Asgpr binding compounds and conjugates

Abstract

The present disclosure provides a class of compounds including a ligand moiety that specifically binds to a cell surface asialoglycoprotein receptor (ASGPR). The cell surface ASGPR binding compounds can trigger the receptor to internalize into the cell a bound compound. The ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface receptor ASGPR. Also provided are compounds that are conjugates of the ligand moieties linked to a biomolecule, such as an antibody, which conjugates can harness cellular pathways to remove specific proteins of interest from the cell surface or from the extracellular milieu. Also provided herein methods of using the conjugates to target a polypeptide of interest for sequestration and / or lysosomal degradation.

Description

ASGPR BINDING COMPOUNDS AND CONJUGATES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Numbers 63 / 439,811, filed January 18, 2023, and 63 / 518,532, filed August 9, 2023, each of which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] 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. Thus, there is a need for therapies that can target a wider range of proteins.

[0003] The asialoglycoprotein receptor (ASGPR), also known as the Ashwell Morell receptor, 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.

[0004] Alternative ligands that provide for binding to cell surface ASGPRs followed by transport across cell membranes are of great interest. SUMMARY

[0005] The present disclosure provides a class of compounds including a ligand moiety that specifically binds to a cell surface asialoglycoprotein receptor (ASGPR). The cell surface ASGPR binding compounds can trigger the receptor to internalize into the cell a bound compound. The ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface receptor ASGPR. Also provided are compounds that are conjugates of the ligand moieties linked to a biomolecule, such as an antibody, which conjugates can harness cellular pathways to remove specific proteins of interest from the cell surface or from the extracellular milieu. For example, the conjugates described herein may sequester and / or degrade a target molecule of interest in a cell’s lysosome. Also provided herein are compositions comprising such conjugates and methods of using the conjugates to target a polypeptide of interest for sequestration and / or lysosomal degradation, and methods of using the conjugates to treat disorders or disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0007] FIG.1 shows a graph of cell fluorescence (MFI) versus antibody conjugate concentration ([Ab]) indicating that various antibody conjugates of exemplary ASGPR binding compounds, and an example M6PR binding compound (520) exhibited comparable robust uptake into HepG2 cells after one hour incubation.

[0008] FIG.2A-2D shows graphs of cell fluorescence versus antibody conjugate concentration indicating that various antibody conjugates of exemplary ASGPR binding compounds exhibited robust uptake into HepG2 cells after one hour incubation.

[0009] FIG.3 illustrates the fluorescence polarization screening results for example trivalent compounds (1901 (I-171), 1902 (I-172), XB32 and 2101).

[0010] FIG.4 illustrates the binding of example monovalent compounds (591, XB20, XB23, XB21, 592 and 593) as a percentage of the activity of reference compound XB149.

[0011] FIG.5 illustrates the fluorescence polarization screening results for example monovalent compounds (XB20, XB21, 592, XB23, 591).

[0012] FIG.6 shows a graph of cellular uptake of various conjugates of OMA (anti-IgE) with example compounds I-160 to I-163 and I-141 bound to Alexa488 labeled-target IgE in HepG2 cells.

[0013] FIG.7 illustrates affinity-dependent clearance of OMA-example compounds (I-160 to I-163) as compared to OMA (reference).

[0014] FIG.8 illustrates dose titration OMA-I-163 IgE clearance.

[0015] FIG.9 illustrates affinity-dependent clearance of OMA-example compounds (I-160 to I-163) as compared to hIgE (reference). DETAILED DESCRIPTION

[0016] As summarized above, this disclosure provides classes of compounds including a ligand moiety that specifically binds an ASGPR of a cell of interest.

[0017] This disclosure includes compounds of formula (I): XnL Y (I) or a prodrug thereof, or a salt thereof, wherein: X is a moiety that binds to a ASGPR cell surface receptor (e.g., as described herein); n is 1 to 500; L is a linker (e.g., monovalent or multivalent, as described herein, of defined length); and Y is a moiety of interest (e.g., as described herein).

[0018] Also provided herein are conjugates that comprise a moiety, X, that binds to such an ASGPR internalizing cell surface receptor, for example, for sequestration and / or lysosomal degradation. Accordingly, this disclosure includes target binding conjugate of formula (I):or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: X is a moiety that binds to an ASGPR cell surface receptor (e.g., as described herein); n is 1 to 500; L is a linker (e.g., monovalent or multivalent, as described herein);m is 1 to 20; Y is a biomolecule that specifically binds an extracellular target molecule.

