-C1-6-alkylene-, -NR16C(S)NR16-C1-6-alkylene-, -C1-6-alkylene-NR16C(O)-, -C1-6-alkylene- C(O)NR16-, -C1-6-alkylene-NR16-, -C1-6-alkylene-NR16C(O)N R16-, -C1-6-alkylene-NR16C(S)NR16-, - O(CH2)p-, -(OCH2CH2)p-, -NR16C(O)-, -C(O)NR16-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or -NR16-; and each R16is independently -H, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted monocyclic heteroaryl or monocyclic heteroaryl. In some embodiments, each L1to L5is independently selected from -C1-20-alkylene-, -NHC(O)- C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NH-C1-6-alkylene-, -NHC(O)NH-C1-6-alkylene-, -NHC(S)NH- C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C( )NH-, -C1-6-alkylene-NH-, -C1-6-alkylene- NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and , In some embodiments of the linker of the Formulas described herein, the linker comprises one or more (1 to 20, 1-10, or 1-6) linker components (e.g., L1to L6) wherein each independently comprises one or more linking moieties independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH- C1-6-alkylene-, -NHC1-6-alkylene-, -NHCONH-C1-6-alkylene-, - NHCSNH-C1-6-alkylene-, -C1-6-alkylene- NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene- NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3- linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (naturally or non- naturally occurring amino acid residue), -NH-, and -NCH3-, wherein each p is independently1 to 50. In some embodiments of the linker of the Formulas described herein, any of the linker components (e.g., L1-L6) comprises repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In some embodiments of the linker of the Formulas described herein, any of the linker components (e.g., L1-L6) comprises 1 to 25 ethylene glycol moieties, such as 3 to 25, 5 to 25, 7 to 25, 10 to 25, 15 to 25, 17 to 25, 20 to 25, or 22 to 25 ethylene glycol moieties. In some embodiments, the linker comprises 3 or more ethylene glycol moieties, such as 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, or even more ethylene glycol moieties. In some embodiments of the linker of formula (II), n is 1, such that b is 0, and the linker is of the formula (L-IIa): wherein L1and L3are independently a linker (e.g., as described herein), wherein L1to L3together provide a linear linker between X and Y; a is 1; c is 0 or 1; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y-B. It should be understood that in the conjugates described herein, the linker can be attached to an amino acid on Y or B of the Y-B complex (i.e., Y-B or [Y-B]). In some embodiments, the linear linker has a backbone of 20 or more consecutive atoms covalently linking X to Y-B via Z1, such as a backbone of 25 or more consecutive atoms, or 30 or more consecutive atoms, and in some cases, up to 100 consecutive atoms. In some embodiments of formula(IIa), the linear linker separates X and Y-B (or Z1) by a chain of 20 to 50 consecutive atoms. In someembodiments, the linear linker separates X and Y-B (or Z1) by a chain of 21 to 50 consecutive atoms, by a chain of 22 to 50 consecutive atoms, by a chain of 23 to 50 consecutive atoms, by a chain of 24 to 50 consecutive atoms, by a chain of 25 to 50 consecutive atoms, by a chain of 26 to 50 consecutive atoms, by a chain of 27 to 50 consecutive atoms, by a chain of 28 to 50 consecutive atoms, or by a chain of 29 to 50 consecutive atoms. In some embodiments of formula (IIa), the linear linker separates X and Y-B (or Z1) by a chain of 30 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y-B (or Z1) by a chain of 31 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y-B (or Z1) by a chain of 32 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y-B (or Z1) by a chain of 33 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y-B (or Z1) by a chain of 34 to 60 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y-B (or Z1) by a chain of 35 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y-B (or Z1) by a chain of 36 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y-B (or Z1) by a chain of 41 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y-B (or Z1) by a chain of 46 to 50 consecutive atoms. In some embodiments, n is 2 or more, such that any one or more of L1- L6together provide a branched linker between X and Y. In some embodiments of the linker of the Formulas described herein, n is 1, such that b is 0, and the linker is of the Formula L-IIb: wherein n is 1, 2, or 3; each L1and L3are independently a linker component (e.g., as described herein) each L2is independently a branched linker component; a is 1, 2, or 3; b is 1, 2, or 3; c is 1, 2, or 3; ** represents the point of attachment to X via Z1; and *** represents the point of attachment to Y-B, optionally via Z. In some embodiments, n is 2 or more, and L2is selected from:

[0018] wherein each x and y are independently 1 to 10. In some embodiments, L1-L2comprises a backbone of 14 or more consecutive atoms between X and the branching atom, such as 14 to 50, 14 to 40, 14 to 35 or 14 to 30 consecutive atoms between X and the branching atom. In some embodiments, L3comprises a backbone of 10 to 80 consecutive atoms, such as 12 to 70, 12 to 60, or 12 to 50 consecutive atoms. In some embodiments, wherein L3comprises a linking moiety selected from (C10-C20-alkylene (e.g., C12-alkylene), or -(OCH2CH2)p-, where p is 1 to 25, such as 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25 or 20 to 24. In some embodiments, L1to L5each independently comprise one or more linking moieties independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH-C1-6-alkylene-, -NH C1-6-alkylene-, -NHCONH-C1-6-alkylene-, - NHCSNH-C1-6-alkylene-, -C1-6-alkylene-NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene-NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3-linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (naturally or non- naturally occurring amino acid residue), -NH-, and -NCH3-, wherein each p is independently1 to 50. In some embodiments, -(L1)a- comprises an optionally substituted alkyl or ethylene glycol linking moiety. In some embodiments, L1comprises an optionally substituted -C1-6-alkylene-. In some embodiments, L1comprises an ethylene glycol linking moiety. In some embodiments, each L1is independently selected from -C1-6-alkylene-, -(CH2CH2O)t-, -C1-6-alkylene-NR4CO-, -C1-6-alkyleneCONH-, or OCH2, wherein t is 1 to 20; and each R4is independently selected from H, and optionally substituted (C1-C6)alkyl. In some embodiments, each L1is -C1-6-alkylene-, such as -C1-3-alkylene-. In some embodiments, each L1is -(CH2CH2O)t-, where t is 1 to 20, such as 1 to 15, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In some embodiments, each L1is --C1-6-alkylene- NR4CO-. In some embodiments, each L1is -C1-6-alkyleneCONH-. In some embodiments, each L1is or OCH2. In some embodiments, one or more L1is independently -CH2O-, -(CH2CH2O)t-, -NR4CO-, - , wherein R13is selected from H, halogen, OH, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, COOH, NO2, CN, NH2, -N(R21)2, -OCOR21, -COOR21, -CONHR21, and -NHCOR21; and each r independently 0 to 20, and any of the L1moieties are optionally further substituted. In some embodiments, one linker component (e.g. L2) is -OCH2-. In certain other embodiments, L2is (OCH2CH2)q-, and q is 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2. In some embodiments, q is 2 to 8, such as 2 to 6 , 4 to 6, or 2 to 4. In some embodiments, one linker component (e.g. L3) is absent or is independently selected from -C1-6-alkylene-, -(CH2CH2O)t-, -C1-6-alkylene-NHCO-, -C1-6-alkyleneCONH-,or OCH2, wherein t is 1 to 20. In some embodiments, L3is absent. In some embodiments, one linker component (e.g. L3) comprises -C1-6-alkylene-. In some embodiments, one linker component (e.g. L3) comprises -(CH2CH2O)t-, where t is 1 to 20, such as 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3. In some embodiments, one linker component (e.g. L3) comprises -C1-6-alkylene-NHCO-. In some embodiments, one linker component (e.g. L3) comprises -C1-6-alkyleneCONH-. In some embodiments, one linker component (e.g. L3) comprises OCH2. In some embodiments of the Formulas described herein, the linker comprises one or more branched linking moiety. In some embodiments of the Formulas described herein, the linker comprises one or more branched linking moiety selected from: , wherein each x and y are each independently 1 to 10, such as 1-6, 1-3, e.g., 1 or 2. In In some embodiments, each x is 1, 2 or 3, e.g., 2. In some embodiments, one linker component (e.g. L4, L5, or L6) comprises one or more of: an amino acid residue (e.g., Asp, Lys, Orn, Glu), an amino acid analogue, N-substituted amido (-N(-)C(=O)- ), tertiary amino, polyol (e.g., O-substituted glycerol), and the like. Analogs of an amino acid, include but not limited to, unnatural amino acids, as well as other modifications known in the art. The amino acid includes L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. In some embodiments, the linker includes a polypeptide scaffold where some or all of the sidechain groups of the amino acid residues have been modified to attach a X binding moiety (e.g., as described herein). It is understood that X binding moieties (e.g., as described herein) can be conjugated to amino acid residues, such as Asp, Lys, Orn, Glu, and Ser, of a polypeptide containing linker via a convenient conjugation chemistry. In some embodiments, the linker contains a polylysine polypeptide. In some embodiments, the linker contains a polyornithine polypeptide. In some embodiments, the linker contains a polyserine polypeptide. In some embodiments, the linker contains a polyaspartate polypeptide. The polypeptide can be a randomly polymerized polymer having an average length, or a polymer of defined length prepared e.g., in a controlled stepwise fashion. In some cases, the polypeptide linker segment has a length of 10-100 amino acid residues, such as 20-90, or 20-50 amino acid residues. In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified to include a linking unit to an additional M6PR binding moiety (e.g., as described herein). In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified with one or more linking units (e.g., as described herein) suitable for attachment to a Y moiety of interest. In some embodiments, a is 1. In some embodiments, at least one of b, c, d, and e is not 0. In some embodiments, b is 1 or 2. In some embodiments, c is 1 or 2. In some embodiments, e is 1 or 2. In some embodiments, b, d and e are independently 1 or 2. In some embodiments, a, b, d, and e are each 1, and c is 0. In some embodiments, the linker comprises 20 to 100 consecutive atoms, such as 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40 or 20 to 30 consecutive atoms. In some embodiments, the linker comprises 25 to 100 consecutive atoms, such as 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive atoms. In some embodiments, the linker comprises 25 or more consecutive atoms, such as 26 or more, 27 or more, 28 or more, 29 or more or 30 or more consecutive atoms. In some embodiments, the linker comprises 30 or more consecutive atoms, such as 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37, or more, 38 or more, 39 or more, 40 or even more consecutive atoms. In some embodiments, the linker is a branched linker or linking moiety as shown in Table 1.

[0019]

[0020] 4.1.4 Chemoselective ligation group A chemoselective ligation group is a group having a reactive functionality or functional group capable of conjugation to a compatible group of a second moiety (e.g., a polypeptide or chemically modified polypeptide). For example, chemoselective ligation groups (or a precursor thereof) may be one of a pair of groups associated with a conjugation chemistry such as azido-alkyne click chemistry, copper free click chemistry, Staudinger ligation, tetrazine ligation, hydrazine-iso-Pictet-Spengler (HIPS) ligation, cysteine-reactive ligation chemistry (e.g., thiol-maleimide, thiol-haloacetamide or alkyne hydrothiolation), lysine-reactive ligation chemistry (e.g., amine-active ester coupling, e.g., PFP ester or NHS ester), tyrosine specific conjugation chemistry (e.g., e-Y-CLICK), methionine specific conjugation chemistry (e.g., oxaziridine-based or ReACT chemistry), reductive amination, dialkyl squarate chemistry, etc. Chemoselective ligation groups that may be utilized in linking two moieties include, but are not limited to, amino (e.g., a N-terminal amino or a lysine sidechain group of a polypeptide), azido, aryl azide, alkynyl (e.g., ethynyl or cyclooctyne or derivative), active ester (e.g., N-hydroxysuccinimide (NHS) ester, sulfo-NHS ester, pentafluorophenyl (PFP) ester, tetrafluorophenyl (TFP) ester, or thioester), haloacetamide (e.g., iodoacetamide or bromoacetamide), chloroacetyl, bromoacetyl, hydrazide, maleimide, vinyl sulfone, 2-sulfonyl pyridine, cyano-alkyne, thiol (e.g., a cysteine residue), disulfide or protected thiol, isocyanate, isothiocyanate, aldehyde, ketone, alkoxyamine, hydrazide, aminooxy, phosphine, HIPS hydrazinyl-indolyl group, or aza-HIPS hydrazinyl-pyrrolo-pyridinyl group, tetrazine, cyclooctene, squarate, and the like. In some embodiments, the chemoselective ligation group is capable of spontaneous conjugation to a compatible chemical group when the two groups come into contact under suitable conditions (e.g., copper free Click chemistry conditions). In some instances, the chemoselective ligation group is capable of conjugation to a compatible chemical group when the two groups come into contact in the presence of a catalyst or other reagent under suitable conditions (e.g., copper catalyzed Click chemistry conditions). In some embodiments, the chemoselective ligation group is a photoactive ligation group. For example, upon irradiation with ultraviolet light, a diazirine group can form reactive carbenes, which can insert into C-H, N-H, and O-H bonds of a second moiety. In some embodiments, the terminal of a linker precursor includes a precursor of the reactive functionality or functional group capable of conjugation (e.g., forming a covalent bond) to a compatible group of a polypeptide (e.g., with a compatible amino acid sidechain of the polypeptide). The reactive moiety can be referred to as a chemoselective ligation group. For example, a carboxylic acid is a precursor of an active ester chemoselective ligation group. In certain embodiments, the terminal of a linker precursor is a thiol-reactive chemoselective ligation group (e.g., as described herein). A residual moiety Z (e.g., of formula (Ia) can result from the covalent linkage of the thiol-reactive chemoselective ligation group to one or more cysteine residue(s) (Cys) of a protein, e.g., carrier protein and / or MuSK polypeptide. In certain embodiments, the Cys- reactive chemoselective ligation group is a maleimide derivative, e.g., as described herein. In some cases, the Cys-reactive chemoselective ligation group is a maleimide. In certain embodiments, the terminal of a linker precursor is an amino-reactive chemoselective ligation group (e.g., as described herein). A residual moiety Z (e.g., of formula (Ia)) can result from the covalent linkage of the amine-reactive chemoselective ligation group to one or more lysine residue(s) (Lys) of a protein, e.g., carrier protein and / or MuSK polypeptide. For amine-active ester couplings, the residual moiety Z is an amide bond. In some embodiments the Lys-reactive chemoselective ligation group is a PFP ester. In some embodiments the Lys-reactive chemoselective ligation group is a TFP ester. In some embodiments the Lys-reactive chemoselective ligation group is a NHS or sulfo-NHS ester. Exemplary chemoselective ligation groups, and synthetic precursors thereof, which may be adapted for use in the compounds and conjugates of this disclosure are shown in Table 4A.

[0021] In Table 4A, the can represent a point of attachment to a linking moiety, linker or linker precursor that includes the linked X moiety. Table 4B shows exemplary residual moieties, wherein the “***” indicates the point of attachment of Y.

[0022] 4.1.5 Exemplary Ligand Moiety-Linkers This disclosure includes compounds of formula (I) which compounds can be prepared from a precursor ligand-linker compound including: (1) one or more particular ASGPR ligand (X) (e.g., as described herein), (2) a linker including one or more linking moieties (e.g., as described herein); and (3) a chemoselective ligation group (Y) e.g., as described herein). In some embodiments, the compound of formula (I) is an ASGPR binding compound as described in International Application No. PCT / US2022 / 037227, filed July 14, 2022, and the disclosure of which is herein incorporated by reference in its entirety. Tables 5-8 illustrate several exemplary ASGPR binding compounds of this disclosure that include a chemoselective ligation group, or a precursor thereof. It is understood that this disclosure includes Y (e.g., as described herein) conjugates of each of the exemplary compounds of Tables 5-8. For example, conjugates where the chemoselective ligation group has been conjugated to a different Y, such as an antibody or antibody fragment for a target protein. The chemoselective ligation group of such compounds can be utilized to connect to another Y moiety of interest (e.g., as described below). It is understood that any of these compounds can also be prepared de novo to include an alternative Y moiety of interest (e.g., as described below) rather than the chemoselective ligation group. In some embodiments, such compounds are referred to as a conjugate, e.g., a biomolecule conjugate that specifically binds a target protein as a conjugate, e.g., a biomolecule conjugate that specifically binds a target protein.

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] Table 8: Multivalent ASGPR binding compounds having chemoselective ligation group and X group of formula (Iib) # Structure HO OH HO N OONN O O O HN 1918 H O H N NON OH O (I-165) O O NNO HO O NH HOOHO O O HO N OH N O N OH O FFF N O N OH N O N N N H OH HO O HOOHO HO O NH N NH O NO N NO N O O O N N OH 1919 F H FFH HN O O (I-166) O O H N ONN O N HO N OH N HO F FF

[0038]

[0039] Table 9 illustrates exemplary monovalent ASGPR binding intermediate compounds of this disclosure that include a promoiety and X groups that are of formula (Iia).

[0040] Table 10A illustrates exemplary ASGPR binding intermediate compounds of this disclosure that include X groups that are of formula (Iid). Table 10B illustrates exemplary ASGPR binding intermediate compounds which comprise a chemoselective ligation group for use in preparing the conjugates described herein.

[0041]

[0042]

[0043] bidi i di d bidi i di d

[0044]

[0045]

[0046]

[0047] The present disclosure is meant to encompass stereoisomers of any one of the compounds described herein. In some instance, the compound includes an enantiomer of the D- N- acetylgalactosamine (GalNAc), or an analog or derivative of GalNAc. 4.1.6 Conjugates The bifunctional molecules of this disclosure can be referred to as a conjugate, e.g., when the target binding moiety of interest is a polypeptide (a MuSK polypeptide, e.g., in the form of B or Y-B) (e.g., as described herein, see Formula (Ia)). Such conjugates can be prepared by conjugation of a chemoselective ligation group of any one of the ligand moiety-linker compounds described herein with a compatible reactive group of a molecule B or Y-B. The compatible group of the molecule B or Y-B can be introduced by modification prior to conjugation, or can be a group present in the molecule. Alternatively, such conjugates can be prepared de novo, e.g., via modification of a B or Y-B molecule of interest starting material to introduce a linker, e.g., to which an ASGPR ligand moiety (X) can be attached. In some cases, the linking moiety between X-L and B or Y-B incorporates the residual group (e.g., Z of Formula (Ia)) that is the product of the chemoselective ligation chemistry. As summarized above, in some embodiments of formula (I), the bifunctional molecule is a conjugate of formula (Ia): wherein: Z is residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; n is 1, 2, or 3; and m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is in the range from about 1 to about 80 (e.g., m is 1 to 20, 1 to 10, 1 to 8, 2 to 8, 3 to 6, or 4 to 5, or m is from 1 to 3, such as 1, 2 or 3). In certain embodiments of formula (Ia), Z is a residual moiety resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y-B; or Z is a residual moiety resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y-B. In certain embodiments of formula (Ia), Y-B is a chimeric fusion protein including a carrier polypeptide and a polypeptide that specifically binds the target anti-MuSK autoantibody. In certain embodiments of formula (I)-(Ia), Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation moiety of Table 4. In certain embodiments of the conjugates described herein, L is bonded through an amide bond (Z) to a lysine residue of the polypeptide. In certain embodiments of the conjugates described herein, L is bonded through a thioether bond (Z) to a cysteine residue of the polypeptide. In certain embodiments, conjugation to the polypeptide, or the antibody Ab may be via site- specific conjugation. Site-specific conjugation may, for example, result in homogeneous loading and minimization of conjugate subpopulations with potentially altered antibody-binding or pharmacokinetics. In certain embodiments, for example, conjugation may include engineering of cysteine substitutions at positions on the carrier and / or MuSK polypeptides that provide reactive thiol groups and do not disrupt polypeptide folding and assembly or alter polypeptide binding. In another non-limiting approach, selenocysteine is co-translationally inserted into a polypeptide or antibody sequence by recoding the stop codon UGA from termination to selenocysteine insertion, allowing site specific covalent conjugation at the nucleophilic selenol group of selenocysteine in the presence of the other natural amino acids (see, e.g., Hofer et al., Proc. Natl. Acad. Sci. USA 2008; 105: 12451-56; and Hofer et al., Biochemistry 2009; 48(50): 12047-57). Yet other non-limiting techniques that allow for site-specific conjugation to polypeptides or antibodies include engineering of non-natural amino acids, including, e.g., p-acetylphenylalanine (p-acetyl-Phe), p-azidomethyl-N-phenylalanine (p- azidomethyl-Phe), and azidolysine (azido-Lys) at specific linkage sites, and can further include engineering unique functional tags, including, e.g., LPXTG, LLQGA, sialic acid, and GlcNac, for enzyme mediated conjugation. See Jackson, Org. Process Res. Dev.2016; 20: 852-866; and Tsuchikama and An, Protein Cell 2018; 9(1):33-46, the contents of each of which is incorporated by reference in its entirety. See also US 2019 / 0060481 A1 & US 2016 / 0060354 A1, the contents of each of which is incorporated by reference in its entirety. All such methodologies are contemplated for use in connection with making the conjugates described herein. The loading of a ligand-linker moiety (e.g., Xn-L-) with respect to a polypeptide or protein construct (e.g., Y-B of a conjugate of formula (I)) refers to the number (a discrete or average loading) of ligand-linker moieties attached per molecule of polypeptide or protein construct. The loading is related to the concept of a drug to antibody ratio (“DAR”) in antibody drug conjugates. As used herein, the loading can be referred to as the linker to polypeptide ratio (“LPR”). The loading of the ligand-linker moiety (Xn- L-) with respect to the MuSK-HSA protein construct (Y-B) of formula (I) described herein can be represented by the symbol “m”. The symbol “m” of formula (I) can refer to an average number of units of “Xn-L-” per polypeptide conjugate molecule, or alternatively, “m” can refer to a discrete number of units of “Xn-L-” per polypeptide conjugate molecule. The number of “X” moieties per each unit of “Xn-L-” is represented by “n” in formula (I). As used herein, the terms “valency” and “multivalency” refer to a number of “X” moieties per unit (i.e., “n”). Thus, a bivalent ligand-linker moiety has n = 2, and a trivalent ligand-linker moiety has n = 3. It will be understood that the loading, or LPR, is not necessarily equivalent to the total number of “X” moieties per conjugate molecule, which is rather a combination of n and m. By means of example, where there is one “X” moiety per unit (n = 1; valency is “1”), and one “Xn-L-” unit per conjugate (m = 1), there will be 1 x 1 = 1 “X” moiety per conjugate. However, where there are two “X” moieties per unit (n = 2; valency is “2”), and about four “Xn-L-” units per conjugate (m = 4), there will be about 2 x 4 = about 8 “X” moieties per conjugate. Accordingly, for the conjugates described herein, the total number of “X” moieties per conjugate molecule will be n x m. LPR (loading) may range from 1 to 20 ligand-linker moieties per protein conjugate. The conjugates provided herein may include collections of polypeptides conjugated with a range of ligand- linker moieties, e.g., from 1 to 20. The number of ligand-linker moieties per polypeptide in preparations of the conjugate from conjugation reactions may be characterized by conventional means such as mass spectroscopy. It is understood that the definition of “m” as a discrete loading value, or as an average loading value is determined in part by the nature of the chemoselective ligation chemistry and groups utilized in preparation of the conjugates. By way of example, stoichiometric thiol-maleimide conjugation chemistry can provide discrete conjugates via site specific conjugation to particular and specific target cysteine residues of interest. Alternatively, when an amine-specific conjugation chemistry is used, conjugation to one or up to several of the accessible lysine residues in the protein may occur, where the resulting conjugate preparation may contain several different species conjugates, and the loading can be represented by an average number. In some embodiments, the quantitative distribution of LPR (loading) in terms of “m” may also be determined. In some instances, separation, purification, and characterization of a homogeneous conjugate where “m” is a discrete value may be achieved by means such as electrophoresis. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 80. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 20. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 18. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 15. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 12. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 10. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 9. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 8. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 7. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 6. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 5. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 4. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to 3. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 12. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 10. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 9. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 8. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 7. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 6. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 5. In certain embodiments, the LPR for a conjugate provided herein ranges from 2 to 4. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 12. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 10. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 9. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 8. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 7. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 6. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 5. In certain embodiments, the LPR for a conjugate provided herein ranges from 3 to 4. In certain embodiments, the LPR for a conjugate provided herein ranges from 1 to about 8; from about 2 to about 6; from about 3 to about 5; from about 3 to about 4; or from about 4 to about 6. In certain embodiments, the LPR for a conjugate ranges from about 3.1 to about 3.9; from about 3.2 to about 3.8; from about 3.2 to about 3.7; from about 3.2 to about 3.6; from about 3.3 to about 3.8; or from about 3.3 to about 3.7. In certain embodiments, the LPR for a conjugate ranges from about 4.1 to about 4.9; from about 4.2 to about 4.8; from about 4.2 to about 4.7; from about 4.2 to about 4.6; from about 4.3 to about 4.8; or from about 4.3 to about 4.7. In certain embodiments, the LPR for a conjugate provided herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or more. In some embodiments, the LPR for a conjugate provided herein is about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, or about 3.9. In some embodiments, the LPR for a conjugate provided herein is about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, or about 4.9. In some embodiments, the LPR for a conjugate provided herein ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, or 2 to 13. In some embodiments, the LPR for a conjugate provided herein ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, or 3 to 13. In some embodiments, the LPR for a conjugate provided herein is about 1. In some embodiments, the LPR for a conjugate provided herein is about 2. In some embodiments, the LPR for a conjugate provided herein is about 3. In some embodiments, the LPR for a conjugate provided herein is about 4. In some embodiments, the LPR for a conjugate provided herein is about 5. In some embodiments, the LPR for a conjugate provided herein is about 6. In some embodiments, the LPR for a conjugate provided herein is about 7. In some embodiments, the LPR for a conjugate provided herein is about 8. In some embodiments, the LPR for a conjugate provided herein is about 9. In some embodiments, the LPR for a conjugate provided herein is about 10. In certain embodiments, fewer than the theoretical maximum of units are conjugated to the polypeptide during a conjugation reaction. A polypeptide may contain, for example, lysine residues that do not react with the compound or linker reagent. Generally, for example, polypeptides do not contain many free and reactive cysteine thiol groups which may be linked to a ligand-linker moiety; indeed many cysteine thiol residues in polypeptides or proteins exist as disulfide bridges. In certain embodiments, a polypeptide may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups. In certain embodiments, a polypeptide is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine. In some embodiments, the ligand-linker moiety is conjugated via a lysine residue on the polypeptide. In some embodiments, the ligand-linker moiety is conjugated via a cysteine residue on the polypeptide. The loading (LPR) of a conjugate may be controlled in different ways, e.g., by: (i) limiting the molar excess of compound or conjugation reagent relative to polypeptide, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the polypeptide, such that the number and position of cysteine residues is modified for control of the number and / or position of linker- drug attachments (such as for thiomabs prepared as disclosed in WO2006 / 034488. It is to be understood that the preparation of the conjugates described herein may result in a mixture of conjugates with a distribution of one or more ligand-linker moieties attached to a polypeptide. Individual conjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g. hydrophobic interaction chromatography, including such methods known in the art. In certain embodiments, a homogeneous conjugate with a single LPR (loading) value may be isolated from the conjugation mixture by electrophoresis or chromatography. In certain embodiments of the conjugate of formula (I) m is 1 to 20, such as 2 to 10, 2 to 8, or 2 to 6. In certain cases, m is 10 or less. In certain cases, m is 2 to 8. In certain cases, m is 2 to 6. In certain cases, m is an average loading of about 4. 4.1.7 MuSK Polypeptides As summarized above, the bifunctional compounds of this disclosure can include a muscle specific kinase (MuSK) polypeptide that specifically binds a target anti-MuSK autoantibody. The MuSK polypeptide can be referred to as autoantibody “bait”. Muscle specific kinase is a postsynaptic integral membrane protein that plays a pivotal role in the development of the neuromuscular junction synapse (NMJ). Anti-MuSK autoantibodies are associated with the autoimmune disease myasthenia gravis (MG). In some embodiments, the anti-MuSK autoantibody is an IgG antibody, e.g., an IgG4 antibody. MuSK is a 100 kDa single-pass transmembrane receptor tyrosine kinase with an N-terminal extracellular domain followed by a short transmembrane domain and then a C-terminal cytoplasmic domain. The extracellular domain of MuSK, which is required for interaction with agrin and lrp4, includes three immunoglobulin (Ig)-like domains (e.g., Ig1 (amino acids 28-116), Ig2 (amino acids 121- 205), Ig3 (amino acids 212-302)) followed by a cysteine-rich frizzled-like region (Fzd) (amino acids 312- 450). The first two extracellular Ig-like domains are rigidly joined in a linear array and appear to play a dual role in activation of MuSK signaling. Ig1 is crucial for binding to the MuSK ligand. The cytoplasmic domain (amino acids 575-856) contains the kinase activity and signaling components of the molecule that lead to the development of the postsynaptic apparatus. The extracellular domains of the MuSK molecule contain the sites of binding (e.g., epitopes) of the disease-causing anti-MuSK autoantibodies. In particular, the Ig1 and / or Ig2 domains of MuSK can be considered antigens that contain the primary immunogenic or epitope-containing regions of the MuSK protein where anti-MuSK autoantibodies predominantly bind. In some embodiments, the MuSK polypeptide is an antigen that includes one or more epitope- containing domains, or antibody binding fragments thereof, of the full length MuSK protein. In some embodiments, the MuSK polypeptide includes Ig1 domain of MuSK, or an antigenic (e.g., epitope- containing) fragment thereof. In some embodiments, the MuSK polypeptide includes Ig2 domain of MuSK, or an antigenic fragment thereof. In some embodiments, the MuSK polypeptide includes the Ig1 and Ig2 domains, or antigenic fragments of both domains. In some embodiments, the MuSK polypeptide has at least 80% sequence identity (e.g., at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity) to an antigenic portion (e.g., antigenic domain or fragment thereof) of the MuSK protein (SEQ ID NO: 1). In SEQ ID NO: 1 below, Ig1 like domain is in bold and underlined, Ig2 like domain is italic and underlined, Ig3 like domain is underlined, Fz domain is bold, and the protein kinase domain is italic: In some embodiments, the MuSK polypeptide includes a sequence having at least 80% sequence identity (e.g., at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity) to a sequence of Table 11, or an antigenic fragment thereof. In some embodiments, the MuSK polypeptide includes a polypeptide of Table 11. Table 11: exemplary MuSK polypeptide sequences

[0048] 4.1.8 Carrier Polypeptide A number of strategies, such as attachment of a carrier, for imparting desirable pharmacokinetic properties to a peptide or protein (e.g., avoidance of rapid renal clearance, and / or optimizing Fc receptor mediated recycling) can be adapted for use in the bifunctional molecules of this disclosure that contain a target binding MuSK polypeptide. The MuSK polypeptide can be connected to a carrier polypeptide Y that imparts one or more desirable properties onto the resulting bifunctional molecule (e.g., increase in vivo stability and / or half- life), and / or provides for conjugation sites to a ligand-linker moiety, e.g., without disrupting the autoantibody binding properties of the MuSK polypeptide. In some embodiments, the MuSK polypeptide is synthetically linked to a carrier polypeptide Y. In some embodiments of formula (I), the carrier polypeptide Y is conjugated to a MuSK polypeptide (B) via a bifunctional linker. In some embodiments, the MuSK polypeptide is linked to a carrier polypeptide Y as part of a protein construct, such as a chimeric fusion protein. In some embodiments, the MuSK polypeptide B and the carrier polypeptide Y are fused directly to each other, e.g., via N-terminal to C-terminal fusion, or C- terminal to N-terminal fusion. In some embodiments, the MuSK polypeptide B and the carrier polypeptide Y are fused indirectly via a spacer domain. In some embodiments, the Y-B of formula (I) is a chimeric protein having a polypeptide encoded by a nucleic acid molecule that encodes for both a MuSK polypeptide B and the carrier polypeptide Y. The carrier polypeptide (Y) can be a serum protein or domain of a serum protein. In some embodiments, the serum protein is an albumin. In some embodiments, the serum protein is an immunoglobulin. In some embodiments, the carrier polypeptide (Y) is an engineered serum protein or domain thereof. The carrier polypeptide (Y) can be prepared synthetically, or recombinantly. FIG.2 illustrates an exemplary protein (Y-B) that includes a MuSK polypeptide (autoantibody “bait”) linked to carrier polypeptide (e.g., HSA carrier protein). In some embodiments, the Y-B is referred to as a protein construct, where the engineered chimeric protein is amenable to preparation using recombinant protein technology. 4.1.8.1 Albumin The carrier polypeptide can be a serum albumin protein or domain or subdomain thereof, or fragment thereof. In some embodiments, the carrier polypeptide is human serum albumin (HSA). Albumins generally have a long plasma half-life (e.g., about 3 weeks) and can provide a scaffold to which bioactive molecules can be attached or fused. HSA has a long serum half-life in humans that is attributed in part to its interaction with neonatal Fc receptor (FcRn). HSA (molecular mass 66.5 kDa) includes three structurally similar and flexible domains: I (residues 1–195), II (196–383) and III (384– 585). Each domain (D) is composed of two subdomains A and B (e.g., DIA [5-105], DIB [119-195], DIIA [196-292], DIIB [314-383], DIIIA [384-491], DIIIB [510-582], e.g., as referenced to SEQ ID NO: 2 of WO2017 / 029407) with common structural motifs. In some embodiments, the carrier protein is an HSA variant having enhanced FcRn binding. FcRn binds to the C-terminal end of DIII of HSA and protects albumin from intracellular degradation. For instance, a single amino acid substitution within HSA DIII (K537P) shows 12-fold improved binding affinity to FcRn, which translates into longer half-life. Various amino acid residues of albumin located in Domain I or Domain II also affect HSA interaction with FcRn (e.g., WO 2013 / 135896 describes albumin variants having one or more alterations in Domain I and one or more alterations in Domain III; WO 2015 / 036579 describes albumin variants having one or more alterations in Domain II). Any convenient albumin protein can be a parent for an albumin variant that can be utilized as a carrier polypeptide. As an example, human serum albumin (HSA) such as AAA98797, P02768-1, SEQ ID NO.7 (mature HSA), or SEQ ID NO.6 (immature HSA). In some embodiments, other albumins are utilized as a carrier polypeptide. Such other albumins include, but are not limited to, primate serum albumin (e.g.,, chimpanzee serum albumin, XP_517233.2), gorilla serum albumin or macaque serum albumin (e.g., NP_001182578), rodent serum albumin (e.g.,, hamster serum albumin, A6YF56), guinea pig serum albumin (e.g., Q6WDN9-1), mouse serum albumin (e.g., AAH49971, P07724-1 Version 3) and rat serum albumin (e.g., AAH85359, P02770-1 Version 2), bovine serum albumin (e.g., cow serum albumin P02769-1), equine serum albumin such as horse serum albumin (e.g., P35747-1), or donkey serum albumin (e.g., Q5XLE4-1), rabbit serum albumin (e.g., P49065-1 Version 2), goat serum albumin (e.g., ACF10391), sheep serum albumin (e.g., P14639-1), dog serum albumin (e.g., P49822-1), chicken serum albumin (e.g., P19121 -1 Version 2) and pig serum albumin (e.g., P08835- 1 Version 2) or a polypeptide having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.2%, 99.4%, 99.6%, or at least 99.8% amino acid sequence identity to such an albumin. Non-mammalian albumins of interest include ovalbumin (e.g., P01012.pro: chicken ovalbumin; 073860. Pro: turkey ovalbumin). In some embodiments, albumin, a fragment thereof, or conjugation-competent albumin variant, or albumin part of a fusion polypeptide or conjugate comprising albumin or a fragment thereof has a polypeptide sequence having at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 6 (e.g., P02768-1) below, where Domain I is in bold, Domain II is underlined, and Domain III is in italic: In some embodiments, albumin, a fragment thereof, or conjugation-competent albumin variant, or albumin part of a fusion polypeptide or conjugate comprising albumin or a fragment thereof has a polypeptide sequence having at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 7 below: N In some embodiment, the albumin, a fragment thereof, or conjugation-competent albumin variant, or variant thereof of the bifunctional molecule has a sequence identity to the sequence of HSA shown in SEQ ID NO.7 of at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. It is preferred that the albumin maintains at least one of the major properties of albumin or a similar tertiary structure as an albumin, such as HSA. A functional fragment of albumin may have a sequence identity of at least 60%, 70%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.2%, 99.4%, 99.6%, 99.8%, or 100% to the sequence of HSA Domain III as shown in SEQ ID NO.8, or to the sequence of HSA Domain II and Domain III as shown in SEQ ID NO.9, or to a molecule consisting of or comprising two copies of Domain III (e.g., SEQ ID NO.10), or to a molecule consisting of or comprising three copies of Domain III (e.g., SEQ ID NO.11), or to a molecule consisting of or comprising Domain I and two copies of Domain III (e.g., SEQ ID NO.12). Table 12

[0049] The human serum albumin (HSA) polypeptide chain has 35 cysteine residues, which form 17 disulfide bonds and one unpaired (free) cysteine at position 34 located in DI of the mature protein. The albumin, a fragment thereof, or conjugation-competent albumin variant, or albumin part of a fusion polypeptide or conjugate comprising albumin or a fragment thereof according to the disclosure, when folded, may have several, for example at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16 and suitably all 17, of the native disulfide bonds of the polypeptide of SEQ ID NO.7. Albumin carrier polypeptides which can be adapted for use in the bifunctional molecules of this disclosure are described in WO2017 / 029407, WO 2013 / 135896, WO 2015 / 036579, the disclosures of which are herein incorporated by reference in their entireties. Conjugation of molecules to the free thiol on cysteine-34 of HSA can provide site-selective conjugation. To increase loading potential, recombinant HSA (rHSA) variants can be engineered to contain additional free, conjugation-competent cysteines. The term “thio-albumin” is used to describe an albumin variant which comprises one or more (e.g. several) unpaired cysteine residues, particularly an albumin variant in which one or more (e.g. several) of the unpaired cysteine residues does not occur in a naturally occurring variant of an albumin. A thio-albumin refers to a conjugation-competent albumin. The rHSA variant can be a thio-albumin or a conjugation-competent albumin. The rHSA may have one or more free, conjugation-competent cysteines introduced in DI, DII, and / or DIII. In some embodiments, the rHSA variant has at least one free, conjugation-competent cysteines introduced in DI or DII. In some embodiments, the rHSA variant has at least one free, conjugation-competent cysteine introduced in DI and DIII. In some embodiments, the rHSA variant has a conjugation site at Cys34 and at least one or more free, conjugation-competent cysteines introduced in DI, DII, and / or DIII. In some embodiments, the carrier polypeptide is a rHSA variant having a conjugation position at Cys34 (e.g., in reference to SEQ ID NO.: 2) and one or more conjugation-competent cysteines introduced at positions selected from K93, A226, E230, I271, E294, E358, L24, F49, V54, D56, A92, Q94, E97, H128, F156, E227, D237, K240, D259, K262, N267, Q268, L275, L284, K317, A322, E333, D340, E354, K359, A362, E382, and L398 of SEQ ID NO.7. The free, conjugation-competent cysteines may be introduced by substitution of an amino acid other than cysteine at any one of positions corresponding to or equivalent to any of residues selected from K93, A226, E230, I271, E294, E358, L24, F49, V54, D56, A92, Q94, E97, H128, F156, E227, D237, K240, D259, K262, N267, Q268, L275, L284, K317, A322, E333, D340, E354, K359, A362, E382, and L398 of SEQ ID NO. 7, or by insertion of a cysteine at a position adjacent to N- or C- side of an amino acid corresponding to a position equivalent to any of residues selected from K93, A226, E230, I271, E294, E358, L24, F49, V54, D56, A92, Q94, E97, H128, F156, E227, D237, K240, D259, K262, N267, Q268, L275, L284, K317, A322, E333, D340, E354, K359, A362, E382, and L398 of SEQ ID NO. 7. In some embodiments, at least one or more free, conjugation-competent cysteines is introduced at one or more positions corresponding to or equivalent to any of residues selected from C34, V54, H128, K240, and K262. In some embodiments, the carrier polypeptide is a rHSA variant that exhibits up to 95% monomeric stability and retains hFcRn engagement compared with a wildtype unconjugated control (e.g., as demonstrated by Biolayer Interferometry). In some embodiments, introduction of the free, conjugation- competent cysteines into the rHSA variant does not interfere with FcRN binding. In some embodiments, introduction of the free, conjugation-competent cysteines maintains the albumin half-life in circulating blood. 4.1.8.2 Immunoglobulin In some embodiments, the carrier polypeptide is an Fc fragment, a monomer, a dimer, a domain, or fragments thereof. Fc fragments contain the CH2 and CH3 domains and part of the hinge region held together by one or more disulfides and noncovalent interactions. Fc and Fc5µ fragments are produced from fragmentation of IgG and IgM, respectively. Fc fragments are derived from the heavy chain constant region of an immunoglobulin. In some embodiments, Fc fragments are derived from IgG immunoglobulins of any subclass (e.g., IgG1, IgG2, IgG3, IgG4). In preferred embodiments, Fc fragments are derived from human IgG1. The term “Fc dimer” refers to an Fc fragment containing two CH2-CH3 chains. The dimer is typically about 54k Da. An “Fc monomer” is generally half the size of the dimer (e.g., about 27k Da). Methods for generating Fc dimers and monomers are described in Wang et al. Engineering soluble monomeric IgG1 Fc with significantly decreased non-specific binding. Front. Immunol. (2017) 8:1545; Ying et al. Soluble monomeric IgG1 Fc. J. Biol Chem (2012) 287(23): 19399-408, each of which is incorporated herein by reference in its entirety. In some embodiments, the Fc fragment has a polypeptide sequence having at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 5 (human IgG1 hinge-Fc) below: In some embodiments, the Fc fragment is a variant of a human IgG Fc region. In some embodiments, the Fc fragment is a variant of human IgG Fc comprising one or more amino acid substitutions in the CH2 and / or CH3 domains. In some embodiments, the carrier polypeptide (Y) is an Fc fragment generated from the heavy chain constant region of an immunoglobulin, an Fc monomer, an Fc dimer, or fragments thereof. In some embodiments, the carrier polypeptide (Y) Fc is conjugated to an antibody fragment comprising an antigen-binding region (e.g., nanobody, scFv, VHH) to form an engineered antibody. In some embodiments, the carrier polypeptide (Y) Fc is conjugated to an antigen to form an Fc-antigen fusion. In various embodiments, the Fc fragment is conjugated to polypeptide B at a cysteine residue on the Fc fragment. 4.2 Pharmacological Class A lysosome-targeting chimera (LYTAC) is a protein-based therapeutic designed to bind and rapidly clear, via targeted degradation, muscle-specific tyrosine kinase (MuSK) autoantibodies. Structurally, in some embodiments, a fusion protein of MuSK domains 1 and 2 and human serum albumin that is conjugated, using nonspecific lysine conjugation, to a linker-internalizer comprising a non- cleavable linker bound to a stabilized tri-GalNAc derivative. The fusion protein binds to MuSK autoantibodies, while the linker-internalizer promotes rapid systemic clearance mediated by cellular uptake via binding to the liver specific asialoglycoprotein receptor (ASGPR). ASGPR is a heterotrimer with two ASGPR1 and one ASGPR2 subunits. The human ASGPR1 carbohydrate recognition domain shares 79-99% sequence identity across monkey, dog, rabbit, rat and mouse proteins and complete conservation of residues within 5 Å of a bound GalNAc based on a co-crystal structure. No structural information is available for ASGPR2, but the human carbohydrate recognition domain shares 67-96% sequence identity across monkey, dog, rabbit, rat, and mouse proteins. Furthermore, ASGPR-mediated liver distribution of GalNAc-conjugated siRNAs has been demonstrated for rat and monkey (McDougall et al, 2021). In some embodiments, provided is a conjugate (or LYTAC) is selected from:

[0050] wherein m is 1-3; wherein m is 1-3;

[0051] wherein m is 1-3; and Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; and B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. In the conjugates shown above, “m x Lys” and “m x Cys” refer to the number (m) of ASGPR binding compounds bonded a Lys or Cys on the Y-B complex. In addition, each Z is a residual moiety resulting from the covalent linkage of a maleimide to one or more cysteine residue(s) (Cys) of the Y-B complex. In some embodiments, Z is: 4.3 mixture thereof; wherein *** represents the point of attachment to the Y-B complex. Pharmaceutical Compositions In another embodiment, provided herein are pharmaceutical compositions including one or more bifunctional molecules (e.g., conjugates) disclosed herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the conjugates provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. Pharmaceutical carriers suitable for administration of the conjugates provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. The conjugates described herein can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. In certain embodiments, the conjugate is formulated into one or more suitable pharmaceutical preparations, such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers. In compositions provided herein, a conjugate described herein may be mixed with a suitable pharmaceutical carrier. The concentration of the conjugate in the compositions can, for example, be effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof. In certain embodiments, the pharmaceutical compositions provided herein are formulated for single dosage administration. To formulate a composition, the weight fraction of conjugate is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated. Concentrations of the conjugate in a pharmaceutical composition provided herein will depend on, e.g., the physicochemical characteristics of the conjugate, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. Pharmaceutical compositions described herein are provided for administration to a subject, for example, humans or animals (e.g., mammals) in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage form, including oral or nasal solutions or suspensions and oil-water emulsions containing suitable quantities of a conjugate or pharmaceutically acceptable derivatives thereof. The conjugate is, in certain embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human or animal (e.g., mammal) subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of a conjugate sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged capsules. Unit-dose forms can be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit- dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of capsules or bottles. Hence, in specific aspects, multiple dose form is a multiple of unit-doses which are not segregated in packaging. In certain embodiments, the conjugates herein are in a liquid pharmaceutical formulation. Liquid pharmaceutically administrable formulations can, for example, be prepared by dissolving, dispersing, or otherwise mixing a conjugate and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, and the like, to thereby form a solution or suspension. In certain embodiments, a pharmaceutical composition provided herein to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see, e.g., Remington: The Science and Practice of Pharmacy (2012) 22nded., Pharmaceutical Press, Philadelphia, PA Dosage forms or compositions containing antibody in the range of 0.005% to 100% with the balance made up from non-toxic carrier can be prepared. Parenteral administration, in certain embodiments, is characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. Other routes of administration may include, enteric administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous infusion, intrathecal administration, and intraperitoneal administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions can be either aqueous or nonaqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. In certain embodiments, intravenous or intraarterial infusion of a sterile aqueous solution containing a conjugate described herein is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing a conjugate described herein injected as necessary to produce the desired pharmacological effect. In certain embodiments, the pharmaceutical formulations are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels. The lyophilized powder is prepared by dissolving a conjugate provided herein, in a suitable solvent. In some embodiments, the lyophilized powder is sterile. Suitable solvents can contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. A suitable solvent can also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in certain embodiments, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides an example of a formulation. In certain embodiments, the resulting solution will be apportioned into vials for lyophilization. Lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature. Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. In certain embodiments, the conjugates provided herein can be formulated for local administration or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. 4.4 Methods of Use Binding of the ligand moiety of the bifunctional molecule to the ASGPR can trigger internalization and lysosomal degradation of a bound target anti-MuSK autoantibody. In some embodiments, the bifunctional molecule is a conjugate of a protein that includes the polypeptide that specifically binds anti-MuSK autoantibody and a linked ligand moiety. The bifunctional molecules of this disclosure find use in reducing levels of the extracellular target molecule anti-MuSK autoantibody in a biological system or sample. The biological system can be a human subject. The methods of using the conjugates described herein can thus remove anti-MuSK autoantibodies from the extracellular space (the extracellular milieu) of a cell in the biological system by sequestering the target protein in the cell’s lysosome and degrading the target anti-MuSK autoantibodies. Removal of a target protein may refer to reduction of the amount of, or depletion of, the target protein from the extracellular space, or the extracellular milieu. In some embodiments, the biological system or sample is a cellular sample. The term “sample” refers to an aliquot or portion taken from a source and / or provided for analysis or processing. In some embodiments, a sample is from a biological source such as a tissue, cell or component part (e.g., a body fluid, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen). In some embodiments, a sample may be or include a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, or organs. In some embodiments, a sample is or includes a medium, such as a nutrient broth or gel, which may contain cellular components, such as proteins. In some embodiments, a “primary” sample is an aliquot of the source. In some embodiments, a primary sample is subjected to one or more processing (e.g., separation, purification, etc.) steps to prepare a sample for analysis or other use. 4.4.1 Methods of treating myasthenia gravis Provided herein are methods of treating a disease or disorder caused by the target anti- MuSK autoantibody in a human subject. The present disclosure thus provides methods related to using the bifunctional molecules, conjugates and compositions of this disclosure for therapeutic treatment of myasthenia gravis (MG), including generalized myasthenia gravis (gMG). Myasthenia gravis (MG) can be treated according to the subject methods by depletion of pathogenic anti-MuSK autoantibodies by degradation through the lysosomal pathway. In some embodiments, the method of treating MG includes administering to a subject, e.g., a human subject in need thereof, an effective amount of a bifunctional molecule or pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the bifunctional molecule (e.g., as described herein). In some embodiments, the myasthenia gravis (MG) is generalized MG (gMG). Generalized myasthenia gravis (gMG) is a rare complement-mediated autoimmune disease characterized by the production of autoantibodies targeting proteins that are critical for the normal transmission of chemical or neurotransmitter signals from nerves to muscles, e.g., acetylcholine receptor (AChR) proteins or MuSK protein. Anti-MuSK autoantibodies are detected in 1-10% of patients with MG, which is about 40% of the AchR Ab-negative patients. MuSK-MG is a distinct autoimmune disease from AchR-MG. Although MuSK-MG is an Ab-mediated disease, inflammatory damage to the NMJ does not occur. The majority of the autoantibodies are of the IgG4 immunoglobulin subclass, which is characterized partly by inability to activate complement or bind to Fc receptors. The anti-MuSK autoantibodies mask the binding site on MuSK that interact with its binding proteins (e.g., ligands). Blockade of MuSK ligand binding may lead to these auto-Abs blocking MuSK ligand binding and the normal function of MuSK, which leads to reduce postsynaptic density of AchRs. In some embodiments, the patient treated according to the methods of this disclosure is a patient who is anti-MuSK antibody positive. Patients with gMG present with muscle weakness that characteristically becomes more severe with repeated use and recovers with rest. Muscle weakness can be localized to specific muscles, such as those responsible for eye movements, but often progresses to more diffuse muscle weakness. gMG may even become life-threatening when muscle weakness involves the diaphragm and the other chest wall muscles responsible for breathing. This is the most feared complication of gMG, known as myasthenic crisis or MG crisis, and requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG experience a myasthenic crisis within two years of diagnosis. The terms “administer”, “administration”, or “administering” refer to the act of injecting or otherwise physically delivering a substance (e.g., a conjugate or pharmaceutical composition provided herein) to a subject or a patient (e.g., human), such as by mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art. In some embodiments, administration is oral. In some embodiments, administration is by subcutaneous injection. In some embodiments, administration is by intravenous infusion. The term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition (e.g., myasthenia gravis). Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. A treatment or preventive effect is evident when there is a significant improvement, often statistically significant, in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given compound or composition can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant modulation in a marker or symptom is observed. The terms “effective amount” or “therapeutically effective amount” refer to an amount of a therapeutic (e.g., a conjugate or pharmaceutical composition provided herein) which is sufficient to treat, diagnose, prevent, delay the onset of, reduce and / or ameliorate the severity and / or duration of a given condition, disorder or disease (e.g., myasthenia gravis) and / or a symptom related thereto. These terms also encompass an amount necessary for the reduction, slowing, or amelioration of the advancement or progression of a given disease, reduction, slowing, or amelioration of the recurrence, development or onset of a given disease, and / or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy or to serve as a bridge to another therapy. In some embodiments, “effective amount” as used herein also refers to the amount of a conjugate described herein to achieve a specified result. The term “treatment dose” refers to one or more doses of a therapeutic agent administered in the course of addressing or alleviating a therapeutic indication. Treatment doses may be adjusted to maintain a desired concentration or level of activity of a therapeutic agent in a body fluid or biological system. A bifunctional molecule of this disclosure and additional therapeutic agent(s) and / or therapies for MG can be administered in combination. Such combinations may be in the same composition, or the additional therapeutic agents or therapies can be administered as part of a separate composition or by another method described herein. During administration of the compounds and conjugates according to methods of this disclosure, subjects may receive standard of care (SOC) therapy for MG, e.g., gMG. Standard of care therapies for gMG may include, but are not limited to, plasma exchange (PLEX), intravenous immunoglobin (IVIg) treatment, biologics (e.g., rituximab or eculizumab or ravulizumab), pyridostigmine treatment, corticosteroid treatment, and / or immunosuppressive (e.g., non-steroidal immunosuppressive) drug treatment. The terms “subject” and “patient” are used interchangeably. A subject can be a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkey and human), for example a human. In certain embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In some embodiments, the subject is human. Patients treated with bifunctional molecule according to the methods of this disclosure may be screened prior to administration. The terms “patient”, “subject” and “individual” are used interchangeably herein. The term “screen” refers to a review or evaluation carried out for the purpose of selection or filtration. Patients may be screened to select individuals in need of treatment. In some embodiments, subjects are screened to select individuals most likely to respond favorably to treatment. Screening may include selecting subjects previously diagnosed with gMG. The gMG diagnosis may be made according to Myasthenia Gravis Foundation of America (MGFA) criteria; Class II-IVa (see Howard, J.F., 2009. Myasthenia Gravis A Manual for the Health Care Provider, Myasthenia Gravis Foundation of America, Inc.). In some embodiments of the methods of this disclosure, screening includes assessing whether a human patient is positive for auto- antibodies that bind to MuSK. 4.5 Definitions Unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1% or 0.05% of a given value or range. In certain embodiments, where an integer is required, the term “about” means within plus or minus 10% of a given value or range, rounded either up or down to the nearest integer. As used herein, the phrases “for example,” “for instance,” “such as,” or “including” are meant to introduce examples that further clarify more general subject matter. These examples are provided only as an aid for understanding the disclosure, and are not meant to be limiting in any fashion. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. The term “autoantibody” or “autoantibodies” refers to an antibody that recognizes, binds, or otherwise interacts with an antigen normally found in a subject, or a tissue or cell of a subject. Autoantibodies are abnormal antibodies which are generated by pathogenic B cells when targeting an individual’s own tissue. The term “autoimmunity” refers to the presence of antibodies (which are made by B lymphocytes) and T lymphocytes directed against normal components of a person (autoantigens). These components are called autoantigens or self-antigens and typically consist of proteins (or proteins complexed to nucleic acids). The antibodies and T lymphocytes that recognize autoantigens are called “autoantibodies” and “autoreactive T cells”. The terms “protein” and “polypeptide” are used interchangeably. Proteins may include moieties other than amino acids (e.g., may be glycoproteins, etc.) and / or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that a “protein” can be a complete protein chain as produced by a cell (with or without a signal sequence), or can be a protein portion thereof. Those of ordinary skill will appreciate that a protein can sometimes include more than one protein chain, for example non-covalently or covalently attached, e.g., linked by one or more disulfide bonds or associated by other means. In certain embodiments, a polypeptide can occur as a single chain or as two or more associated chains, e.g., may be present as a multimer, e.g., dimer, a trimer. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art. Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc. In some embodiments, proteins may include natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. An “antibody fragment” comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2fragments, Fab’ fragments, scFv fragments, and VHH fragments. An “antigen” is a moiety or molecule that contains an epitope to which an antibody can specifically bind. As such, an antigen is also specifically bound by an antibody. An “epitope” is a term known in the art and refers to a localized region of an antigen to which an antibody can specifically bind. An epitope can be a linear epitope of contiguous amino acids or can include amino acids from two or more non-contiguous regions of the antigen. A “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” means an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes both one and more than one such excipient, diluent, carrier, and adjuvant. A “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general, a “pharmaceutical composition” is sterile, and preferably free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intrathecal, intramuscular, subcutaneous, and the like. The term “pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and, more particularly in humans. The term “pharmaceutically acceptable salt” refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the conjugate compounds, or separately by reacting the free base function or group of a compound with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids. Compounds are described using standard nomenclature. The compounds in any of the formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context. As used herein, the phrase “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. The term “independently selected from” is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —(C═O)NH2is attached through carbon of the carbonyl (C═O) group. The present disclosure includes compounds (e.g., as described herein) with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as2H,3H,11C,13C,14C,15N,18F31P,32P,35S,36Cl, and125I respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location. In some embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of Formulas described herein. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R1, R2, R3, R4, R6, R11, R21, R22, R23, R24, R25R, R’, and R’’ etc. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non- limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3etc.). In certain other embodiments, when two substituents are combined to form a cycle the unsubstituted carbons may be deuterated. “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5or C1-C6. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C1-C6aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C6alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example and without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one point of unsaturation. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one triple bond. “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C1- C2alkylene, C1-C3alkylene, C1-C4alkylene, C1-C6alkylene, or C1-C6alkylene. “Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number ofcarbon atoms, for example C2-C4alkenylene.“Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene. The term “amino” refers to the group -NRR’ wherein R and R’ are independently hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and / or heteroatom-containing variants thereof. “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule. “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. “Halo” and “halogen” refers to fluorine, chlorine, bromine or iodine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl. “Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). The term “heteroaliphatic” refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. “Heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, —O-alkyl-O-alkyl, alkyl- O-haloalkyl, etc. “Heterocycloalkyl” is an alkyl group as defined herein substituted with a heterocyclo group as defined herein. “Arylalkyl” is an alkyl group as defined herein substituted with an aryl group as defined herein. “Heteroarylalkyl” is an alkyl group as defined herein substituted with a heteroaryl group as defined herein. The term “alkynyl” refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl” refers to alkynyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively. The term aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocycles or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocycles or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocycle or heterocyclyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C6-14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl. An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo. The term “heterocyclyl” (or “heterocyclo”) includes saturated, and partially saturated heteroatom- containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing —O—O—.—O—S— or —S—S— portions. Said “heterocyclyl” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′- benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. Heterocyclo groups also include radicals where heterocyclic radicals are fused / condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms. The term “heteroaryl” denotes aryl ring systems that contain one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH- 1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. As used herein, the terms “may,” “optional,” “optionally,” or “may optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. The term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C12cycloalkyl, C3- C12cycloalkenyl, C1-C12heterocycloalkyl, C3-C12heterocycloalkenyl, C1-C10alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10alkylamino, C1-C10dialkylamino, arylamino, diarylamino, C1- C10alkylsulfonamino, arylsulfonamino, C1-C10alkylimino, arylimino, C1-C10alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C1-C10alkylthio, 212midazoli, C1-C10alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, alkyl including C1- C6alkyl, alkenyl including C2-C6alkenyl, alkynyl including C2-C6alkynyl, —C1-C6alkoxy, alkanoyl including C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1-C6alkylamino)C0-C2alkyl, haloalkyl including C1-C6haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide, —C1- C6alkyl(heterocyclo), C1-C6alkyl(heteroaryl), —C1-C6alkyl(C3-C7cycloalkyl), O—C1-C6alkyl(C3- C7cycloalkyl), B(OH)2, phosphate, phosphonate and haloalkoxy including C1-C6haloalkoxy. When the term “substituted” appears prior or after a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase “substituted alkyl and aryl” is to be interpreted as “substituted alkyl and substituted aryl.” In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined herein. In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “hydroxyalkyl” refers to the group HO- (alkyl)-. As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds. In certain embodiments, a substituent may contribute to optical isomerism and / or stereo isomerism of a compound. A compound of this disclosure may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the present disclosure includes a solvated form of the compound. The term “solvate” refers to a molecular complex of a compound (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6- DMSO. A solvate can be in a liquid or solid form. Salts, solvates, hydrates, and prodrug forms of a compound are of interest. All such forms are embraced by the present disclosure. Thus, the compounds described herein include salts, solvates, hydrates, prodrug and isomer forms thereof, including the pharmaceutically acceptable salts, solvates, hydrates, prodrugs and isomers thereof. In certain embodiments, a compound may be a metabolized into a pharmaceutically active derivative. Unless otherwise specified, reference to an atom is meant to include isotopes of that atom. For example, reference to H is meant to include1H,2H (i.e., D), and3H (i.e., T), and reference to C is meant to include12C and all isotopes of carbon (such as13C). Definitions of other terms and concepts appear throughout the detailed description. 4.6 Numbered Embodiments Embodiment 1. A conjugate of formula (I): or a pharmaceutically acceptable salt thereof, wherein: B is a muscle-specific kinase (MuSK) polypeptide that specifically binds anti-MuSK autoantibody; Y is a carrier polypeptide connected to B; X is an asialoglycoprotein receptor (ASGPR) binding moiety of formula (II): wherein: R1is selected from –Z1–*, –H, –OH, –CH3, –OCH3, and –OCH2CH=CH; R2is selected from –Z1–*, –NHCOCH3, –NHCOCF3, –NHCOCH2CF3, –OH, and optionally substituted triazole; R6is selected from –Z1–*, –OH, –OC(O)R, -C(O)NHR, and optionally substituted triazole, where R is optionally substituted (C1-C6)alkyl or optionally substituted aryl; wherein one of R1, R2, and R6is –Z1–*, and “ * ” represents a point of connection of Z1to the linker (L); R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H, or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-, -A2-, -NR21CO-, - CONR21-, -NR21SO2-, - SO2NR21-, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl; n is 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, or 1 to 10, such as 1, 2, or 3); L is a linker conjugated to Y-B; and m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is in the range from about 1 to about 20 (e.g., about 1 to about 3, such as 1, 2 or 3, or about 1 to about 10, about 1 to about 8, about 2 to about 8, about 3 to about 6, or about 4 to about 5). Embodiment 2. The conjugate of Embodiment 1, wherein R1is –Z1–* and each X is independently of formula (IIa): Embodiment 3. The conjugate of Embodiment 2, wherein each X is independently of formula (IIIa) or (IIIb): (IIIa) (IIIb) wherein: -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; and -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. Embodiment 4. The conjugate of Embodiment 3, wherein Z11is -S-. Embodiment 5. The conjugate of Embodiment 2 or 3, wherein each X is independently of formula (IIa-1): (IIa-1). Embodiment 6. The conjugate of Embodiment 5, wherein Z1is S, and each X is independently of formula (XA-1): (XA-1). Embodiment 7. The conjugate of Embodiment 2 or 3, wherein each X is independently of formula (IIa-2): (IIa-2). Embodiment 8. The conjugate of Embodiment 7, wherein Z1is S, and each X is independently of formula (XB-1): (XB). Embodiment 9. The conjugate of Embodiment 2, 3, 5 or 7, wherein Z11is -C(R22)2. Embodiment 10. The conjugate of Embodiment 9, wherein each X is independently of formula (XB-2): (XB-2). Embodiment 11. The conjugate of Embodiment 9, wherein each X is independently of formula (IIIb-1): wherein: -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. Embodiment 12. The conjugate of Embodiment 11, wherein each X is independently of formula (XC-1) or (XC-2): ( XC-1) ( XC-2). Embodiment 13. The conjugate of Embodiment 1, wherein R2is –Z1–* and each X is independently of formula (IIb): (IIb). Embodiment 14. The conjugate of Embodiment 13, wherein each X is independently of formula (IVa): (IVa). Embodiment 15. The conjugate of Embodiment 14, wherein each X is independently of formula (IVb) or (IVc):