[0019] In some embodiments target binding conjugate is of formula (II’):(II’) or a prodrug thereof, or a salt thereof, wherein: n is 1 to 3; m is 1 to 3; X and Y are each independently as defined herein; each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; and a, b, c, d, and e are each independently 1, 2, 3, 4, or 5.

[0020] The ASGPR binding compounds and conjugates and methods of this disclosure are described in greater detail below. Linkers (L) and moieties of interest (Y) which find use in the ASGPR binding compounds, and the biomolecule conjugates are also described. Methods in which the compounds and conjugates of this disclosure find use are also described. ASGPR Ligands

[0021] As summarized above, this disclosure provides a class of compounds including a ligand moiety that specifically binds to a cell surface ASGPR. The ASGPR ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface ASGPR. In certain embodiments, compounds of this disclosure can utilize the functions of cell surface ASGPRs in a biological system, e.g., for internalization and sequestration of a compound to the lysosome of a cell, and in certain embodiments subsequent lysosomal degradation. The compounds of this disclosure find use in a variety of applications.

[0022] The term “asialoglycoprotein receptor” (ASGPR), also known as the Ashwell Morell receptor, means 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. In particular embodiments, the ASGPR is Homo sapiens asialoglycoprotein receptor 1 (ASGR1) (see, e.g., NCBI Reference Sequence: NM_001197216).

[0023] A compound comprising such ASGPR binding moiety (X) (e.g., as described herein), may bind to other receptors, for example, may bind with lower affinity as determined by, e.g., immunoassays or other assays known in the art. In a specific embodiment, X, or a compound as described herein comprising such X specifically binds to the cell surface ASGPR with an affinity that is at least 2 logs, 2.5logs, 3 logs, 4 logs or greater than the affinity when X or the compound or the conjugate bind to another cell surface receptor. In a specific embodiment, X or a compound as described herein comprising X, specifically binds to ASGPR with an affinity (Kd) 20 mM or less. In particular embodiments, such binding is with an affinity (Kd) is 10 mM or less, 1 mM or less, 100 uM or less, 10 uM or less, 1 uM or less, 100 nM or less, 10 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.

[0024] The ASGPR binding compounds of this disclosure include a moiety (X) that specifically binds to the cell surface receptor ASGPR. The ASGPR binding compounds can be monovalent or multivalent (e.g., bivalent or trivalent or of higher valency), where a monovalent compound includes a single ASGPR ligand moiety, and a multivalent compound includes two or more such moieties.

[0025] In certain embodiments, the ASGPR binding moiety X is able to bind to a specific cell surface ASGPR, and direct (or target) the molecule to this receptor. In certain embodiments, the ASGPR binding moiety X is capable of binding to the ASGPR and directing (or targeting) a compound or conjugate described herein for internalization and sequestration to the lysosome, and / or subsequent lysosomal degradation.

[0026] In some embodiments, the ASGPR binding moiety X includes an amino sugar ring derivative of galactose (e.g., N-acetylgalactosamine, and analogs thereof), that is linked via a linking moiety to the 1, 6 or 2-position of the sugar ring. The linking moiety can be of 1-10 atoms in length, such as 1-6, or 1- 5, 1-4, or 1-3 atoms in length. In some embodiments, the amino sugar ring derivative of galactose is linked via a linking moiety to an oxygen, sulfur, nitrogen or carbon atom at the 1-position of the ring. In some embodiments, the amino sugar ring derivative of galactose is linked via a linking moiety to an oxygen, sulfur, nitrogen or carbon atom the 6-position of the ring. In some embodiments, the amino sugar ring derivative of galactose is linked via a linking moiety to an oxygen, sulfur, nitrogen or carbon atom the 2-position of the ring. In certain embodiments, the amino sugar derivative of galactose is linked via a linking moiety to a heteroaryl group at the 1, 6 or 2 position of the ring. In certain embodiments, the amino sugar derivative of galactose is a bicyclic structure.