[0052] (IVb) (IVc) wherein -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2. Embodiment 16. The conjugate of Embodiment 14 or 15, wherein R1is H. Embodiment 17. The conjugate of any one of Embodiments 14 to 16, wherein R11is H. Embodiment 18. The conjugate of Embodiment 14 or 15, wherein each X is independently of formula (IVb-1) or (IVc-1): (IVb-1) (IVc-1) wherein R11is the bridging moiety that connects the 5-position carbon to the 1-position carbon. Embodiment 19. The conjugate of Embodiment 18, wherein R11is -CH2O- or -OCH2-. Embodiment 20. The conjugate of any one of Embodiments 15 to 19, wherein: -Z11- is -N(R21)-; and -A1- and -A2- are optionally substituted monocyclic heteroarylene (e.g., triazole or pyrimidine). Embodiment 21. The conjugate of Embodiment 20, wherein each X is independently of formula (IVf) or (IVg):

[0053] (IVf) (IVg) wherein R21and R22are independently selected from H, halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). Embodiment 22. The conjugate of Embodiment 1, wherein R6is –Z1–* and each X is independently of formula (IIc): * (IIc). Embodiment 23. The conjugate of any one of Embodiments 1 to 22, wherein B comprises one or more extracellular domains of MuSK, or an antigenic fragment thereof. Embodiment 24. The conjugate of Embodiment 23, wherein B comprises the IgG1 extracellular domain of MuSK. Embodiment 25. The conjugate of Embodiment 23, wherein B comprises the IgG2 extracellular domain of MuSK. Embodiment 26. The conjugate of Embodiment 23, wherein B comprises the IgG1 and IgG2 extracellular domains of MuSK. Embodiment 27. The conjugate of any one of Embodiments 23 to 26, wherein B comprises a polypeptide having at least 80% (e.g., at least 85%, or at least 90%) sequence identity with a sequence of SEQ ID NOs: 1-4. Embodiment 28. The conjugate of Embodiment 27, wherein B comprises a polypeptide having at least 95% sequence identity with a sequence of SEQ ID NOs: 1-4. Embodiment 29. The conjugate of Embodiment 28, wherein B comprises a polypeptide having at least 98% sequence identity with a sequence of SEQ ID NOs: 1-4. Embodiment 30. The conjugate of Embodiment 23, wherein B comprises a polypeptide of one of SEQ ID NOs: 2-4. Embodiment 31. The conjugate of Embodiment 23, wherein B consists essentially of a polypeptide of one of SEQ ID NOs: 2-4. Embodiment 32. The conjugate of any one of Embodiments 1 to 31, wherein Y is a half- life extending carrier protein. Embodiment 33. The conjugate of any one of Embodiments 1 to 32, wherein Y is selected from albumin, albumin binding domain, multimerization domain, Fc domain, Fc (monomer), Fc (dimer), fragments thereof (e.g., synthetic peptides), and variants thereof. Embodiment 34. The conjugate of Embodiment 33, wherein Y comprises an albumin, a fragment thereof, or a variant thereof. Embodiment 35. The conjugate of Embodiment 34, wherein Y comprises human serum albumin (HSA), an HSA domain, bovine serum albumin (BSA), a fragment thereof, or a variant thereof. Embodiment 36. The conjugate of Embodiment 34, wherein Y is an HSA variant engineered for increased stability, conjugation efficiency (Cys or Lys), and / or FcRn binding. Embodiment 37. The conjugate of any one of Embodiments 34 to 36, wherein Y comprises a polypeptide having 1 to 10 amino acid substitutions, deletions or additions (for example, 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) as compared to a sequence of SEQ ID NOs: 6-12. Embodiment 38. The conjugate of Embodiment 37, wherein the 1 to 10 amino acid substitutions, deletions or additions are selected from C34A, V54C, K93C, H128C, K262C, and E294C. Embodiment 39. The conjugate of any one of Embodiments 35 to 38, wherein Y comprises a site-specific mutation of a naturally occurring amino acid residue. Embodiment 40. The conjugate of Embodiment 39, wherein the site-specific mutation is a cysteine residue suitable for conjugation to a cysteine reactive linker (e.g., one, two or three cysteine residues suitable for conjugation). Embodiment 41. The conjugate of any one of Embodiments 35 to 40, wherein Y comprises a polypeptide having at least 80% (e.g., at least 90%, at least 95%, at least 98%) sequence identity with a sequence of SEQ ID NOs: 6-12. Embodiment 42. The conjugate of Embodiment 41, wherein Y comprises a polypeptide of SEQ ID NOs: 6-12. Embodiment 43. The conjugate of Embodiment 33, wherein Y comprises a Fc domain, a fragment thereof, or a variant thereof. Embodiment 44. The conjugate of Embodiment 43, wherein Y comprises Fc (monomer). Embodiment 45. The conjugate of Embodiment 43, wherein Y comprises Fc (dimer) (e.g., KiH Fc heterodimer). Embodiment 46. The conjugate of any one of Embodiments 43 to 45, wherein Y comprises a Fc domain engineered for increased stability, conjugation efficiency (Cys or Lys), and / or FcRn binding. Embodiment 47. The conjugate of any one of Embodiments 43 to 46, wherein Y comprises a polypeptide having 1 to 10 amino acid substitutions, deletions or additions (for example, 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions ) as compared to a sequence of SEQ ID NOs: 6-12. Embodiment 48. The conjugate of Embodiment 47, wherein the 1 to 10 amino acid substitutions, deletions or additions are selected from T366W, T366S, X368A, A378C, X407V, and L443C. Embodiment 49. The conjugate of any one of Embodiments 43 to 48, wherein Y comprises a (e.g., at least one) site-specific mutation of a naturally occurring amino acid residue. Embodiment 50. The conjugate of Embodiment 49, wherein the site-specific mutation is a cysteine residue suitable for conjugation to a cysteine reactive linker (e.g., one, two or three cysteine residues suitable for conjugation). Embodiment 51. The conjugate of any one of Embodiments 43 to 50, wherein Y comprises a polypeptide having at least 80% (e.g., at least 90%, at least 95%, at least 98%) sequence identity with a sequence of SEQ ID NO.7. Embodiment 52. The conjugate of Embodiment 51, wherein Y comprises a polypeptide of SEQ ID NO.7. Embodiment 53. The conjugate of any one of Embodiments 1 to 52, wherein Y-B is a chimeric fusion protein. Embodiment 54. The conjugate of Embodiment 53, wherein Y is fused directly to B. Embodiment 55. The conjugate of clause / embodiment 53 wherein Y comprises SEQ ID No.7 and B comprises SEQ ID No.4. Embodiment 56. The conjugate of Embodiment 53, wherein Y is fused indirectly to B via a spacer domain. Embodiment 57. The conjugate of any one of Embodiments 53 to 55, wherein the N- terminal of Y is fused to the C-terminal of B. Embodiment 58. The conjugate of any one of Embodiments 53 to 55, wherein the C- terminal of Y is fused to the N-terminal of B. Embodiment 59. The conjugate of any one of Embodiments 1 to 52, wherein Y is covalently linked to B via a non-peptidic linking moiety (e.g., a bifunctional linker). Embodiment 60. The conjugate of any one of Embodiments 1 to 58, wherein n is 1, and L comprises a linear linker having a backbone of 20 or more consecutive atoms covalently linking X to Y-B. Embodiment 61. The conjugate of any one of Embodiments 1 to 58, wherein n is 2, and L is a branched linker that covalently links the X moieties to Y-B. Embodiment 62. The conjugate of any one of Embodiments 1 to 58, wherein n is 3, and L is a branched linker that covalently links the X moieties to Y-B. Embodiment 63. The conjugate of any one of Embodiments 1 to 61, wherein the linker L comprises a backbone of 20 to 60 consecutive atoms between each X and Y-B (e.g., 20 to 50, 20 to 40, 30 to 40, 30 to 60, or 40 to 60 consecutive atoms). Embodiment 64. The conjugate of any one of Embodiments 1 to 62, wherein L is of formula (XI): wherein each L1and L3are independently a linear linking moiety, and L2is a branched linking moiety, wherein L1to L3together provide a linear or branched linker between X and Y; a, b and c are independently 0 or 1, wherein when n is 1, b is 0 and at least one of a and c is 1; and when n is 2 or 3, a, b and c are each 1; * represents the point of connection of L1to X via Z1; and ** represents a point of conjugation of the linker L to Y-B. Embodiment 65. The conjugate of Embodiment 63, wherein: n is 1; and a is 1, b is 0 and c is 1, whereby L is of formula (XIa): (XIa). Embodiment 66. The conjugate of Embodiment 63, wherein: n is 2; and a is 1, b is 1, and c is 1, whereby L is of formula (XIb): * (XIb). Embodiment 67. The conjugate of Embodiment 63, wherein: n is 3; and a is 1, b is 1, and c is 1, whereby L is of formula (XIc): (XIc). Embodiment 68. The conjugate of any one of Embodiments 63 to 66, wherein each L1is of the formula (XII) * wherein: L10is a linking moiety; and L11to L19are independently absent or a linking moiety, wherein L10to L19of each L1are independently selected from –C1-20-alkylene–, –NHCO-C1-6- alkylene–, –CONH-C1-6-alkylene–, –NH C1-6-alkylene–, –NHCONH-C1-6-alkylene–, – NHCSNH-C1-6- alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene–NH-, –C1-6-alkylene– NHCONH-, –C1-6-alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, –CONH–, –NHSO2–, – SO2NH–, –NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, – NH–, and –N(CH3)–, wherein each p is independently 1 to 50. Embodiment 69. The conjugate of any one of Embodiments 63 to 67, wherein each L1comprises a linear backbone of 6 to 20 consecutive atoms (e.g., 6 to 16 consecutive atoms, such as 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive atoms). Embodiment 70. The conjugate of any one of Embodiments 63, and 65 to 68, wherein L2is of formula (XIIIa) or (XIIIb): (XIIIa) (XIIIb) wherein: L20is a branched linking moiety comprising: a carbon atom or nitrogen atom that is the branching point of the branched linking moiety; and one or more (e.g., 1 to 20, 1 to 10, or 1 to 6) linking moieties independently selected from amino acid residue (e.g., a residue such as Gly, β-Ala, Lys, Orn, Asp, Glu, Ser, Cys, or a derivative thereof), –NH-CH[(CH2)q]2O– or –NH-C[(CH2)q]3O–, –C1-6-alkylene–, – NHCO-, –CONH–, –NHSO2–, –SO2NH–, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3- triazole, –NH–, and –N(CH3)–, –NHC(=O)NH–, – NHC(=S)NH–, –O(CH2)p–, and – (OCH2CH2)p–, wherein each p is independently 1 to 50, and q is 1-6. Embodiment 71. The conjugate of any one of Embodiments 63, and 65 to 69, wherein L2comprises a linking moiety selected from: , wherein: each Z2and Z3is independently selected from –NHCO-, –CONH–, –CO–, –O–, –NH–, and – N(CH3)–; x is 1 to 12 (e.g., 1 to 6, or 1 to 3); and y is 0 to 12 (e.g., 1 to 6, or 1 to 3). Embodiment 72. The conjugate of Embodiment 70, wherein L2comprises a linking moiety selected from: . Embodiment 73. The conjugate of Embodiment 71, wherein L2comprises a linking moiety of formula (XIV): wherein: r is 1 or 2; and when n is 2, r is 1, when n is 3, r is 2. Embodiment 74. The conjugate of Embodiment 72, wherein L2is of formula (XVa) or (XVb): (XVa) (XVb). Embodiment 75. The conjugate of Embodiment 70 or 71, wherein L2is of formula (XVc) or (XVd): (XVc) (XVc) wherein r is 1 or 2. Embodiment 76. The conjugate of Embodiment 69, wherein L2comprises two 2 or more amino acid residues (e.g., 3 or more, or 4 or more amino acid residues, linear or dendrimer). Embodiment 77. The conjugate of Embodiment 69, wherein L2comprises 4 or more amino acid residues that are branched linking moieties selected from Lys, Orn, Asp, Glu, Ser, and Cys (e.g., where the sidechain, amino and carboxylic acid are each linked to an adjacent moiety). Embodiment 78. The conjugate of any one of Embodiments 63 to 76, wherein each L3is of the formula (XVI): wherein: L30to L39are independently absent or a linking moiety; and Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; wherein L30to L39of L3are each independently selected from –C1-20-alkylene–, –NHCO-C1-6- alkylene–, –CONH-C1-6-alkylene–, –NH C1-6-alkylene–, –NHCONH-C1-6-alkylene–, – NHCSNH-C1-6- alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene–NH-, –C1-6-alkylene– NHCONH-, –C1-6-alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, –CONH–, –NHSO2–, – SO2NH–, –NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, – NH–, and –N(CH3)–, wherein each p is independently 1 to 50. Embodiment 79. The conjugate of Embodiment 77, wherein L3comprises a linear backbone of 6 to 40 consecutive atoms (e.g., 10 to 30 consecutive atoms, or 20 to 30 consecutive atoms). Embodiment 80. The conjugate of Embodiment 77 or 78, wherein the linker L has one of the following structures: , , wherein: a is 1 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (e.g., 1, 2, or 3); g is 1 to 20 (e.g., 1 to 12, or 6 to 20 or 6 to 12); Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B. Embodiment 81. The conjugate of Embodiment 79, wherein the linker L comprises one of the following structures:

[0054] . Embodiment 82. The conjugate of any one of Embodiments 63 to 80, wherein the conjugate is of formula (Ia): wherein: Z is residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; n is 1, 2, or 3, wherein: when n is 1, b is 0 and at least one of a and c is 1; and when n is 2 or 3, a, b and c are each 1; and m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is in the range from about 1 to about 8. Embodiment 83. The conjugate of Embodiment 81, wherein Z is a residual moiety resulting from the covalent linkage (e.g., via a thioether bond) of a thiol-reactive chemoselective ligation group to one or more (e.g., “m”) cysteine residue(s) of Y-B. Embodiment 84. The conjugate of Embodiment 82, wherein the thiol-reactive chemoselective ligation group comprises maleimide, bromomaleimide, haloacetamide, vinyl sulfone, or thiolactone. Embodiment 85. The conjugate of Embodiment 83, wherein the thiol-reactive chemoselective ligation group is selected from one of the following structures: wherein: u is 1 to 11 (e.g., 1 to 5); v is 1 to 11 (e.g., 1 to 5); and X is H or Br. Embodiment 86. The conjugate of any one of Embodiments 82 to 84, wherein m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m corresponds to the number of solvent accessible cysteine residues in Y-B. Embodiment 87. The conjugate of Embodiment 85, wherein m is about 3 or less. Embodiment 88. The conjugate of Embodiment 86, wherein m is about 1. Embodiment 89. The conjugate of Embodiment 86, wherein m is about 2. Embodiment 90. The conjugate of Embodiment 86, wherein m is about 3. Embodiment 91. The conjugate of Embodiment 81, wherein Z is a residual moiety resulting from the covalent linkage (e.g., via an amide bond) of an amine-reactive chemoselective ligation group to one or more (e.g., “m”) lysine residue(s) of Y-B. Embodiment 92. The conjugate of Embodiment 90, wherein the amine-reactive chemoselective ligation group comprises an active ester (e.g., N-hydroxysuccinimidyl (NHS) ester, sulfo- NHS ester, pentafluorophenyl (PFP) ester, tetrafluorophenyl (TFP) ester, or the like). Embodiment 93. The conjugate of Embodiment 90 or 91, wherein m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is about 3 to about 8. Embodiment 94. The conjugate of Embodiment 92, wherein m is about 3 to about 4. Embodiment 95. The conjugate of Embodiment 92, wherein m is about 4 to about 5. Embodiment 96. The conjugate of Embodiment 92, wherein m is about 5 to about 6. Embodiment 97. The conjugate of Embodiment 92, wherein m is about 6 to about 7. Embodiment 98. The conjugate of Embodiment 92, wherein m is about 7 to about 8. Embodiment 99. The conjugate of any one of Embodiments 1 to 97, wherein n is 1. Embodiment 100. The conjugate of any one of Embodiments 1 to 97, wherein n is 2. Embodiment 101. The conjugate of any one of Embodiments 1 to 97, wherein n is 3. Embodiment 102. The conjugate of any one of Embodiments 1 to 97, wherein n is 4 to 30 (e.g., 4 to 10, 11 to 20, or 21 to 30). Embodiment 103. The conjugate of any one of Embodiments 1 to 101, wherein the conjugate is derived from the conjugation of Y-B with a ligand-linker precursor compound of Formula (Ib): wherein: H * H L is:

[0055] , ZP is a precursor to Z that is

[0056] ZE, or ZF; * is the point of attachment of X to L; and ** is the point of attachment of L to ZP. Embodiment 104. The conjugate of Embodiment 102, wherein the ligand linker precursor compound of formula (Ib) is a compound of the following table: . Embodiment 105. The conjugate of Embodiment 1, wherein the conjugate is of one of the following structures: w a is 2 to 6; b is 1 to 3; c is 1 to 3; r is 1 or 2; d is 1 to 3; e is 3 to 6; f is 1 to 3; and m is 2 to 8. Embodiment 106. The conjugate of Embodiment 1, wherein the conjugate is of the structure:

[0057] wherein m is 4 to 6, or a pharmaceutically acceptable salt thereof. Embodiment 107. The conjugate of Embodiment 1, wherein the conjugate is of the structure: wherein m is 4 to 6, or a pharmaceutically acceptable salt thereof. Embodiment 108. The conjugate of Embodiment 1, wherein the conjugate is a conjugate of FIGs.4-5.