[0027] In some embodiments, the ASGPR binding compounds is monovalent (e.g., in Formula (I), n is 1), such that the ASGPR binding compound includes a single ASGPR ligand moiety (X) that is linked to a moiety of interest (Y) via a linking moiety at the 1, 6, or 2-position of (X). In certain embodiments of formula (I), n is 1, and L comprises a linear linker having a backbone of 20 or more consecutive atoms covalently linking the ASGPR ligand (X) to Y via a linking moiety at any of the 1, 2 or 6-positions of X. In certain embodiments, L is 20 to 100 consecutive atoms, such as 25 to 80, 25 to 60, or 25 to 50. In certain embodiments of formula (I), n is 1, and L comprises a backbone of 25 or more consecutive atoms covalently linking the ASGPR ligand (X) to Y.

[0028] In some embodiments, the ASGPR binding compounds are multivalent (e.g., in Formula (I), n is 2 or more, such that the ASGPR binding compound includes two or more ASGPR ligand binding moieties (X) that are each covalently linked to a moiety of interest (Y) via a branched linker (e.g., L is a branched linker). In certain embodiments, the ASGPR binding compound is divalent (e.g., n is 2 inFormula I). In certain other cases, the ASGPR binding compound is trivalent (e.g., n is 3 in Formula I). In certain embodiments, each branch of the branched linker comprises a liner linker of 14 or more consecutive atoms to covalently link a linking moiety of each X to a branching point in the linker. In certain embodiments, each branch of the linker includes 14 to 50 consecutive atoms, such as 14 to 40, 14 to 30, or 14 to 20 atoms. In certain embodiments, each branch of the linker includes a linear linker of 20 or more consecutive atoms. In certain embodiments, the linker comprises a linear linker of 12 or more consecutive atoms to covalently link the branching point of L to a moiety of interest (Y), such as 15 or more, 20 or more, 30 or more, or even more consecutive atoms to covalently link the branching point of L to Y.

[0029] Exemplary ASGPR ligand moieties which can be adapted for use in the conjugates of this disclosure are described in WO / 2023288033, filed July 14, 2022, the disclosure of which is herein incorporated by reference in its entirety.

[0030] Certain ASGPR ligand moieties are described below.

[0031] In some embodiments, the ASGPR ligand moieties (e.g., Xn-L or (X-L)nof formula (I), and other formulae described herein), 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.

[0032] In some embodiments, provided is a compound of formula (I):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 500; m is 1 to 20; Y is a moiety of interest; L is a linker; and 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.

[0033] In some embodiments, Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and - A2- are optionally substituted heterocyclylene; or -A2- is optionally substituted isoxazolyl.

[0035] In some embodiments, R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl–NHCOR, or –NRCOR, provided the heteroaryl is other than triazole; where 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.

[0036] In some embodiments, R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1- C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl.

[0037] In some embodiments, at least one R21is -COR or optionally substituted heteroaryl.

[0038] In some embodiments, n is 1, 2, or 3; and m is 1-3.

[0039] In some embodiments, provided is a compound of formula (I):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 500; m is 1 to 20; Y is a moiety of interest; L is a linker; and X is an asialoglycoprotein receptor (ASGPR) binding moiety of formula (II):(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; provided at least one of the following occurs: A) Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and -A2- are optionally substituted heterocyclylene; or -A2- is optionally substituted isoxazolyl; B) -L-Y comprises:C) R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, - C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl–NHCOR, or –NRCOR, provided the heteroaryl is other than triazole; where 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; D) R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl; or E) at least one R21is -COR or optionally substituted heteroaryl.

[0040] In some embodiments, n is 1, 2, or 3; and m is 1-3.

[0041] In some embodiments, X is of formula (a-II):(a-II).

[0042] In some embodiments, X is of formula (a-II), R1is n-propyl; and R2is -Z1-*.

[0043] In some embodiments, Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and - A2- are optionally substituted heterocyclylene.

[0044] In some embodiments,

[0045] In some embodiments, -L-Y comprises:monocyclic heteroaryl.

[0046] In some embodiments, -L-Y comprises:

[0047] In some embodiments, R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, or optionally substituted heteroaryl, provided the heteroaryl is other than triazole; where R is 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.

[0048] In some embodiments, R6is -O-(C1-C6)alkyl, optionally substituted heterocyclyl, or -O-aryl.

[0049] In some embodiments, R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1- C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl

[0050] In some embodiments, R1is optionally substituted C2-6alkyl.

[0051] In some embodiments, at least one R21is -COR or optionally substituted heteroaryl.

[0052] In some embodiments, Y is an antibody or antibody fragment.

[0053] In some embodiments, provided is a compound of formula (I):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 500;m is 1 to 20; L is a linker; and 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, 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, and optionally substituted heteroaryl, R is 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; 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; and Y is a chemoselective ligation group.