[0058] Embodiment 109. The conjugate of Embodiment 1, wherein the conjugate is of the structure: wherein: m is 4 to 6; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. Embodiment 110. The conjugate of any one of Embodiments 104-107, wherein: Y is a human serum albumin (HSA) comprising a sequence having at least 90% sequence identity to one of SEQ ID NOs: 6-12; B is a MuSK polypeptide comprising a sequence having at least 90% sequence identity to one of SEQ ID NOs: 2-4. Embodiment 111. The conjugate of Embodiment 1, wherein the conjugate is of the structure:

[0059] H

[0060] wherein: Z is a residual moiety resulting from conjugation of N-maleimidyl group and cysteine sidechain thiol; m is 1 to 3, or a pharmaceutically acceptable salt thereof. Embodiment 112. The conjugate of Embodiment 1, wherein the conjugate is derived from a compound of FIG.6. Embodiment 113. The conjugate of Embodiment 1, wherein the conjugate is of the structure:

[0061] wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. Embodiment 114. The conjugate of Embodiment 1, wherein the conjugate is of the structure: wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. Embodiment 115. The conjugate of Embodiment 1, wherein the conjugate is of the structure: wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. Embodiment 116. The conjugate of Embodiment 1, wherein the conjugate is of the structure: wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof. Embodiment 117. The conjugate of any one of Embodiments 109-116, wherein: Y is human serum albumin (HSA) comprising a sequence having at least 90% sequence identity to one of SEQ ID NOs: 6-12; B is MuSK polypeptide comprising a sequence having at least 90% sequence identity to one of SEQ ID NOs: 2-4; and the cysteine residue(s) of Y-B that are conjugated to the linker comprise Cys34 of the HSA. Embodiment 118. A method of reducing levels of an extracellular target molecule in a biological system, the method comprising: contacting the biological system with an effective amount of a conjugate according to any one of Embodiments 1 to 117, wherein the compound specifically binds the extracellular target molecule and specifically binds a lysosomal targeting molecule of cells in the biological system to facilitate cellular uptake and degradation of the extracellular target molecule. Embodiment 119. A method of treating myasthenia gravis in a human subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate according to any one of Embodiments 1 to 117. Embodiment 120. A fusion protein of formula comprising: a muscle-specific kinase (MuSK) polypeptide (B) that specifically binds anti-MuSK autoantibody (e.g., as described herein); and a carrier polypeptide (Y) (e.g., as described herein). Embodiment 121. A nucleic acid molecule encoding the fusion protein according to Embodiment 120, comprising: a first nucleic acid sequence encoding for the MuSK polypeptide (B); and a second nucleic acid sequence encoding for the carrier polypeptide (Y). Embodiment 122. A vector comprising the nucleic acid of Embodiment 121. Embodiment 123. A host cell which has been transfected, infected or transformed by the nucleic acid molecule of Embodiment 121 and / or the vector of Embodiment 122.. 5. EXAMPLES The examples in this section are offered by way of illustration, and not by way of limitation. Preparation of ASGPR ligand-linker compounds ASGPR binding compounds and conjugates are described in International Application No. PCT / US2022 / 037227, filed July 14, 2022, and the disclosure of which is herein incorporated by reference in its entirety. The following are additional illustrative schemes and examples of how the compounds described herein can be prepared and tested. Although the examples can represent only some embodiments, it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein. Example 1: Preparation of Monovalent Amine Intermediates The following section provides details for the preparation of monovalent amine intermediate compounds which can be used in the preparation of ASGPR ligand-linker example compounds. Table 13 illustrates various monovalent amines useful for the synthesis and binding experiments.

[0062] The compounds depicted in Table 13 can be synthesized according to the examples described herein. (16) Synthesis of N-((2R,3R,4R,5R,6R)-2-(6-aminohexyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB45) sB To a stirred solution of N-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2- ethynyltetrahydro-2H-pyran-3-yl)acetamide (intermediate 4, 2.0 g, 1.0 eq., 4.0 mmol), piperidine (0.852 g, 2.5 eq., 10.0 mmol), copper(I) bromide (0.056 g, 0.1 eq., 0.4 mmol), and hydroxylamine hydrochloride (0.055 g, 0.2 eq., 0.4 mmol) in methanol (8.0 mL) under nitrogen atmosphere at room temperature, was added a degassed solution of 4-bromobut-3-yn-1-ol (54i-1, 0.656 g, 1.1 eq., 2.2 mmol) in methanol (2 mL) over a period of 1.5 hrs. The mixture was stirred for 2 h. After completion (monitored by LCMS & TLC), solvent was removed under reduced pressure to get crude residue which was dissolved again in ethyl acetate and washed with ice cold water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was purified by silica gel flash column chromatography using 0-50% ethyl acetate in hexane to afford N-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)- 6-((benzyloxy)methyl)-2-(6-hydroxyhexa-1,3-diyn-1-yl)tetrahydro-2H-pyran-3-yl)acetamide (54i-2) as an off white solid. Yield: 1.9 g, 83.0%. LCMS m / z 568.13 [M+H]+. To a stirred solution of N-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(6- hydroxyhexa-1,3-diyn-1-yl)tetrahydro-2H-pyran-3-yl)acetamide (54i-2, 0.80 g, 1.0 eq., 1.41 mmol) in dichloromethane (10 mL), pyridine (0.341 mL, 3.0 eq., 4.23 mmol), 4-dimethylaminopyridine (0.08 g, 0.3 eq., 0.50 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.80 g, 3.0 eq., 4.23 mmol) were added sequentially at 0 °C. Then reaction mixture was stirred for 16h at room temperature. After completion (monitored by TLC), the reaction mixture was poured into cold 1N HCl, and extracted with dichloromethane. The organic part was then washed with saturated bicarbonate followed by brine, and dried over anhydrous sodium sulfate, filtered, and concentrated to give crude residue which was purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane to afford 6- ((2R,3S,4R,5R,6R)-3-acetamido-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2- yl)hexa-3,5-diyn-1-yl 4-methylbenzenesulfonate (54i-3) as white solid. Yield: 0.81 g, 80.0%; LCMS, m / z 722.06 [M+H]+. A solution of 6-((2R,3S,4R,5R,6R)-3-acetamido-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)hexa-3,5-diyn-1-yl 4-methylbenzenesulfonate (54i-3, 0.715 g, 1 eq., 0.990 mmol) in N, N-dimethylformamide (5 mL) was treated with sodium azide (0.322 mg, 5 eq., 4.95 mmol). The suspension was then heated at 80°C for 6h. After completion (monitored by TLC), the reaction mixture was allowed to come to room temperature, and poured in to water, and extracted with ethyl acetate. The organic part was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude which was purified by silica gel flash column chromatography using 0-30% ethyl acetate in hexane to afford N-((2R,3S,4R,5R,6R)-2-(6-azidohexa-1,3-diyn-1-yl)-4,5-bis(benzyloxy)- 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)acetamide (54i-4) as an off white solid. Yield: 0.330 g, 56.0%; LCMS m / z 593.20 [M+H]+. To a stirred solution of N-((2R,3S,4R,5R,6R)-2-(6-azidohexa-1,3-diyn-1-yl)-4,5-bis(benzyloxy)- 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)acetamide (54i-4, 1.0 eq.,0.2 g, 0.337 mmol) in a mixture of methanol (5 mL), tetrahydrofuran (2 mL), acetic acid (0.20 mL) and water (0.20 mL) was added 10% palladium on carbon (0.30 g) and the reaction mixture was stirred at room temperature under H2gas balloon pressure. After completion of reaction, the reaction mixture was filtered through celite bed and rinsed with methanol. The filtrate was concentrated under vacuum and purified by prep HPLC (30% acetonitrile in water with 0.1 % TFA) to afford N-((2R,3R,4R,5R,6R)-2-(6-aminohexyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB45) Yield: 0.051 g, 49.6%; LCMS m / z 305.15 [M+H]+.1H NMR (400 MHz, DMSO-d6with D2O exchange) δ 4.02-3.94 (m, 1H), 3.83-3.80 (m, 1H), 3.70 (s, 1H), 3.56-3.46 (m, 4H), 2.73 (t, J = 7.6 Hz, 2H), 1.82 (s, 3H), 1.52-1.47 (m, 3H), 1.31-1.12 (m, 7H). (ii) Synthesis of N-((2R,3R,4R,5R,6R)-2-((1-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB46) F - To a solution of 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine (54ii-1) (101.3 mg, 0.464 mmol, 1.00 eq) and N-((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(prop-2-yn-1- yl)tetrahydro-2H-pyran-3-yl)acetamide (XB4B) (116.1 mg, 0.477 mmol, 1.03 eq) in 2 mL dimethyl sulfoxide was added tetrakis(acetonitrile)copper(I) hexafluorophosphate(187.3 mg, 0.403 mmol, 1.1 eq) as a solid in one portion. The mixture stirred under nitrogen atmosphere at ambient temperature for approximately 30 minutes, then directly purified by preparatory HPLC, eluting with 1-30% acetonitrile in water with 0.1% trifluoroacetic acid. Fractions containing the desired product were combined and lyophilized to dryness to afford trifluoroacetic acid salt of Compound XB46, as a white foam. Yield: 217 mg (81%); LCMS m / z 462.4 [M+1]+. (iii) Synthesis of N-((2R,3R,4R,5R,6R)-2-(5-(2-(2-aminoethoxy)ethoxy)pentyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB47) B XB47To a mixture of benzyl N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (1.00 eq, 816 mg, 2.94 mmol) in acetone (29 mL) were added NBS (1.34 eq, 704 mg, 3.95 mmol) and silver nitrate (0.144 eq, 72.0 mg, 0.424 mmol). The mixture was stirred at room temperature for 1h and concentrated. The residue was diluted with EtOAC and washed with water (1x). The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried, concentrated, purified by column (0 – 50% EtOAc / hexane) to give 54iii-1 as clear oil (930 mg, yield: 89%). LCMS m / z 378.0 [M + Na]+. To a mixture of N-[(2R,3S,4R,5R,6R)-4,5-dibenzyloxy-6-(benzyloxymethyl)-2-ethynyl- tetrahydropyran-3-yl]acetamide (1.00 eq, 201 mg, 0.403 mmol; Intermediate 4) in MeCN (7.6 mL) and water (4.4 mL) was added benzyl N-[2-[2-(3-bromoprop-2-ynoxy)ethoxy]ethyl]carbamate (54iii-1, 1.20 eq, 172 mg, 0.484 mmol). The mixture was cooled to 0oC and piperidine (5.00 eq, 0.20 mL, 2.02 mmol) was added. The mixture was purged with N2and CuCl (0.240 eq, 9.6 mg, 0.0967 mmol) was added. The mixture was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% citric acid (1x) and brine (1x), dried, concentrated, purified by column (0 -80% EtOAC / hexane) to give 54iii-2 as a white solid (232.2 mg, yield: 74%). LCMS m / z 775.2 [M + H]+. To a mixture of benzyl N-[2-[2-[5-[(2R,3S,4R,5R,6R)-3-acetamido-4,5-dibenzyloxy-6- (benzyloxymethyl)tetrahydropyran-2-yl]penta-2,4-diynoxy]ethoxy]ethyl]carbamate (54iii-2, 1.00 eq, 232 mg, 0.300 mmol) in HOAc (6 mL) were added10% Pd / C (220 mg) and 20% Pd(OH)2 / C (230 mg). The mixture was stirred at room temperature under hydrogen for 2.5h, filtered, concentrated, and purified by prep. HPLC (2 – 40% MeCN / 20 mM NH4OH aqueous solution) to give XB47 as a white solid (83.6 mg, yield: 74%). LCMS m / z 379.3 [M + H]+. (iv) Synthesis of N,N-dibenzyl-2-(2-((3-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)-3-nitrotetrahydro-2H-pyran-2-yl)prop-2-yn-1-yl)oxy)ethoxy)ethan-1-amine (XB48) ° (iv) Synthesis of N,N-dibenzyl-2-(2-((3-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)-3-nitrotetrahydro-2H-pyran-2-yl)prop-2-yn-1-yl)oxy)ethoxy)ethan-1-amine (XB48) A mixture of 2-[2-(2-Propynyloxy)ethoxy]ethylamine (1.00 eq, 9.75 g, 68.1 mmol), anhydrous potassium carbonate (2.32 eq, 21.82 g, 158 mmol) and acetonitrile (306.46 mL) was treated with benzyl bromide (2.10 eq, 17 mL, 143 mmol) then heated to 50 °C for 2h. The reaction was filtered through celite and the filtrate concentrated under vacuum. The residue was adsorbed to silica then purified by column chromatography (5-100% EtOAc in hexanes) to give N,N-dibenzyl-2-(2-prop-2- ynoxyethoxy)ethanamine as a clear oil. Yield: 18.4 g, 83%. LCMS m / z 324.22 [M+H]+. N,N-dibenzyl-2-(2-prop-2-ynoxyethoxy)ethanamine (1.43 eq, 3.70 g, 11.4 mmol) was dissolved in 10 mL toluene then concentrated to dryness and left under high vacuum. Next, (2R,3R,4R)-3,4- dibenzyloxy-2-(benzyloxymethyl)-5-nitro-3,4-dihydro-2H-pyran (1.00 eq, 3.70 g, 8.02 mmol) was dissolved in 10 mL toluene and concentrated under high vacuum. In an oven dried flask, a solution of (114-13) N,N-dibenzyl-2-(2-prop-2-ynoxyethoxy)ethanamine (1.43 eq, 3.70 g, 11.4 mmol) in anhydrous THF (31.814 mL) under nitrogen via balloon was cooled in a -50 °C (dry-ice bath – 1:1 MeOH / water) then treated with the slow addition of butyl lithium, 2.5M in hexanes (1.20 eq, 3.8 mL, 9.62 mmol) and the reaction was stirred @ -50 °C for 60 minutes. Next, a solution of (2R,3R,4R)-3,4- dibenzyloxy-2-(benzyloxymethyl)-5-nitro-3,4-dihydro-2H-pyran (1.00 eq, 3.70 g, 8.02 mmol) in dry THF (700 uL) was added dropwise over 5 minutes while maintaining -50 °C. After 60 minutes, the reaction was quenched with the addition of 7.1M aq. Ammonium chloride (32.8 eq, 37 mL, 263 mmol) (pH 9- 10) then the cold bath was removed and the slurry was warmed to room temperature. Desired product was extracted with EtOAc (100 mL, 50 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude oil. The oil was adsorbed to silica gel then purified by silica gel chromatography (10% then 20% 2-MeTHF in hexanes) to give: N,N-dibenzyl-2-[2-[3- [(2R,3S,4R,5R,6R)-4,5-dibenzyloxy-6-(benzyloxymethyl)-3-nitro-tetrahydropyran-2-yl]prop-2- ynoxy]ethoxy]ethanamine (2.19 g, 2.79 mmol, 35 % yield). LCMS m / z 785.34 [M+H]+. A solution of N,N-dibenzyl-2-[2-[3-[(2R,3S,4R,5R,6R)-4,5-dibenzyloxy-6-(benzyloxymethyl)-3- nitro-tetrahydropyran-2-yl]prop-2-ynoxy]ethoxy]ethanamine (1.00 eq, 2.40 g, 3.06 mmol) in THF (182.03 mL), water (77.673 mL) and acetic acid (46.055 mL) was cooled over ice then treated with zinc dust (18.8 eq, 3.76 g, 57.5 mmol) followed by 12M HCl (44.3 eq, 11 mL, 135 mmol). After 90m, the reaction was filtered then re-cooled in an ice bath before it was treated with 5M sodium hydroxide (350 eq, 214 mL, 1070 mmol) at such a rate as to keep the internal temperature below 24 °C. Next, the layers were partitioned then the aqueous layer was washed with DCM (80mL) – LCMS-Org1(initial partition), Aq2, Org2 (DCM). The aqueous layer was washed with DCM (50mL) then the combined organic layer was washed with brine then dried over Na2SO4, filtered and concentrated under reduced pressure and left under high vacuum. The crude amine from step 3 (2.3 g) was dissolved in DCM (20 mL) before adding triethylamine (6.00 eq, 2557 uL, 18.3 mmol), 4-(Dimethylamino)pyridine (0.050 eq, 18.7 mg, 0.153 mmol) then acetic anhydride (9.80 eq, 2.8 mL, 30.0 mmol). After several hours, the reaction was quenched with water (20 mL) for several minutes. The organic layer was collected, and the aqueous layer was washed with DCM (2x10 mL). The organic layer was dried over Na2SO4, filtered and concentrated in the presence of silica gel for purification by silica gel chromatography (0%, 5%, 10%, 15% 2MeTHF in DCM) to give N- [(2R,3S,4R,5R,6R)-4,5-dibenzyloxy-6-(benzyloxymethyl)-2-[3-[2-[2- (dibenzylamino)ethoxy]ethoxy]prop-1-ynyl]tetrahydropyran-3-yl]acetamide. Yield: 1.86 g, 76%. LCMS m / z 797.5 [M+H]+. A mixture of N-[(2R,3S,4R,5R,6R)-4,5-dibenzyloxy-6-(benzyloxymethyl)-2-[3-[2-[2- (dibenzylamino)ethoxy]ethoxy]prop-1-ynyl]tetrahydropyran-3-yl]acetamide (1.00 eq, 3.45 g, 4.33 mmol), palladium hydroxide (0.500 eq, 3.04 g, 2.16 mmol) and 10% Pd / C, Evonik Noblyst (0.500 eq, 4.61 g, 2.16 mmol) in acetic acid (86.576 mL) under nitrogen was evacuated then back-filled with hydrogen gas via balloon – a process that was repeated 3 times before leaving under an atmosphere of hydrogen. After 3 hours, the reaction was filtered over a pad of celite, the filter cake was rinsed while stirring with 100 mL methanol. Solvents were removed under reduced pressure and the residue was azeotroped with toluene then left under high vacuum. The residue was purified by RPHPLC (5-30% acetonitrile in water w / 20mM NH4OH) and fractions lyophilized to give 927 mg of N,N-dibenzyl-2-(2- ((3-((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-nitrotetrahydro-2H-pyran-2-yl)prop- 2-yn-1-yl)oxy)ethoxy)ethan-1-amine, XB48, as a white solid (61% yield). (v) Synthesis of 3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-N-(5-aminopentyl)propenamide (XB49) A L 54v-42 To a solution of (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5- triyl triacetate (54v-1, 1.0 eq, 4.0 g, 10.3 mmol) in toluene (33.2 mL), Lawesson’s reagent (0.85 eq, 3.53 g, 8.73 mmol) was added and reaction mixture was heated at 100 °C for 1.5 h. After completion, reaction mixture was cooled, water was added, neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 0-20 % ethyl acetate in dichloromethane to afford (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H- pyrano[3,2-d]thiazole-6,7-diyl diacetate (54v-2) as a light yellow viscous liquid. Yield: 2.0 g, 56.37 %; LCMS m / z 346.10 [M+18]+. A solution of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H- pyrano[3,2-d]thiazole-6,7-diyl diacetate (54v-2, 1.0 eq, 1.6 g, 4.63 mmol) in methanol (16 mL) and water (0.16 mL) was cooled at 0 °C, trifluoroacetic acid (0.16 mL) was added and reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was concentrated, azeotroped with toluene (2-3 times) and dried to get afford (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6- mercaptotetrahydro-2H-pyran-3,4-diyl diacetate (54v-3) as a light yellow viscous liquid. Yield: 1.6 g (Crude); LCMS m / z 364.10 [M+1]+. A solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-mercaptotetrahydro-2H- pyran-3,4-diyl diacetate (54v-3, 1.0 eq, 2.4 g, 6.6 mmol) in N,N-dimethylformamide (24 mL) was cooled at -78 °C, Lithium bis(trimethylsilyl)amide (LiHMDS, 1M in tetrahydrofuran) (1.0 eq, 6.6 mL, 6.6 mmol) was added and reaction mixture was stirred at the same temperature for 1 h. Then, oxetan-2-one (54v-3a, 1.3 eq, 0.617 g, 8.58 mmol) was added and reaction mixture stirred at room temperature for 16 h. After completion, reaction mixture was concentrated to get crude which was first purified by column chromatography using silica gel (100-200 mesh) and 0-10 % methanol in dichloromethane and then by prep HPLC (10-25 % acetonitrile in water with 0.1 % trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford 3-(((2R,3R,4R,5R,6R)-3-acetamido- 4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)thio)propanoic acid (Cpd. No.54v-4) as a white solid. Yield: 0.732 g, 25.68 %; LCMS m / z 436.05 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 12.26 (bs, 1H), 8.15 (d, J = 7.2 Hz, 1H), 5.60 (d, J = 5.2 Hz, 1H), 5.34 (d, J = 2.4 Hz, 1H), 4.88 (dd, J = 12.0 Hz & 3.2 Hz, 1H), 4.45 (t, J = 6.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.09-4.00 (m, 2H), 2.76-2.64 (m, 2H), 2.54 (d, J = 7.2 Hz, 2H), 2.10 (s, 3H), 2.10 (s, 3H), 1.90 (s, 3H), 1.80 (s, 3H). A solution of 3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro- 2H-pyran-2-yl)thio)propanoic acid (1.00 eq, 100 mg, 0.230 mmol) and tert-butyl (5- aminopentyl)carbamate (1.1 eq, 51.1 mg, 0.253 mmol) and Diisopropylethylamine (DIPEA) (3.0 eq, 0.12 mL, 0.689 mmol) in DMF (1.15 mL) was cooled in an ice bath before adding HATU (1.2 eq, 105 mg, 0.276 mmol). After 45 minutes, the reaction was diluted with water (5 mL) and brine (5 mL) and the products were extracted with EtOAc (2x5 mL). The partitioned aqueous layer was washed with EtOAc (5 mL) and the combined organic layer was washed with citric acid then with sodium bicarbonate before being dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give crude material that was used in the next step without further purification. LCMS m / z 620.0 [M+H]+. A solution of 25% w / w sodium methoxide in methanol (6.0 eq, 0.29 mL, 1.26 mmol) in methanol (0.839 mL) was treated with (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((3-((5-((tert- butoxycarbonyl)amino)pentyl)amino)-3-oxopropyl)thio)tetrahydro-2H-pyran-3,4-diyl diacetate (1.0 eq, 130 mg, 0.210 mmol). After 30 minutes, the reaction was cooled in an ice bath and the reaction solution was neutralized with 12M HCl (5.9 eq, 103 uL, 1.24 mmol) then diluted with DCM (7mL) and filtered. The filtrate was concentrated under reduced pressure to give 177 mg of crude material that was used in the next step without further purification. LCMS m / z 494.0 [M+1]+. A mixture of tert-butyl (5-(3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)propanamido)pentyl)carbamate (1.0 eq, 103 mg, 0.209 mmol) and trifluoroacetic acid (40.0 eq, 595 uL, 8.35 mmol) in DCM (1.04 mL) was stirred at room temp for 2 h. The reaction was concentrated under reduced pressure then dissolved in water and ammonium hydroxide for purification by reversed-phase HPLC (3-50% acetonitrile in water with 200 mM NH4OH) to give 3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-N-(5-aminopentyl)propenamide, XB49, as a white solid. Yield: 46 mg, 56 % (over 3 steps). LCMS m / z 394.2 [M+1]+. (vi) Synthesis of N-((2R,3R,4R,5R,6R)-2-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)thio)- 4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB50) A 2 A solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-mercaptotetrahydro-2H- pyran-3,4-diyl diacetate (54vi-1, 1.0 eq, 0.800 g, 2.2 mmol) in N,N-dimethylformamide (8 mL) was cooled at -78 °C, Lithium bis(trimethylsilyl)amide (LiHMDS, 1M in tetrahydrofuran) (1.0 eq, 2.2 mL, 2.2 mmol) was added and reaction mixture was stirred at the same temperature for 1 h. Then, tert-butyl (2-(2- (2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (54vi-1a, 1.2 eq, 0.940 g, 2.64 mmol) was added and reaction mixture stirred at room temperature for 16 h. After completion, reaction mixture was concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 0-5 % methanol in dichloromethane to afford (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6- ((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)thio)tetrahydro-2H-pyran-3,4-diyl diacetate (Cpd. No.54vi-1b) as a colourless semi solid. Yield: 0.600 g, 44.11 %; LCMS m / z 639.05 [M+1]+;1H NMR (400 MHz, DMSO-d6with D2O) δ 5.57 (d, J = 5.2 Hz, 1H), 5.31-5.30 (m, 1H), 4.89- 4.85 (m, 1H), 4.43 (t, J = 6.0 Hz, 1H), 4.36-4.32 (m, 1H), 4.06-3.97 (m, 2H), 3.60-3.56 (m, 1H), 3.54- 3.51 (m, 4H), 3.36 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 5.6 Hz, 2H), 2.92 (s, 2H), 2.76 (s, 1H), 2.73-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.06 (s, 3H), 1.96-1.94 (m, 5H), 1.87 (s, 3H), 1.79 (s, 3H), 1.33 (s, 9H). A solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((2,2-dimethyl-4-oxo- 3,8,11,14-tetraoxa-5-azahexadecan-16-yl)thio)tetrahydro-2H-pyran-3,4-diyl diacetate (54vi-1b, 1.0 eq, 0.450 g, 0.705 mmol) in methanol (5 mL) was cooled at 0 °C, sodium methoxide (25 % solution in methanol) (2.0 eq, 0.33 mL, 1.41 mmol) was added and reaction mixture was stirred at room temperature for 3 h. After completion, reaction mixture was neutralized with Dowex 50WX8 hydrogen form (200-400 mesh) and filtered through sintered funnel (without celite). The filtrate was concentrated, washed with diethyl ether and dried to afford tert-butyl (2-(2-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54vi-2) as an off white solid. Yield: 0.320 g, 88.64 %; LCMS m / z 513.10 [M+1]+. A solution of tert-butyl (2-(2-(2-(2-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54vi-2, 1.0 eq, 0.320 g, 0.624 mmol) in dichloromethane (1.6 mL) was cooled at 0 °C, trifluoroacetic acid (1.6 mL) was added and reaction mixture was stirred at room temperature for 1 h. After completion, reaction mixture was concentrated, azeotroped with dichloromethane (2-3 times), washed with diethyl ether (2-3 times) and purified by prep HPLC (32-50 % acetonitrile in water with 0.1 % trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford N-((2R,3R,4R,5R,6R)- 2-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)thio)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-3-yl)acetamide, XB50, as a light yellow viscous liquid. Yield: 0.220 g, 85.33 %; LCMS m / z 413.10 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 7.79-7.73 (m, 3H), 5.43 (d, J = 5.6 Hz, 1H), 4.67-4.60 (m, 3H), 4.18-4.12 (m, 1H), 3.88 (t, J = 5.6 Hz, 1H), 3.73 (bs, 1H), 3.60-3.45 (m, 15H), 2.98-2.97 (m, 2H), 2.70-2.64 (m, 1H), 2.57-2.54 (m, 1H), 1.81 (s, 3H). (vii) Synthesis of (2R,3R,4R,5S)-5-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-6- (trifluoromethyl)pyrimidin-2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB51) To stirred solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (54viii-1, 1.15 g, 1.0 eq, 4.61 mmol) in tetrahydrofuran (10 mL), sodium hydride (0.277 g, 1.5 eq., 6.91 mmol, 60% in oil) was added portion wise at 0°C under N2and allowed to stir at 0°C for 30 minutes. Then the resultant solution was added dropwise to a solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (1.0 g, 1.0 eq, 4.61 mmol) in tetrahydrofuran (10 mL) under N2atmosphere at 0°C and allowed to stir for 10 minutes. After completion (monitored by TLC), the reaction was quenched by the addition of ice, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated to get crude which was passed through silica gel (silica gel 100-200 mesh, eluent: 10% ethyl acetate in hexane) to get crude product. (1.57 g, 3.65 mmol) as light yellow liquid which was further purified by SFC to get tert- butyl (2-(2-(2-((2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (Cpd. No.54vii-1b) as colourless oil. Yield: 0.60 g, 35%; LCMS m / z 430.3 [M+1]+;1H NMR (400 MHz, DMSO-d6): δ 7.64 (s, 1H), 6.75 (t, J = 4.8 Hz, 1H), 4.56-4.54 (m, 2H), 3.78-3.76 (m, 2H), 3.58-3.56 (m, 2H), 3.51-3.48 (m, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.06-3.02 (m, 2H), 1.35 (s, 9H). SFC Purification Method: Column: AMYLOSE-1 (250*4.6)mm, 5um; Mobile Phase: CO2:0.1% IPAmine in HEXANE:IPA 50:50 (20:80); Flow Rate: 3.0 mL / min; Column Temperature: 40°C. A suspension of tert-butyl N-[2-[2-[2-[2-chloro-6-(trifluoromethyl)pyrimidin-4- yl]oxyethoxy]ethoxy]ethyl]carbamate (1.00 eq, 51.0 mg, 0.119 mmol), (2R,3R,4R,5S)-5-amino-2- (hydroxymethyl)tetrahydropyran-3,4-diol;hydrochloride (48-4, 2.00 eq, 47.4 mg, 0.237 mmol), Diisopropylethylamine (DIPEA) (4.00 eq, 0.083 mL, 0.475 mmol), in 420 uL of anhydrous acetonitrile was heated to 75C under N2in a sealed vial. The mixture was heated for 1 hr, added 1 eq of DIEA (20 uL) and heated overnight at 80C, then heated at 95oC for 24 hours. The mixture was cooled, diluted with water and formic acid, and the crude material was purified by Prep HPLC, eluting from a C18 column with a gradient of 10-100% CH3CN:water + 0.1% FA to give 51 mg of a white powder [77% yield]; LCMS: 557.1 [M+H]. A solution of tert-butyl N-[2-[2-[2-[2-[[(3S,4R,5R,6R)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydropyran-3-yl]amino]-6-(trifluoromethyl)pyrimidin-4- yl]oxyethoxy]ethoxy]ethyl]carbamate (1.00 eq, 31.0 mg, 0.0557 mmol) in 6 mL DCM was cooled to 0C and 2mL of TFA was added. The solution was stirred for 1 hr at room temperature, at which time the solution was concentrated to a crude residue which was subsequently lyophilized from water to give (2R,3R,4R,5S)-5-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-6-(trifluoromethyl)pyrimidin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol, XB51 TFA salt: 37.3 mg of a white solid (crude, TFA salt); LCMS 457.2 [M+1]. (viii) Synthesis of N-((2S,3R,4R,5R,6R)-2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-4,5- dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB52) B B XB52 To a stirred solution of (2R,3R,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-nitro-3,4- dihydro-2H-pyran (54viii-1, 5.0 g, 1.0 eq., 10.8 mmol) and tert-butyl (2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-1a, 4.77 g, 1.5 eq., 16.3 mmol) in anhydrous toluene (40 mL) under Ar, activated molecular sieves (3 Å, 1.50 g) were added and the mixture stirred for 1h at room temperature Thereafter, t-BuOK (0.608 g, 0.5 eq., 5.42 mmol, 1M solution in THF) was added at 0°C, and stirred for 12h at room temperature. After completion (monitored by LCMS, & TLC), acetic acid (0.05 mL) was added to quench the reaction. Molecular sieves were filtered off and the filtrate was removed under reduced pressure to afford crude which was purified by silica gel flash column chromatography to (using 0-70% ethyl acetate in hexane) to afford tert-butyl (2-(2-(2-(2- (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-nitrotetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-2) as colorless syrup. Yield: 2.5 g, 30.0%; LCMS m / z 755.37 [M+H]+. To a solution of tert-butyl (2-(2-(2-(2-(((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)-3-nitrotetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-2, 2.5 g, 3.31 mmol, 1.0 eq.) in glacial acetic acid (30 mL); zinc (2.6 g, 12.0 eq., 39.7 mmol) was added and then heated at 40°C for 3h. After completion (monitored by TLC), reaction mixture was diluted with methanol and was filtered through celite pad. The volatiles were evaporated out on high vacuum to yield crude tert-butyl (2-(2-(2-(2-(((2S,3R,4R,5R,6R)-3-amino-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-3) as syrup which was used for next step without further purification. Yield: 2.5 g (crude); LCMS m / z 725.65 [M+H]+. To a solution of tert-butyl (2-(2-(2-(2-(((2S,3R,4R,5R,6R)-3-amino-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-3, 2.5 g, 3.45 mmol, 1.0 eq.) in pyridine (20 mL), acetic anhydride (10 mL) was added at 0°C and stirred the reaction mixture for 16h at room temperature. After completion, the volatiles were evaporated under reduced pressure to get crude which was purified by silica gel flash column chromatography (40-60% ethyl acetate / hexane) to afford tert-butyl (2-(2-(2-(2-(((2S,3R,4R,5R,6R)-3-acetamido-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (Cpd. No.54viii-4) as off-white semi solid Yield: 2.5 g, 94.52%.; LCMS m / z 767.50 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.8 Hz, 1H), 7.35- 7.23 (m, 15H), 6.74 (t, J = 5.6 Hz, 1H), 5.75 (s, 1H), 4.76-4.70 (m, 3H), 4.59-4.43 (m, 4H), 4.29-4.23 (m, 1H), 4.04 (bs, 1H), 3.94 (t, J = 6.4 Hz, 1H), 3.75 (dd, J = 11.2, 2.4 Hz 1H), 3.68-3.63 (m, 1H), 3.58-3.54 (m, 4H), 3.53-3.47 (m, 9H), 3.37-3.34 (m, 2H), 3.05 (q, J = 6.0 Hz, 2H), 1.83 (s, 3H), 1.36 (s, 9H). To a solution of tert-butyl (2-(2-(2-(2-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (54viii-3, 1.0 g, 1.0 eq., 1.3 mmol) in methanol (15 mL), 10% Pd / C (1.0 g), and concentrated HCl (0.083 mL, 2.0 eq.,2.61 mmol) were added. Then reaction mixture was stirred at room temperature under H2 gas balloonpressure for 48h. After completion, the reaction mixture was filtered on celite pad and washed the pad with methanol. The volatiles were evaporated in high vacuum to afford crude which was purified by prep- HPLC (25% acetonitrile in water with 0.1 % TFA) to afford N-((2S,3R,4R,5R,6R)-2-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethoxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3- yl)acetamide (XB52) as light brown semi solid Yield: 0.109 g., 21.09%; LCMS m / z 397.15 [M+H]+ 1H NMR (400 MHz, DMSO-d6with D2O exchange) δ 4.70 (d, J = 2.0 Hz, 1H), 4.01-3.98 (m, 1H), 3.77-3.72 (m, 2H), 3.63-3.44 (m, 16H), 2.95 (t, J = 4.8 Hz, 2H), 1.84 (s, 3H). (ix) Synthesis of N-((2R,3R,4R,5R,6R)-2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-4,5- dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB53) - 2 To a solution of 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-ol (54ix-1) (246 mg, 1.12 mmol, 0.9eq.) and (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (54ix-1a) (486 mg, 1.24 mmol, 1.0 eq.) in 5 mL of 1,2-dicholomethane, stirring at ambient temperature under nitrogen atmosphere, was slowly added trimethylsilyl trifluoromethanesulfonate (45 mL, 0.25 mmol, 0.2 eq.). The mixture stirred at ambient temperature for approximately 5 minutes, then was heated to 60C. After 3 hrs., the mixture was cooled to ambient temperature and quenched with addition of triethylamine (70 mL, 0.51 mmol, 0.4 eq.). The reaction mixture was diluted further with 1,2- dicholomethane, evaporated onto silica, and purified by flash column chromatography column, eluting with 0-100% ethyl acetate / dichloromethane to afford Compound 54ix-2 as a clear thick syrup. Yield: 520 mg (75%); LCMS m / z 548.97 [M+H]+. To a solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate (54ix-2) (492 mg, 0.897 mmol) in 6 mL of methanol, stirring under nitrogen atmosphere at 0-5C, was added sodium methoxide (25% w / w in methanol) (1359 mg, 6.29 mmol, 7.0 eq) diluted in 3 mL of methanol. The reaction mixture stirred at ambient temperature for 30 minutes, at which time 8 mL of 1N aqueous hydrochloric acid was added slowly to achieve approximate final pH of 1-2. The reaction mixture was concentrated to approximately ¼ volume and purified by preparatory HPLC, eluting with 1-30% acetonitrile in water with 0.1% trifluoroacetic acid. Fractions containing the desired product were combined and lyophilized to dryness to afford Compound 54ix-3 as white solid. Yield: 244 mg (64%); LCMS m / z 423.06 [M+1]+. To a solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyl diacetate (54ix-3) (239 mg, 0.566 mmol) in 15 mL methanol was added 10% w / w palladium on carbon (128 mg). The mixture was degassed under vacuum then stirred under hydrogen atmosphere via balloon. After approximately 15 minutes, the solution was filtered over Celite and washed with methanol. The filtrate was concentrated to residue, then co-evaporated from acetonitrile to afford XB53, as a clear oil. Yield: 243 mg (108%); LCMS m / z 397.25 [M+1]+. (x) Synthesis of 3-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-(5-aminopentyl)propenamide (XB54) A solution of (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate (54x-1, 1.0 eq, 5.0 g, 12.8 mmol) and methyl 3-mercaptopropanoate (54x-1a, 2.0 eq, 3.09 mL, 25.7 mmol) in dichloromethane (50 mL) was cooled at 0 °C, boron trifluoride diethyl etherate (5.0 eq, 8.28 mL, 64.2 mmol) was added dropwise and reaction mixture was heated at 40 °C for 16 h. Reaction was monitored by ELSD. After completion, reaction mixture was cooled, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 0-5 % methanol in dichloromethane to afford (2R,3R,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((3-methoxy-3-oxopropyl)thio)tetrahydro-2H- pyran-3,4-diyl diacetate (54x-2) as a colorless viscous liquid. Yield: 5.2 g, 87.39 %; LCMS m / z 450.1 [M+1]+. To a solution of (2R,3R,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((3-methoxy-3- oxopropyl)thio)tetrahydro-2H-pyran-3,4-diyl diacetate (54x-2, 1.0 eq, 4.0 g, 8.9 mmol) in methanol (40 mL), sodium methoxide (25 % solution in methanol) (0.1 eq, 0.21 mL, 0.89 mmol) was added and reaction mixture was stirred at room temperature for 3 h. After completion, reaction mixture was neutralized with Dowex 50WX8 hydrogen form (200-400 mesh) and filtered through sintered funnel (without celite). The filtrate was concentrated and dried to afford methyl 3-(((2S,3R,4R,5R,6R)-3- acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)propanoate (54x-3) as an off white solid. Yield: 1.7 g, 59.0 %; LCMS m / z 324.0 [M+1]+. To a solution of methyl 3-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)propanoate (54x-3, 1.0 eq, 2.0 g, 6.19 mmol) in tetrahydrofuran (18 mL), methanol (12 mL) and water (6 mL), lithium hydroxide monohydrate (2.0 eq, 0.519 g, 12.4 mmol) was added and reaction mixture was stirred at room temperature for 2 h. After completion, reaction mixture was concentrated, methanol was added, neutralized with Dowex 50WX8 hydrogen form (200-400 mesh) and filtered through sintered funnel (without celite). The filtrate was concentrated and dried to afford 3- (((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)propanoic acid (54x-4) as an off white sticky solid. Yield: 2.4 g (Crude); LCMS m / z 310.0 [M+1]+. To a solution of 3-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)propanoic acid (54x-4, 1.0 eq, 1.1 g, 3.56 mmol) in pyridine (11 mL), acetic anhydride (10.0 eq, 3.36 mL, 35.6 mmol) was added and reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 0-7 % methanol in dichloromethane to afford 3- (((2S,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2- yl)thio)propanoic acid (54x-5) as a colorless viscous liquid. Yield: 1.25 g, 76.74 %; LCMS m / z 436.0 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 5.27 (d, J = 3.2 Hz, 1H), 4.95 (dd, J = 2.4, 10.8 Hz, 1H), 4.66 (d, J = 10.4 Hz, 1H), 4.10-3.96 (m, 4H), 2.85-2.79 (m, 1H), 2.74-2.69 (m, 1H), 2.58 (t, J = 7.2 Hz, 2H), 2.11(s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.77 (s, 3H). A solution of tert-butyl (5-aminopentyl)carbamate (1.2 eq, 166 mg, 0.821 mmol) and 3- (((2S,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2- yl)thio)propanoic acid (1.0 eq, 302 mg, 0.694 mmol) and DIPEA (3.0 eq, 0.36 mL, 2.08 mmol) in DMF (3.5 mL) was cooled in an ice bath before adding HATU (1.2 eq, 316 mg, 0.832 mmol) then removing the ice bath. After 45 minutes, the reaction was diluted with water (10 mL) and brine (10 mL) and the products were extracted with EtOAc (2x10 mL). The partitioned aqueous layer was washed with EtOAc (5 mL) and the combined organic layer was dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give crude material that was adsorbed to silica gel for purification by column chromatography (50-100% EtOAc in hexanes) to give (2R,3R,4R,5R,6S)-5-acetamido-2- (acetoxymethyl)-6-((3-((5-((tert-butoxycarbonyl)amino)pentyl)amino)-3-oxopropyl)thio)tetrahydro-2H- pyran-3,4-diyl diacetate. Yield: 319 mg, 74.2 %. LCMS m / z 619.95 [M+H]+. A solution of [(2R,3R,4R,5R,6S)-5-acetamido-3,4-diacetoxy-6-[3-[5-(tert- butoxycarbonylamino)pentylamino]-3-oxo-propyl]sulfanyl-tetrahydropyran-2-yl]methyl acetate (1.0 eq, 188 mg, 0.303 mmol) in methanol (1.5 mL) was treated with 25% w / w sodium methoxide in methanol (4.0 eq, 0.28 mL, 1.21 mmol). After 1 h, the reaction was cooled in an ice bath, neutralized with 4M HCl in dioxane (4.0 eq, 303 mL, 1.21 mmol) then concentrated under reduced pressure to give crude material. The residue was dissolved in 1:1 MeOH / DCM (3 mL) then treated with 4M HCl in dioxane (4.0 eq, 303 mL, 1.21 mmol). After 1h, the reaction was concentrated under reduced pressure. The residue was dissolved in concentrated NH4OH then purified by reversed-phase HPLC (3-30% acetonitrile in water + 10 mM NH4OH) then lyophilized to give 3-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-(5-aminopentyl)propenamide (XB54). Yield: 102 mg,85.5 %. LCMS m / z 394.2 [M+H]+.