[0054] In some embodiments, n is 1, 2, or 3; and m is 1-3.

[0055] In some embodiments, the chemoselective ligation group comprises a carboxylic acid or active ester, maleimide, isocyanate or isothiocyanate, alkyl halide, alkyl tosylate, aldehyde, haloacetamide or alpha-leaving group acetamide, 2-sulfonylpyridine, diazirine, sulfonyl halide or vinyl sulfone, hydrazide, hydrazino, hydroxylamino, pyridyl disulfide, (HIPS) hydrazinyl-indolyl group, or (aza-HIPS) hydrazinyl-pyrrolo-pyridinyl group, alkyne or cyclooctyne, azide, or amine.

[0056] In some embodiments, the chemoselective ligation group is selected from:.

[0057] In some embodiments, at least one of the following occurs: A) Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and -A2- are optionally substituted heterocyclylene; or -A2- is optionally substituted isoxazolyl; B) -L-Y comprises:C) R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, - C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl–NHCOR, or –NRCOR, provided the heteroaryl is other than triazole; where 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; D) R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl; or E) at least one R21is -COR or optionally substituted heteroaryl.

[0058] In some embodiments, the compound of formula (II) is represented by formula (a-II):(a-II).

[0059] In some embodiments, R1is –Z1–*, –H, or (C1-C6)alkyl.

[0060] In some embodiments, R2is –Z1–* or –NHCOCH3.

[0061] In some embodiments, R3and R4are each –H.

[0062] In some embodiments, R6is –OH, –OC(O)R, -NRxxRyy, or aryl; R is (C1-C6)alkyl; and Rxxand Ryycyclize to form an optionally substituted heterocyclyl.wherein “ * ” represents a point of connection of Z1to the linker (L).

[0064] In some embodiments, R1is –Z1–*.

[0065] In some embodiments, R2is –Z1–*.

[0066] In some embodiments, L comprises of 10 to 60 consecutive linear or branched chain atoms.

[0067] In some embodiments, L is of formula (IIb’):wherein: 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 to L1of X via Z1; and *** represents the point of attachment to Y.

[0068] In some embodiments of formula (IIb’), n is 1-3. In some embodiments of formula (IIb’), n is 1. In some embodiments of formula (IIb’), n is 2. In some embodiments of formula (IIb’), n is 3.

[0069] In some embodiments, L is of formula (IIb’):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 to L1of X via Z1; and *** represents the point of attachment to Y.

[0070] In some embodiments, provided is a compound of formula (II’):(II’) or a prodrug thereof, or a salt thereof, wherein: n is 1 to 3; m is 1 to 20; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5;each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; X and Y are each independently as defined herein.

[0071] In some embodiments, provided is a compound of formula (II’):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 3; m is 1 to 20; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; Y is as defined herein; each X is an asialoglycoprotein receptor (ASGPR) binding moiety of formula (a-II):(a-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, 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, and optionally substituted heteroaryl, R is 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 apromoiety; 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; 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.

[0072] 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–, –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(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, amino acid residue, –NH–, and – NMe–; 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–; andeach R16is independently –H, (C1-C6)alkyl, or monocyclic heteroaryl.

[0073] In some embodiments, each R16is independently (C1-C6)alkyl or monocyclic heteroaryl. In some embodiments, each R16is independently R”.

[0074] 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(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 cycloalkyl, amino acid residue, –NH–, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and; and R16is (C1-C6)alkyl or monocyclic heteroaryl.

[0075] 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(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 monocyclicaryl, monocyclic heterocycle, monocyclic cycloalkyl, amino acid residue, –NH–, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo;

[0076] 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(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, amino acid residue, –NH–, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and

[0077] In some embodiments of formula (II’), n is 1.

[0078] In some embodiments of formula (II’), n is 2.

[0079] In some embodiments of formula (II’), n is 3.

[0080] In some embodiments, at least one L1is –C1-20-alkylene– optionally substituted with one to five halo.

[0081] In some embodiments, at least one L1is -CF2CH2-.

[0082] In some embodiments, at least one L2is –(OCH2CH2)p–.

[0083] In some embodiments, p is 2-3.

[0084] In some embodiments, at least one L3is NHCONH-C1-6-alkylene–.

[0085] In some embodiments, at least one L4is –C1-6-alkylene–NHCONH-.

[0086] In some embodiments, at least one L5is –(OCH2CH2)p–.

[0087] In some embodiments, the lysosomal targeting bifunctional molecules of this disclosure (e.g., of formula (I)-(Ia)) include an ASGPR ligand moiety of formula (II):(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.

[0088] In some embodiments of formula (II): 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, R2is –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. 1-linked ASGPR ligand moieties

[0089] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Iia):(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.

[0090] In some embodiments of formula (II), Z1is in a beta configuration, and can be described by formula (Iia-1):(Iia-1).

[0091] In some embodiments of formula (II), Z1is in an alpha configuration, and can be described by formula (Iia-2)(Iia-2).

[0092] 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.

[0093] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (IIIa) or (IIIb):(IIIa) (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.

[0094] In some embodiments of formula (IIIa) or (IIIb), Z11is -S-.

[0095] In some embodiments, Z11is -C(R22)2-. In some embodiments, Z11is -CH2-.

[0096] In certain embodiments, Z11is -C(R22)2, where at least one R22is H. In certain embodiments, 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.

[0097] In certain embodiments, -A1- is triazole.

[0098] In certain embodiments, Z1is -C(R22)2-triazole-. In certain embodiments, Z1is: * *. In certain embodiments, Z1is:.

[0099] In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is Z11. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl.

[0100] In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), Z1is monocyclic 5 or 6-membered heteroaryl or aryl. In certain embodiments, Z1is. In certain embodiments, Z1.

[0101] In certain embodiments of formula (Iia), (Iia-1) or (Iia-2), 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.

[0102] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z1is optionally substituted (C1- C6)alkyl. In certain embodiments, of Z1the alkyl is methyl. In certain embodiments, of Z1, the alkyl is ethyl. In certain embodiments, of Z1, the alkyl is propyl. In certain embodiments, of Z1, the alkyl is butyl. In certain embodiments, of Z1, the alkyl is pentyl. In certain embodiments, of Z1, the alkyl is hexyl.

[0103] In certain embodiments, the ASGPR binding moiety (X) of formula (Iia-1) is selected from one of the following structures:

[0104] 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.

[0105] In some embodiments of formula (IIIb-2), A1is a triazole. In some embodiments of formula (IIIb-2), X is of formula (XA-4).

[0106] In some embodiments of formula (Iia-1), Z1is in a alpha 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).

[0107] In certain embodiments, the compound of formula (Iia-2) is selected from one of the following structures:

[0108] In some embodiments of formula (Iia-2), each X is of formula (XB-1).

[0109] In some embodiments of formula (Iia-2), each X is of formula (XB-2).

[0110] In some embodiments of formula (Iia-2), each X is of formula (XB-3).

[0111] In some embodiments of formula (Iia-2), each X is of formula (XB-4).

[0112] 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.

[0113] In certain embodiments of formula (IIIb-1), 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.

[0114] In certain embodiments, the X of formula (IIIb-1) is selected from one of the following structures:

[0115] In some embodiments of formula (IIIb-1), each X is of formula (XC-1).

[0116] In some embodiments of formula (IIIb-1), each X is of formula (XC-2).

[0117] 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:

[0118] 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

[0119] 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.

[0120] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure are described by formula (Iib’):wherein R3-R4, R6, and Z1are as defined herein.

[0121] 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.

[0122] In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1 is selected from optionally substituted –(C(R22)2)q-heteroarylene,, wherein q is 0 or 1.

[0123] In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1is optionally substituted – (C(R22)2)q-triazole wherein q is 0 or 1.

[0124] In some embodiments of formulae (Iib),some embodiments,

[0125] In some embodiments of formulae (Iib),23, wherein Ris H, or C(1-3)-alkyl.

[0126] In some embodiments of formulae (Iib), (Iib’) or (Iva), Z1is -NR23CO-, wherein R23is H or C(1-3)-alkyl.

[0127] 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.

[0128] 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 embodiments,

[0129] In certain cases of formulae (Iib),, wh23erein R is H, orC(1-3)-alkyl.

[0130] In certain cases of formulae (Iib), (Iib’) or (Iva), Z1is -NR23CO-, wherein R23is H or C(1-3)- alkyl.

[0131] In certain embodiments of formula of formulae (Iib), (Iib’) or (Iva), Z1is monocyclic 5 or 6- membered heteroarylene or arylene. In certain embodiments,

[0132] In certain embodiments of formula of formulae (Iib), (Iib’) or (Iva), Z1is selected from -O-, -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.