(xi) Synthesis of N-((2R,3R,4R,5R,6R)-2-(3-(2-(2-aminoethoxy)ethoxy)propoxy)-4,5-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB55)ChA A solution of 3-oxo-1-phenyl-2,7,10-trioxa-4-azatridecan-13-oic acid (54xi-1, 7.0 g, 1.0 eq., 22.5 mmol) in dry tetrahydrofuran (70 mL) was cooled to 0° C. To this, borane tetrahydrofuran complex (1M in THF, 112.5 mL, 5.0 eq., 112.5 mmol) was added slowly, and the resulting reaction mixture was stirred at room temperature for 21h. After completion, conc. HCl was added dropwise to quench excess borane complex, and the resulting mixture was stirred for another 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 2-5% methanol in dichloromethane to afford benzyl (2-(2-(3- hydroxypropoxy)ethoxy)ethyl)carbamate (54xi-2) as colourless viscous liquid. Yield: 2.8 g, 41.88%; LCMS: m / z 298.1 [M+H]+. To a stirred solution of (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran- 2,4,5-triyl triacetate (54xi-2a, 1.45 g, 1.0 eq., 3.72 mmol), and benzyl (2-(2-(3- hydroxypropoxy)ethoxy)ethyl)carbamate (54xi-2, 1.11 g, 1 eq., 3.72 mmol) in 1,2-dichloroethane (15 mL) at room temperature, was added trimethylsilyl trifluoromethanesulfonate (67.6 µL, 0.1 eq., 372 µmol) drop-wise and the reaction mixture was heated at 65° C for 6h. After completion, the reaction mixture was quenched with triethyl amine and concentrated under reduced pressure to get crude which was purified by column chromatography using silica gel (100-200 mesh) and 2-5% methanol in dichloromethane to afford (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((3-oxo-1-phenyl-2,7,10- trioxa-4-azatridecan-13-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate (54xi-3) as colourless viscous liquid. Yield: 2.08 g, 89.13%; LCMS: m / z 627.0 [M+H]+. A solution of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((3-oxo-1-phenyl-2,7,10-trioxa-4- azatridecan-13-yl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate (54xi-3, 0.350 g, 0.559 mmol) in methanol (4 mL) was cooled to 0° C. To this, sodium methoxide (25% solution in methanol) (0.02 mL, 0.4 eq., 0.223 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 3h. After completion, the reaction mixture was neutralized with Dowex 50WX8 hydrogen form (200-400 mesh) and filtered through sintered funnel (without celite). The filtrate was concentrated to afford benzyl (2-(2- (3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)propoxy)ethoxy)ethyl)carbamate (54xi-4) as colorless viscous liquid. Yield: 0.26 g, 93.0%; LCMS: m / z 501.1 [M+H]+. To a stirred solution of benzyl (2-(2-(3-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)propoxy)ethoxy)ethyl)carbamate (54xi-4, 0.26 g, 0.519 mmol) in methanol (4 mL), 10% palladium on carbon (0.166 g) and conc. HCl (20 µL, 1.0 eq., 0.519 mmol) were added and the reaction mixture was stirred at room temperature under hydrogen gas balloon pressure for 2h. After completion, the reaction mixture was filtered through syringe filter and washed with methanol. The filtrate was concentrated and purified by prep-HPLC (30-50% acetonitrile in water with 0.1 % trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford N-((2R,3R,4R,5R,6R)-2-(3-(2-(2-aminoethoxy)ethoxy)propoxy)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB55) as a colourless semi-solid. Yield: 0.071 g, 37.3%; LCMS: m / z 367.1 [M+H]+;1H NMR (400 MHz, DMSO-d6with D2O exchange): δ 4.20 (d, J = 8.4 Hz, 1H), 3.76-3.64 (m, 3H), 3.59-3.55 (m, 4H), 3.58-3.48 (m, 4H), 3.47-3.39 (m, 4H), 3.31-3.28 (t, J = 6.0 Hz, 1H), 2.95 (t, J = 5.2 Hz, 2H), 1.86 (s, 3H), 1.66 (t, J = 6.8, 2H). (xii) Synthesis of N-((2S,3R,4R,5R,6R)-2-(5-(2-(2-aminoethoxy)ethoxy)pentyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB56) was prepared by adapting the procedure of XB47. LCMS m / z: 379.4 [M + H]+. (xiii) Synthesis of (1S,2R,3R,4R,5S)-4-(4-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)-1H- 1,2,3-triazol-1-yl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol TFA salt (XB57 TFA salt). 54xiii-1XB57 TFA salt(xiii) Synthesis of (1S,2R,3R,4R,5S)-4-(4-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)-1H-1,2,3- triazol-1-yl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol TFA salt (XB57 TFA salt). To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethan-1-amine (54xiii-1) (39.7 mg, 0.183 mmol, 1.0 eq.) and (1S,2R,3R,4R,5S)-4-azido-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol (XB39) (34.4 mg, 0.184 mmol, 1.0 eq.) in 0.4 mL of dimethyl sulfoxide was added tetrakis(acetonitrile)copper(I) hexafluorophosphate(67.4 mg, 0.181 mmol, 0.99 eq) as a solid in one portion. The mixture was stirred under nitrogen atmosphere at ambient temperature for approximately 15 min until completion. The reaction mixture was diluted with water, which formed a precipitate, then 2 drops of trifluoroacetic acid was added to clear the solution. The product was isolated from diluted mixture by preparatory HPLC, eluting with 1-20% acetonitrile in water with 0.1% trifluoroacetic acid. Fractions containing the desired product were combined and lyophilized to dryness to afford trifluoroacetic acid salt of Compound XB57 as a clear oil. Yield: 47.9 mg (50%); LCMS m / z 405.3 [M+1]+. (xiv) Synthesis of N-((2R,3R,4R,5R,6R)-2-(6-(2-(2-aminoethoxy)ethoxy)hexyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB58) 2 A solution (A) of N-((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(prop-2-yn-1- yl)tetra hydro-2H-pyran-3-yl)acetamide (XB4B, 0.4 g, 1.0 eq., 1.4 mmol), piperidine (0.298 g, 2.5 eq., 3.49 mmol), copper(I) bromide (0.02 g, 0.1 eq., 0.140 mmol) and hydroxylamine hydrochloride (0.0194 g, 0.2 eq., 0.28 mmol) in methanol (8 mL) was purged with N2for 30 minutes. Another solution (B) of tert-butyl (2-(2-((3-bromoprop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (54xiv-3, 0.45 g, 1.0 eq., 1.4mmol) in methanol (4 mL) was purged with N2 for 30 minutes. Solution (B) was added slowly to solution(A) through syringe over a period of 15 minutes, and the reaction mixture was stirred at room temperature for 12 h. After completion, methanol was removed under reduced pressure and the crude product obtained was poured into ice cold water (10 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to afford tert-butyl (2-(2-((6- ((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)hexa-2,4- diyn-1-yl)oxy)ethoxy)ethyl)carbamate (54xiv-4) as colourless viscous liquid. Yield: 0.18 g (Crude); LCMS: m / z 385.2 [M+H]+. To a solution of tert-butyl (2-(2-((6-((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)hexa-2,4-diyn-1-yl)oxy)ethoxy)ethyl)carbamate (54xiv-4, 0.10 g, 1.0 eq., 0.206 mmol) in methanol (3 mL), 10 % palladium on carbon (0.070 g) was added and reaction mixture was stirred under hydrogen gas atmosphere at room temperature for 3h. After completion (monitored by LCMS., reaction mixture was filtered through syringe filter, filtrate was concentrated to afford tert-butyl (2-(2-((6-((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)hexyl)oxy)ethoxy)ethyl)carbamate (54xiv-5) as a colorless viscous liquid. Yield: 0.090 g; LCMS: m / z 493.15 [M+H]+. A solution of tert-butyl (2-(2-((6-((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)hexyl)oxy)ethoxy)ethyl)carbamate (54xiv-5, 1.0 eq, 0.090 g, 0.182 mmol) in dichloromethane (2 mL) was cooled at 0 °C, trifluoroacetic acid (0.4 mL) was added and reaction mixture was stirred at room temperature for 3h. After completion, reaction mixture was concentrated to get crude which was purified by prep HPLC (20-50 % acetonitrile in water with 0.1 % trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford N-((2R,3R,4R,5R,6R)-2-(6-(2-(2-aminoethoxy)ethoxy)hexyl)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (XB58) as a brown solid. Yield: 0.015 g, 20.25 %; LCMS: m / z 393.2 [M+1]+;1H NMR (400 MHz, DMSO-d6with D2O) δ 3.99-3.94 (m, 1H), 3.82-3.79 (m, 1H), 3.70 (bs, 1H), 3.51-3.49 (m, 7H), 3.37 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 4.8 Hz, 2H), 1.8 (s, 3H), 1.53- 1.44 (m, 4H), 1.24-1.15 (m, 6H). Synthesis of (2R,3R,4R,5S)-5-((6-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-1,1-difluoroethyl)pyrazin- 2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB80) XB80 Synthesis of methyl 2-(6-chloropyrazin-2-yl)-2,2-difluoroacetate (2) To a stirred suspension of copper (1.97 g, 3 eq., 31 mmol) in dimethyl sulfoxide (8 mL), methyl 2-bromo-2,2-difluoroacetate (1a, 3.7 mL, 3 eq., 31 mmol) was added at room temperature under inert atmosphere. After 30 minutes, 2-bromo-6-chloropyrazine (1, 2 g, 1 eq., 10.3 mmol) was added and heated at 90 °C for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 25 mL). The combined organic phase was washed with brine, dried with anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford methyl 2-(6-chloropyrazin-2-yl)-2,2-difluoroacetate (2.5 g, crude) as dark brown liquid.1H NMR (400 MHz, DMSO-d6) for crude compound: δ 9.15 (s, 1H), 9.11 (s, 1H), 3.89 (s, 3H). Synthesis of 2-(6-chloropyrazin-2-yl)-2,2-difluoroethan-1-ol (3) To a stirred solution of methyl 2-(6-chloropyrazin-2-yl)-2,2-difluoroacetate (2, 2.5 g, crude) in methanol (20 mL), sodium borohydride (1.2 g, 3 eq., 33 mmol) was added portion wise for 10 min at 0 °C. After stirring 30 minutes at room temperature, the reaction mixture was quenched in ice cold water and organic part was extracted with dichloromethane (3 × 20 mL). Combined dichloromethane layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified by combi flash column chromatography using ethyl acetate / heptane (0-30% gradient) as eluent to afford 2-(6-chloropyrazin-2-yl)-2,2-difluoroethan-1-ol as colorless liquid. Yield: 0.8 g, 39% over two steps.1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.95 (s, 1H), 5.73 (t, J = 6.4 Hz, 1H), 4.03-3.94 (m, 2H). Synthesis of 2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H- pyran-3-yl)amino)pyrazin-2-yl)-2,2-difluoroethan-1-ol (4) To a solution of (3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran- 3-amine-hydrochloride (Int1 in synthesis of XB91, 0.550 g, 1 eq., 1.17 mmol) in 1-methyl-2- pyrrolidinone (4 mL) was added N,N-Diisopropylethylamine (2.16 mL, 10 eq., 11.7 mmol) and stirred at room temperature for 10 minutes. After that, 2-(6-chloropyrazin-2-yl)-2,2-difluoroethan-1-ol (3, 0.228 g, 1 eq., 1.17 mmol) was added and heated the reaction mixture at 150 °C for 48 h. After completion (monitored by LCMS), reaction mixture was concentrated under reduced pressure to give crude which was purified by combi flash column chromatography using ethyl acetate / heptane as eluting system to afford 2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3- yl)amino)pyrazin-2-yl)-2,2-difluoroethan-1-ol (4) as yellow dense liquid. Yield: 0.37 g, 53%. LCMS: m / z 592.44 [M+H]. Synthesis of tert-butyl (2-(2-(2-(2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)-2,2- difluoroethoxy)ethoxy)ethoxy)ethyl)carbamate (5) To a stirred solution of 2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)-2,2-difluoroethan-1-ol (4, 0.37 g, 1 eq., 0.625 mmol) in N,N-dimethylformamide (3 mL), sodium hydride (0.025 g, 1 eq., 625 µmol) was added and stirred for 5 minutes at 0 °C temperature. After that, tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate (4a, 0.195 g, 1 eq., 0.625 mmol) was added. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), ice-cold water (10 mL) was added to the reaction mixture. Organic part was extracted with ethyl acetate (3 × 10 mL), combined and dried over anhydrous sodium sulphate. Then, solvent was evaporated under reduced pressure to give crude which was purified by combi flash column chromatography using 60% ethyl acetate / heptane as eluting system to afford tert-butyl (2-(2-(2-(2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)-2,2- difluoroethoxy)ethoxy)ethoxy)ethyl)carbamate (5) as brown dense liquid. Yield: 0.23 g, 45.0%. LCMS: m / z 823.05 [M+H]. Synthesis of (2R,3R,4R,5S)-5-((6-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-1,1- difluoroethyl)pyrazin-2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB80) To a stirred solution of tert-butyl (2-(2-(2-(2-(6-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)-2,2- difluoroethoxy)ethoxy)ethoxy)ethyl)carbamate (5, 0.43 g, 1 eq., 0.522 mmol) in dichloromethane (4 mL) was added trichloroborane (7.4 mL, 20 eq., 7.31 mmol, 1M solution) solution in dichloromethane at -78 °C dropwise and stirred at the same temperature for 3 h. After completion (monitored by LCMS), reaction mixture was quenched with methanol and concentrated under reduced pressure to afford crude which was purified by RP prep-HPLC (15-20% acetonitrile in water with 0.1% TFA). Fractions containing desire product were combined and lyophilized to afford (2R,3R,4R,5S)-5-((6-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)-1,1-difluoroethyl)pyrazin-2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H- pyran-3,4-diol (XB80) as brown sticky solid. Yield: 0.112 g, 47%.1H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.90 (s, 1H), 7.72 (brs, 3H), 7.35 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 6.4 Hz, 1H), 4.63-4.58 (m, 2H), 4.08-3.98 (m, 3H), 3.94-3.90 (m, 1H), 3.75 (brs, 1H), 3.64-3.58 (m, 2H), 3.57-3.49 (m, 11H), 3.31- 3.28 (m, 1H), 2.97-2.89 (m, 3H). Synthesis of (2R,3R,4R,5R,6R)-5-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)pyrimidin-2-yl)amino)-2- (methoxymethyl)-6-propyltetrahydro-2H-pyran-3,4-diol (XB83) H c XB83 Tert-butyl ((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-propyltetrahydro-2H-pyran- 3-yl)carbamate (1a) To a stirred solution of (2R,3R,4R,5R,6R)-5-amino-2-(hydroxymethyl)-6-propyltetrahydro-2H- pyran-3,4-diol hydrochloride (1b, 5.3 g, 21.9 mmol) in methanol (45 mL), were added triethylamine (3 eq., 9 mL, 65.8 mmol) and di-tert-butyl dicarbonate (1.2 eq., 6.04 mL, 26.3 mmol) gradually at 0° C under nitrogen atmosphere. Then reaction mixture was stirred at room temperature for 12h. After completion the reaction mixture was concentrated under reduced pressure to get a crude which was diluted with water and extracted with ethyl acetate (5 X 120 mL). Organic part was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford tert-butyl ((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-propyltetrahydro-2H-pyran-3-yl)carbamate (1a) as off white solid. Yield: 5.0 g, crude; LCMS m / z 306.1[M + H]+. tert-butyl ((3aR,4R,6R,7S,7aR)-4-(hydroxymethyl)-2,2-dimethyl-6-propyltetrahydro-4H- [1,3]dioxolo[4,5-c]pyran-7-yl)carbamate (1) To a stirred solution of tert-butyl ((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2- propyltetrahydro-2H-pyran-3-yl)carbamate (1a, 1.0 eq., 3.0 g, 9.82 mmol) in 2,2-dimethoxypropane (15.0 mL, 22 eq., 218 mmol) and acetone (15.0 mL) was added camphor sulfonic acid (0.2 eq., 0.454 g, 1.96 mmol) at 0°C and reaction mixture was sonicated for 30 min. Then 0.5 mL of methanol was added to the reaction mixture and reaction was stirred at room temperature for 10 min. After completion of reaction, reaction mixture was neutralized using triethyl amine and concentrated under reduced pressure to afford crude which was purified by silica gel flash column chromatography using 20-50 % ethyl acetate / hexane as eluent to afford tert-butyl ((3aR,4R,6R,7S,7aR)-4-(hydroxymethyl)-2,2-dimethyl-6-propyltetrahydro- 4H-[1,3]dioxolo[4,5-c]pyran-7-yl)carbamate (1) as off white solid. Yield: 1.6 g, 47%; ELSD-MS m / z 346.2 [M + H]+. Synthesis of tert-butyl ((3aR,4R,6R,7S,7aR)-4-(methoxymethyl)-2,2-dimethyl-6- propyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl)carbamate (2) To a stirred solution of tert-butyl ((3aR,4R,6R,7S,7aR)-4-(hydroxymethyl)-2,2-dimethyl-6- propyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl)carbamate (1, 1.0 g, 1 eq., 2.89 mmol) in dry tetrahydrofuran (15 mL), sodium hydride (127 mg, 1.1 eq., 3.18 mmol) was added portion-wise at 0 °C under nitrogen atmosphere. The reaction was allowed to stir at room temperature for 30 min. After that, methyl iodide (0.360 mL, 2 eq., 5.79 mmol) was added slowly at 0 °C, and stirred at room temperature for another 30 min. After completion (monitored by TLC), ice-cold water was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). Combined organic portions were dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude residue which was purified by silica gel flash column chromatography using 40% ethyl acetate in heptane as the eluent to afford tert- butyl ((3aR,4R,6R,7S,7aR)-4-(methoxymethyl)-2,2-dimethyl-6-propyltetrahydro-4H-[1,3]dioxolo[4,5- c]pyran-7-yl)carbamate (2) as yellow sticky liquid. Yield: 0.75 g, 72.0%. LCMS m / z 360.20 [M+H]. Synthesis of (2R,3R,4R,5R,6R)-5-amino-2-(methoxymethyl)-6-propyltetrahydro-2H-pyran-3,4- diol (3) To a stirred solution of ((3aR,4R,6R,7S,7aR)-4-(methoxymethyl)-2,2-dimethyl-6- propyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl)carbamate (2, 1.1 g, 1.0 eq., 3.06 mmol ) in dichloromethane (15 mL), trifluoroacetic acid (15 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), reaction mixture was concentrated under reduce pressure and co-evaporated with dichloromethane three times to obtain crude residue, which was further lyophilized to afford (2R,3R,4R,5R,6R)-5-amino-2-(methoxymethyl)-6- propyltetrahydro-2H-pyran-3,4-diol (3) as light yellow syrup. The crude residue was directly used for next step. Yield: 0.6 g (Crude). LCMS m / z 220.1 [M+H]+. Synthesis of tert-butyl (2-(2-(2-((2-(((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(methoxymethyl)-2- propyltetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (4) To a stirred solution of (2R,3R,4R,5R,6R)-5-amino-2-(methoxymethyl)-6-propyltetrahydro-2H- pyran-3,4-diol (3, 0.7 g, 1.2 eq., 2.1 mmol) in dry 1-methyl-2-pyrrolidinone (2 mL), N,N- Diisopropylethylamine (3.66 mL, 12 eq., 21 mmol) was added at room temperature and then heated at 140 °C for 16h. After completion (monitored by ELSD-MS), reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography using 2-3% methanol in dichloromethane as the eluent to afford tert-butyl (2-(2-(2-((2-(((2R,3R,4R,5R,6R)-4,5- dihydroxy-6-(methoxymethyl)-2-propyltetrahydro-2H-pyran-3-yl)amino)pyrimidin-4- yl)oxy)ethoxy)ethoxy)ethyl)carbamate (4) as brown gummy liquid. Yield: 0.64 g, 67.1%. LCMS m / z 545.90 [M+H]+. Synthesis of (2R,3R,4R,5R,6R)-5-((4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)pyrimidin-2- yl)amino)-2-(methoxymethyl)-6-propyltetrahydro-2H-pyran-3,4-diol (XB83) A solution of tert-butyl (2-(2-(2-((2-(((2R,3R,4R,5R,6R)-4,5-dihydroxy-6-(methoxymethyl)-2- propyltetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (4, 0.140 g, 1 eq., 0.257 mmol) in dichloromethane (1 mL) was cooled at 0 °C and trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred at room temperature for 3h. After completion, the reaction mixture was concentrated under reduce pressure to get crude residue which was purified by RP prep HPLC (25% acetonitrile in water with 0.1% TFA) to afford ((2R,3R,4R,5R,6R)-5-((4-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)pyrimidin-2-yl)amino)-2-(methoxymethyl)-6-propyltetrahydro-2H-pyran- 3,4-diol (XB83) as colorless sticky solid. Yield: 0.058 g, 50.8%. LCMS m / z 445.3 [M+H]+.1H NMR (400 MHz, DMSO-D6with D2O): δ 7.99 (d, J = 6.4 Hz, 1H), 6.18 (d, J = 6.0 Hz, 1H), 4.44-4.43 (m, 2H), 4.18-4.14 (m, 1H), 4.10-4.06 (m, 1H), 3.75-3.70 (m, 5H), 3.60-3.58 (m, 6H), 3.50 (d, J = 4.4 Hz, 1H), 3.25 (s, 3H), 2.97 (t, J = 5.2 Hz, 2H), 1.61-1.55 (m, 1H), 1.33-1.18 (m, 4H), 0.81 (t, J = 6.8 Hz, 3H). Synthesis of (2R,3R,4R,5S)-5-((4-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrimidin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB85) c Synthesis of tert-butyl (2-(2-((3-(2-bromopyrimidin-4-yl)prop-2-yn-1- yl)oxy)ethoxy)ethyl)carbamate (2) A solution of 2,4-dibromopyrimidine (1, 0.5 g, 1.0 eq., 2.1 mmol) and tert-butyl-2-[2-(2- propynyloxy)ethoxy]ethylaminoformylate (2a, 0.511 g, 1.0 eq., 2.1 mmol) in tetrahydrofuran (5 mL) was purged with N2gas for 10 min. To this, triethylamine (0.880 mL, 3 eq., 6.31 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.0738 g, 0.05 eq., 0.105 mmol) and copper (I) iodide (0.04 g, 0.1 eq., 0.210 mmol) were added, and the reaction mixture was purged with N2for another 30 min. Then the resultant reaction mixture was stirred at 50 °C for 12h. After completion, the reaction mixture was filtered using sintered funnel, and the filtrate was concentrated to obtained crude, which was purified by silica gel column chromatography eluting with 30% ethyl acetate-heptane to afford tert-butyl (2-(2-((3-(2-bromopyrimidin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (2) as colorless viscous liquid. Yield: 0.45 g, 53.40%; LCMS: m / z 400.0 [M+H]. Synthesis of tert-butyl (2-(2-(3-(2-bromopyrimidin-4-yl)propoxy)ethoxy)ethyl)carbamate (3) To a solution of tert-butyl (2-(2-((3-(2-bromopyrimidin-4-yl)prop-2-yn-1- yl)oxy)ethoxy)ethyl)carbamate (2, 0.28 g, 0.7 mmol) in tetrahydrofuran (6.0 mL), 10% Pd / C (0.28 g) was added and the reaction mixture was stirred at room temperature under hydrogen gas balloon pressure for 4h. After completion, reaction mixture was filtered through syringe filter and washed with methanol. The filtrate was concentrated and dried to obtained crude. Crude was purified by silica gel chromatography using 10% methanol in dichloromethane to afford tert-butyl (2-(2-(3-(2-bromopyrimidin-4- yl)propoxy)ethoxy)ethyl)carbamate (3) as colourless liquid. Yield: 0.11 g, 38.5%; LCMS: m / z 403.9 [M+H]. Synthesis of tert-butyl (2-(2-(3-(2-(((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-3-yl)amino)pyrimidin-4-yl)propoxy)ethoxy)ethyl)carbamate (4) To a stirred solution of tert-butyl (2-(2-(3-(2-bromopyrimidin-4- yl)propoxy)ethoxy)ethyl)carbamate (3, 0.3 g, 1.0 eq., 742 µmol) and (2R,3R,4R,5S)-5-amino-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol hydrochloride salt (48-4, 0.207 g, 1.4 eq., 1.04 mmol) in N-Methyl-2-pyrrolidone (3 mL), N,N-Diisopropylethylamine (1.29 mL, 10 eq., 7.42 mmol) was added, and the resulting reaction mixture was allowed to stirred at 150° C for 48h. After completion, volatiles were removed under reduced pressure to obtain the crude which was purified by silica gel column chromatography using 5-20% methanol in dichloromethane to afford tert-butyl (2-(2-(3-(2- (((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrimidin-4- yl)propoxy)ethoxy)ethyl)carbamate (4) as viscous oil. Yield: 0.17 g, 44.73%; LCMS: m / z 487.0 [M+H]. Synthesis of (2R,3R,4R,5S)-5-((4-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrimidin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB85) To a stirred solution of tert-butyl (2-(2-(3-(2-(((3S,4R,5R,6R)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrimidin-4-yl)propoxy)ethoxy)ethyl)carbamate (4, 0.119 g, 1.0 eq., 0.245 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.8 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2h. After completion, the reaction mixture was concentrated under vacuum to give crude which was purified by RP prep-HPLC (20-30% acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford (2R,3R,4R,5S)-5-((4-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrimidin-2- yl)amino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB85) as white solid. Yield: 0.064 g, 67.71%; LCMS m / z 387.15 [M+H];1H NMR (400 MHz, DMSO-d6-D2O exchange): δ 8.12 (d, J = 5.20 Hz, 1H), 6.62 (d, J = 5.60 Hz, 1H), 4.08 (m, 1H), 3.87-3.83 (m, 1H), 3.73 (d, J = 3.20 Hz, 1H), 3.57-3.47 (m, 9H), 3.41 (t, J = 6.40 Hz, 2H), 3.29 (t, J = 6.00 Hz, 1H), 3.02 (t, J = 10.80 Hz, 1H), 2.94 (t, J = 5.20 Hz, 2H), 2.60 (t, J = 7.20 Hz, 2H), 1.88-1.81 (m, 2H). Synthesis of (2R,3R,4R,5S)-5-((6-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrazin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB87) rH Synthesis of 2-bromo-6-fluoropyrazine (2) To a solution of 6-bromopyrazin-2-amine (1, 1 g, 1.0 eq.5.75 mmol) in HBF4(3 mL) was added sodium nitrite (0.793 g, 2 eq., 11.5 mmol) in portions at 0 °C. The mixture was stirred at 20 °C for 2h. After completion, the reaction mixture was quenched with water (10 mL) and extracted with pentane (3×20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated via distillation to remove pentane. Desired compound 2-bromo-6-fluoropyrazine (2) was obtained as brown oil. Yield: 0.5 g, 49.16% Synthesis of (2R,3R,4R,5S)-5-((6-bromopyrazin-2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H- pyran-3,4-diol (3) To a stirred solution of 2-bromo-6-fluoropyrazine (2, 0.365 g, 1.0 eq., 2.06 mmol) and (2R,3R,4R,5S)-5-amino-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol hydrochloride (48-4, 0.494 g, 1.2 eq., 2.47 mmol) in N-Methyl-2-pyrrolidone (4 mL), N,N-Diisopropylethylamine (3.59 mL, 10 eq., 20.6 mmol) was added, and the resultant reaction mixture was allowed to stir at 100 °C for 12h. After completion, volatiles were removed under reduced pressure to obtain crude which was purified by silica gel column chromatography using 5-20% methanol in dichloromethane to afford (2R,3R,4R,5S)-5-((6- bromopyrazin-2-yl)amino)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (3) as white semi-solid. Yield: 0.450 g, 66.79%; LCMS: m / z 320.0 [M+H]. Synthesis of tert-butyl (2-(2-((3-(6-(((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-3-yl)amino)pyrazin-2-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (4) A stirred solution of (2R,3R,4R,5S)-5-((6-bromopyrazin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (3, 0.05 mg, 1.0 eq., 0.156 mmol) in tetrahydrofuran (0.5 mL) was purged with N2-gas for 30 min. To this, triethylamine (0.0652 mL, 3 eq., 0.469 mmol), tert-butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (0.038 g, 1.0 eq., 0.156 mmol), copper iodide (0.00297 g, 0.1 eq., 0.0156 mmol) and Bis(triphenylphosphine)palladium(II) dichloride (0.0055 g, 0.05 eq., 0.0078 mmol) were added and the mixture was purged with N2-gas for another 30 minutes. The reaction mixture was stirred at 100 °C for 24h. After completion, the reaction mixture was filtered through celite bed and rinsed with 20% methanol-dichloromethane. The filtrate was dried to obtained crude, which was purified by silica gel chromatography using 5% methanol in dichloromethane to afford tert-butyl (2-(2-((3-(6- (((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)prop-2- yn-1-yl)oxy)ethoxy)ethyl)carbamate (4) as a colourless liquid. Yield: 0.011 g, 14.6%; LCMS: m / z 483.5 [M+H]Synthesis of tert-butyl (2-(2-(3-(6-(((3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-3-yl)amino)pyrazin-2-yl)propoxy)ethoxy)ethyl)carbamate (5) To a solution of tert-butyl (2-(2-((3-(6-(((3S,4R,5R,6R)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)prop-2-yn-1- yl)oxy)ethoxy)ethyl)carbamate (4, 0.28 g, 0.580 mmol) in methanol (5 mL), 10% Pd / C (0.28 g) was added and the reaction mixture was stirred at room temperature under hydrogen gas balloon pressure for 1h. After completion, reaction mixture was filtered through syringe filter and washed with methanol. The filtrate was concentrated and dried to afford crude tert-butyl (2-(2-(3-(6-(((3S,4R,5R,6R)-4,5-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)propoxy)ethoxy)ethyl)carbamate (5) as colour less liquid. Yield: 0.25 g, crude; LCMS: m / z 487.00 [M+H]. Synthesis of (2R,3R,4R,5S)-5-((6-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrazin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB87) To a stirred solution of tert-butyl (2-(2-(3-(6-(((3S,4R,5R,6R)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)pyrazin-2-yl)propoxy)ethoxy)ethyl)carbamate (5, 0.28 g, 0.575 mol) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2h. After completion, the reaction mixture was concentrated under vacuum to get crude which was purified by RP prep-HPLC (20-30% acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the desired product were combined and lyophilized to dryness to afford (2R,3R,4R,5S)-5-((6-(3-(2-(2-aminoethoxy)ethoxy)propyl)pyrazin-2-yl)amino)-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (XB87) as colourless semi solid. Yield: 0.107 g, 48.11%; LCMS m / z 387.10 [M+H] ;1H NMR (400 MHz, DMSO-d6, D2O exchange): δ 7.70 (s, 1H), 7.51 (s, 1H), 4.06-4.00 (m, 1H), 3.90-3.86 (m, 1H), 3.73-3.72 (d, J = 2.8 Hz, 1H), 3.57-3.46 (m, 9H), 3.42-3.39 (t, J = 6.4 Hz, 2H), 3.31-3.28 (t, J = 6.0 Hz, 1H), 2.95-2.90 (m, 3H), 2.56-2.50 (m, 2H), 1.85-1.78 (m, 2H) Synthesis of (R)-5-((2-(2-(2 aminoethoxy)ethoxy)ethoxy)methyl)-3-((3S,4R,5R,6R)-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxazolidin-2-one (XB91) B2 3 XB91 Synthesis of (R)-2-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)oxirane (1a) A solution of 2-(2-(2-azidoethoxy)ethoxy)ethan-1-ol (1a’, 1.0 eq, 0.947 g, 5.4 mmol) in tetrahydrofuran (5 mL) was cooled at 0 °C, sodium hydride (60 % suspension in mineral oil) (1.1 eq, 0.238 g, 5.94 mmol) was added and reaction mixture was stirred at 0° C for 30 minutes. Then, a solution of (R)-2-(chloromethyl)oxirane (1’, 1.0 eq, 0.500 g, 5.4 mmol) in tetrahydrofuran (5 mL) was added and reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get crude residue which was purified by column chromatography using silica gel (100-200 mesh, 0-100 % ethyl acetate in hexane) to afford (R)-2-((2-(2- (2-azidoethoxy)ethoxy)ethoxy)methyl)oxirane (1a) as colorless viscous liquid. Yield: 0.350 g, 28.0 %; LCMS m / z 249.1 [M+18]+. Synthesis of (R)-1-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-3-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)- 6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)propan-2-ol (2) To a solution of (3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran- 3-amine (Int1, 1.0 eq, 0.450 g, 1.04 mmol) and (R)-2-((2-(2-(2- azidoethoxy)ethoxy)ethoxy)methyl)oxirane (1a, 0.9 eq, 0.216 g, 0.93 mmol) in ethanol (9 mL) N,N- diisopropylethylamine (2.0 eq, 0.38 mL, 2.08 mmol) was added and reaction mixture was heated for at 80 °C for 16 h. After completion, the reaction mixture was concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh, 0-3 % methanol in dichloromethane) to afford (R)-1-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-3-(((3S,4R,5R,6R)-4,5-bis(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)propan-2-ol (2) as colorless viscous liquid. Yield: 0.420 g, 60.9 %; LCMS m / z 665.7 [M+H]+. Synthesis of (R)-5-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)-3-((3S,4R,5R,6R)-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxazolidin-2-one (3) To a solution of (R)-1-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-3-(((3S,4R,5R,6R)-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)propan-2-ol (2, 1.0 eq, 0.420 g, 0.63 mmol) in acetonitrile (10 mL), 1,1'-carbonyldiimidazole (CDI) (1.5 eq, 0.154 g, 0.95 mmol) and 4- dimethylaminopyridine (DMAP) (0.1 eq, 0.007 g, 0.063 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated to get crude which was purified by column chromatography using silica gel (100-200 mesh, 0-50 % ethyl acetate in hexane) to afford (R)-5-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)-3-((3S,4R,5R,6R)-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxazolidin-2-one (3) as colorless viscous liquid. Yield: 0.310 g, 71.0 %; LCMS m / z 691.7 [M+H]+. Synthesis of (R)-5-((2-(2-(2 aminoethoxy)ethoxy)ethoxy)methyl)-3-((3S,4R,5R,6R)-4,5-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxazolidin-2-one (XB91) To a solution of (R)-5-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)-3-((3S,4R,5R,6R)-4,5- bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxazolidin-2-one (3, 1.0 eq, 0.310 g, 0.45 mmol) in methanol (6 mL), conc. hydrochloric acid (0.31 mL) and 10 % Palladium on carbon (0.310 g) were added and the reaction mixtur...