[0133] 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.

[0134] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ivb) or (Ivc): OH OH R11R11HO O HO O HO R1HO R1Z11A1A2* * (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.

[0135] In some embodiments, R2is –Z1–*, and 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.

[0136] In some embodiments, –Z1–* or –Z1–L- comprises

[0137] In certain embodiments of formula (Iib), R11is H and the compound is of Table 2:

[0138] In certain embodiments, the compound of formula (Iib) is a compound shown in Table 3: In certain embodiments, the compound of formula (Iib), the configuration at C1 (i.e., R1) is alpha. In certain embodiments, the compound of formula (Iib), the configuration at C1 (i.e., R1) is beta.

[0139] In certain embodiments, the compound of formula (Id’) is a compound shown in Table 4:

[0140] 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.

[0141] In some embodiments of formulae (Ivb), or (Ivb-1), Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H. In certain embodiments, Z11is -O-. In certain embodiments, Z11is -S-. In certain embodiments, Z11is -N(R21), where R21is H or (C1-C3)alkyl.

[0142] In certain embodiments of formulae (Ivb), (Ivc), (Ivb-1) or (Ivc-1), -A1- and -A2- are each independently 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 heteroarylene is a 6-membered heteroarylene.

[0143] 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 embodiments, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain embodiments, the A1ring is triazole. In certain embodiments, the A1ring is pyridine. In certain embodiments, the A1ring is pyrimidine. In certain embodiments, the A1ring is thiadiazole. In certain embodiments, the A1ring is a 5 or 6- membered arylene or heteroarylene that is further substituted with one or more substituents. In certain embodiments, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3).

[0144] 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 embodiments, the A2ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain embodiments, the A2ring is triazole. In certain embodiments, the A2ring is pyridine. In certain embodiments, the A2ring is pyrimidine. In certain embodiments, the A2ring is thiadiazole. In certain embodiments, the A2ring is a 5 or 6- membered arylene or heteroarylene that is further substituted with one or more substituents. In certain embodiments, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3).

[0145] 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:

[0146] In certain embodiments of formulae (Ivc) or (Ivc-1), -A2- is a monocyclic 5 or 6-membered heteroarylene of the following structure:.

[0147] 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:

[0148] 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:.

[0149] 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.

[0150] 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.

[0151] In some embodiments of any one of formulae (Ivd)-(Ivg), the A1ring is a 5 or 6-membered arylene or heteroarylene. In certain embodiments, the A1ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, imidazole, and furan. In certain embodiments, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain embodiments, the A1ring is triazole. In certain embodiments the A1ring is pyridine In certain embodiments the A1ring is pyrimidine In certainembodiments, the A1ring is thiadiazole. In certain embodiments, the A1ring is pyrazine. In certain embodiments, the A1ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In certain embodiments, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3).

[0152] In some embodiments of any one of formulae (Ivd)-(Ivg), the A2ring is a 5 or 6-membered arylene or heteroarylene. In certain embodiments, the A2ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In certain embodiments, the A2ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain embodiments, the A2ring is triazole. In certain embodiments, the A2ring is pyridine. In certain embodiments, the A2ring is pyrimidine. In certain embodiments, the A2ring is thiadiazole. In certain embodiments, the A2ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In certain embodiments, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3).

[0153] In some embodiments of any one of formulae (Ivd)-(Ivg),the A1or A2ring is absent.

[0154] In some embodiments of any one of formulae (Ivd)-(Ivg),the A1or A2ring is phenylene or substituted phenylene.

[0155] 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.

[0156] 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 certain embodiments, R21is -COCH3. In certain embodiments, R21is H.

[0157] 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.

[0158] 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.

[0159] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by any one of formulae (Ivh)-(Ivk):(Ivj), and (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.

[0160] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by any one of formulae (Ivl)-(Ivm):wherein: R6, R4, R3, and R21are as defined herein; Y1-Y3are each independently N or CR25; Y4is N or CR24; Y5is S, O, or NH; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen.

[0161] In some embodiments of formula (Ivi) at least one of Y1to Y3is N.

[0162] In certain embodiments, at least two of Y1to Y3are N.

[0163] In certain embodiments, Y1and Y4are N.

[0164] In certain embodiments, Y1and Y3are N and Y2is CR25.

[0165] In certain embodiments, Y1and Y2are N and Y3is CR25.

[0166] In certain embodiments, Y1and Y2are CR25and Y3is N.

[0167] In certain embodiments of any one of formulae (Ivd)-(Ivk), or (Ivd)-(Ivm), R6is H.

[0168] In some embodiments of any one of formulae (Ivd)-(Ivk), or (Ivd)-(Ivm), R4and R3are each H. In certain embodiments, at least one of R4-R3is a promoiety. In certain embodiments, R4and R3are cyclically linked to form a promoiety (e.g., as described herein).

[0169] In some embodiments, the compound of formula (Ivi) is of formula (Ivi-1):

[0170] 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 embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3. In some embodiments of formula (Ivi) or (Ivi-1), R24is H. In certain embodiments, R24is C(1-3)-alkyl, or C(1-3)- fluoroalkyl. In certain embodiments,, the fluoroalkyl is CF3.

[0171] In some embodiments, the compound of formula (Ivi-1) is of formula (XD):

[0172] In some embodiments, the compound of formula (Ivk-1) is of formula (XE):

[0173] In certain embodiments, the compound of formula (Ivl) 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.

[0174] In certain embodiments, each R25is H.

[0175] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures:.

[0176] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures:

[0177] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures: *

[0178] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by one of the following structures: *

[0179] In certain embodiments of formula (Iib), R1R3, R4, and R11are H, and R6is OH:wherein Z1is -NH-, -CH2-, -S- or -O-.

[0180] In certain embodiments of formula (Iib’), R3, R4are H, and R6is OH:wherein Z1is -NH-, -CH2-, -S-, -O-, triazole,6-linked ASGPR ligand moieties

[0181] 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.

[0182] 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.

[0183] 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 embodiments, Z1is -O-. In certain other cases, Z1is optionally substituted –(C(R22)2)q-triazole wherein q is 0 or 1.

[0184] In certain embodiments,

[0185] In certain embodiments of formula (Iic), Z1is -Z11-A1-, wherein -A1- is or optionally substituted -A1- or optionally substituted arylene. In certain embodiments, -A1- is an optionallysubstituted 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 certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In certain embodiments, Z1is -C(R22)2- * triazole-. In certain embodiments, Z1is:.

[0186] In certain embodiments of formula (Iic), Z1is Z11. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl.

[0187] In certain embodiments of formula (Iic), Z1is monocyclic 5 or 6-membered heteroarylene or arylene. In certain embodiments,

[0188] In certain embodiments of formula (Iic), Z1 is 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.

[0189] In certain embodiments, the compound of formula (Iic) is the following structure:.

[0190] In certain embodiments, the compound of formula (Iic) is the following structure:.

[0191] In certain embodiments of formula (Iic), R11is H and the compound is of Table 5:

[0192] 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.

[0193] 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; 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.

[0194] In some embodiments of formula (Iid)-(Iid’) Y5is O. In certain embodiments, Y5is S. In certain embodiments, Y5is -NR21-. In certain embodiments, Y5is -C(R22)2and each R22is H.

[0195] In some embodiments of formula (Iid)-(Iid’) Y6is -NR21- where R21is H. In certain embodiments, Y6is -NR21- where R21is -C(O)R22. In certain embodiments, R22is methyl.

[0196] In some embodiments of formula (Iid)-(Iid’) the B ring is a 5 or 6-membered heterocycle. In certain embodiments, the B ring is a 5-membered heterocycle. In certain embodiments, the B ring is a 6- membered heterocycle.

[0197] In some embodiments of formula (Iid)-(Iid’) Z1is Z11, where Z11is selected from -O-, -S-, NR21-, and -C(R22)2. In certain embodiments, Z1is -O-. In certain embodiments, Z1is -S-. In certain embodiments, Z1is NR21where R21is H. In certain embodiments, Z1is -C(R22)2where each R22is H.

[0198] 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.

[0199] In some embodiments, the compound of formula (Iid)-(Iid’) has one of the following structures:,.

[0200] In certain embodiments of any one of formulae (Iia), (Iib) or (Iid), R6is OH. In certain other cases, R6is -OC(O)R. In certain embodiments, R6is -C(O)NHR, where R is an optionally substitutedalkyl. In certain embodiments, R terminates in an alkenyl or an alkynyl group. In certain other cases R6is optionally substituted triazole. In certain embodiments, the triazole is of the following structure:.