Claims

WHAT IS CLAIMED IS:

1. A conjugate of formula (I):or a pharmaceutically acceptable salt thereof, wherein: B is a muscle-specific kinase (MuSK) polypeptide that specifically binds anti-MuSK autoantibody; Y is a carrier polypeptide connected to B; X is an asialoglycoprotein receptor (ASGPR) binding moiety of formula (II):wherein: R1is selected from –Z1–*, –H, –OH, –CH3, –OCH3, and –OCH2CH=CH; R2is selected from –Z1–*, –NHCOCH3, –NHCOCF3, –NHCOCH2CF3, –OH, and optionally substituted triazole; R6is selected from –Z1–*, –OH, –OC(O)R, -C(O)NHR, and optionally substituted triazole, where R is optionally substituted (C1-C6)alkyl or optionally substituted aryl; wherein one of R1, R2, and R6is –Z1–*, and “ * ” represents a point of connection of Z1to the linker (L); R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety;R11is H, or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-, -A2-, -NR21CO-, - CONR21-, -NR21SO2-, - SO2NR21-, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl; n is 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, or 1 to 10, such as 1, 2, or 3); L is a linker conjugated to Y-B; and m is the average number of (Xn-L) moieties conjugated to Y-B, wherein m is in the range from about 1 to about 20 (e.g., about 1 to about 3, such as 1, 2 or 3, or about 1 to about 10, about 1 to about 8, about 2 to about 8, about 3 to about 6, or about 4 to about 5).

2. The conjugate of claim 1, wherein each X is independently of formula (IIa):

3. The conjugate of claim 1 or 2, wherein each X is independently of formula (IIIa) or (IIIb):(IIIa) (IIIb) wherein:-Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; and -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene.

4. The conjugate of claim 1 or 2, wherein each X is independently of formula (IIa-2):(IIa-2).

5. The conjugate of any preceding claim, wherein Z11is -C(R22)2.

6. The conjugate of any preceding claim, wherein each X is independently of formula (XB-2):(XB-2).

7. The conjugate of claim 1, wherein R11is H.

8. The conjugate of any preceding claim, wherein B comprises the IgG1 extracellular domain of MuSK.

9. The conjugate of any preceding claim, wherein B comprises the IgG2 extracellular domain of MuSK.

10. The conjugate of any preceding claim, wherein B comprises the IgG1 and IgG2 extracellular domains of MuSK.

11. The conjugate of any preceding claim, wherein B comprises a polypeptide of one of SEQ ID NOs: 2-4.

12. The conjugate of any preceding claim, wherein Y comprises an albumin, a fragment thereof, or a variant thereof.

13. The conjugate of any preceding claim, wherein Y comprises human serum albumin (HSA), an HSA domain, bovine serum albumin (BSA), a fragment thereof, or a variant thereof.

14. The conjugate of any preceding claim, wherein Y comprises a site-specific mutation of a naturally occurring amino acid residue.

15. The conjugate of any preceding claim, wherein the site-specific mutation is a cysteine residue suitable for conjugation to a cysteine reactive linker (e.g., one, two or three cysteine residues suitable for conjugation).

16. The conjugate of any preceding claim, wherein Y comprises a polypeptide of SEQ ID NOs: 6-12.

17. The conjugate of any preceding claim, wherein Y-B is a chimeric fusion protein.

18. The conjugate of any preceding claim, wherein Y is fused directly to B.

19. The conjugate of any preceding claim, wherein Y is fused indirectly to B via a spacer domain.

20. The conjugate of any preceding claim, wherein L is of formula (XI):wherein each L1and L3are independently a linear linking moiety, and L2is a branched linking moiety, wherein L1to L3together provide a linear or branched linker between X and Y; a, b, and c are independently 0 or 1, wherein when n is 1, b is 0 and at least one of a and c is 1; and when n is 2 or 3, a, b and c are each 1; * represents the point of connection of L1to X via Z1; and ** represents a point of conjugation of the linker L to Y-B.

21. The conjugate of any preceding claim, wherein: n is 3; and a is 1, b is 1, and c is 1, wherein L is of formula (XIc):(XIc).

22. The conjugate of any one of claims 20 or 21, wherein each L1is of the formula (XII) *wherein: L10is a linking moiety; and L11to L19are independently absent or a linking moiety, wherein L10to L19of each L1are independently selected from –C1-20-alkylene–, –NHCO-C1-6- alkylene–, –CONH-C1-6-alkylene–, –NH C1-6-alkylene–, –NHCONH-C1-6-alkylene–, – NHCSNH-C1-6- alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene–NH-, –C1-6-alkylene– NHCONH-, –C1-6-alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, –CONH–, –NHSO2–, –SO2NH–, –NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, –NH–, and –N(CH3)–, wherein each p is independently 1 to 50.

23. The conjugate of any preceding claim, wherein each L3is of the formula (XVI):wherein: L30to L39are independently absent or a linking moiety; and Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group of the linker to a compatible group of Y-B; wherein L30to L39of L3are each independently selected from –C1-20-alkylene–, –NHCO-C1-6- alkylene–, –CONH-C1-6-alkylene–, –NH C1-6-alkylene–, –NHCONH-C1-6-alkylene–, – NHCSNH-C1-6- alkylene–, –C1-6-alkylene–NHCO-, –C1-6-alkylene–CONH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHCONH-, –C1-6-alkylene–NHCSNH-, -O(CH2)p–, –(OCH2CH2)p–, –NHCO–, –CONH–, –NHSO2–, –SO2NH–, –NHCONH-, –NHCSNH-, –CO–, –SO2–, –O–, –S–, pyrrolidine-2,5-dione, 1,2,3-triazole, –NH–, and –N(CH3)–, wherein each p is independently 1 to 50.

24. The conjugate of claim 1, wherein the conjugate is of the structure:wherein: m is 4 to 6; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; and B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof.

25. The conjugate of claim 1, wherein the conjugate is of the structure:whereinm is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; and B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof.

26. The conjugate of claim 1, wherein the conjugate is of the structure:wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; and B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof.

27. The conjugate of claim 1, wherein the conjugate is of the structure:wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; and B is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof.

28. The conjugate of claim 1, wherein the conjugate is of the structure:wherein m is 1-3; Y is human serum albumin (HSA) comprising SEQ ID NO.7; B is a MuSK polypeptide comprising SEQ ID NO.4; andB is linked to Y via a (G4S)3 linker; or a pharmaceutically acceptable salt thereof.

29. A method of reducing levels of an extracellular target molecule in a biological system, the method comprising: contacting the biological system with an effective amount of a conjugate according to any one of claims 1 to 28, wherein the compound specifically binds the extracellular target molecule and specifically binds a lysosomal targeting molecule of cells in the biological system to facilitate cellular uptake and degradation of the extracellular target molecule.

30. A method of treating myasthenia gravis in a human subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate according to any one of claims 1 to 28.

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