[0201] In certain embodiments of (Iia), and (Iic), R2is -NHCOCH3. In certain other embodiments, R2is –NHCOCF3. In certain other embodiments, R2is –NHCOCH2CF3. In certain embodiments, R2is – OH. In certain other cases, R2is an optionally substituted triazole. In certain embodiments, the triazole in of the following structure:.

[0202] 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 embodiments, 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.

[0203] 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: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 0 to 6.

[0204] In some embodiments, the subject compounds comprise a -Z1-L1- 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.

[0205] In certain embodiments, the Z1-L1- group is, and o is 1 or 2.

[0206] In certain embodiments, the Z1-L1- group22each R is H, and p is 1 or 2.

[0209] In certain embodiments, the Z1-L1- group is.

[0210] In certain embodiments, the Z1-L1- groupare each independently 1-3.

[0211] In certain embodiments, the Z1-L1- group i

[0212] In certain embodiments, the Z1-L1- group iare each independently is 1-3.

[0213] In certain embodiments, the Z1-L1- group is, where x is 0-3.

[0214] In certain embodiments, the Z1-L1- group

[0215] In certain embodiments, the Z1-L1- group is, where R21is H, and z is 1-4. R21

[0216] In certain embodiments, the Z1-L1- group is, where R21is H, and z1 is 1-4.

[0217] In certain embodiments, the Z1-L1- group is, where each R22is H, and q is0-3. In certain embodiments, the Z1-L1- group is, where each R22is H, and q is 1-3.

[0218] In certain embodiments, the Z1-L1- group is, where q is 1-3.

[0219] In certain embodiments, the subject compounds comprise a -Z1-L- group selected from:

[0220] In certain embodiments, the Z1-L1- group isq O, where q is 1-3. In certainembodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0221] In certain embodiments, the Z1-L1- group i.

[0222] In certain embodiments, the Z1-L1- group i.

[0223] In certain embodiments, the Z1-L1- group is.

[0224] In certain embodiments, -Z1-L1- comprises an optionally substituted -NH-heteroarylene-. In certain embodiments the heteroarylene is a triazole. In certain embodiments, the heteroarylene is pyridine. In certain embodiments, the heteroarylene is pyrimidine. In certain embodiments, the heteroarylene is thiadiazole.

[0225] In certain 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.

[0226] 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.

[0227] In certain embodiments, R21is H. In certain embodiments, R24is C(1-3)-alkyl, or C(1-3)- fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3. In certain embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3.

[0228] In certain embodiments, -

[0229] 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: , ,

[0230] 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, pyrazine, or pyrimidine) , -NH-, - O-, or -CH2- , and / or Z1is attached to a linking moiety as shown in one of the following structures:

[0231] In certain 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:Additional Exemplary ASGPR Binding Moieties

[0232] The ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ia):wherein: R1is selected from –OH, –OC(O)R, -C(O)NHR, –Z1–*, and optionally substituted triazole, where R is optionally substituted C1-6alkyl or optionally substituted aryl; R2is selected from–NHCOCH3, –NHCOCF3,–NHCOCH2CF3, –OH, optionally substituted triazole, and –Z1–*; R3is selected from –H, –OH, –CH3, –OCH3, –OCH2CH=CH and –Z1–*; one of R1to R3is –Z1–*, wherein “ * ” represents a point of attachment of Z1to the linker (L); R4and R5are each independently selected from H, and a promoiety; or R4and R5are cyclically linked to form a promoiety; R11is H, or a group that forms a bridge (e.g., a 2 atom bridge cyclically linked) to the 1-position carbon atom; Z1is a linking moiety selected from Z11, optionally substituted Z11-heteroaryl, optionally substituted Z11-aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z11is selected from -O-, -S-, NR21-, and -C(R22)2, 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.

[0233] In some embodiments of formula (Ia): i) when n is 3, R1is OH, R2is –NHCOCH3,R4-R5are H, and R3is Z1, then Z1is not O; ii) when n is 2 or 3, R1is OAc, R2is –NHCOCH3,R4-R5are Ac, and R3is Z1, then Z1is not O; iii) when n is 2 or 3, R1is OBz, R2is –NHCOCH3,R4-R5are Bz, and R3is Z1, then Z1is not O; iv) when n is 3, R1is OH, R2is –NHCOCH3,R4-R5are H, and R3is Z1, and Z11is O, then Lcomprises a backbone of at least 16 consecutive atoms to a branching point; v) when n is 3, R1is Z1, where Z1is O, and R4-R5are H, then R3is 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,R4-R5are H, then R1and R3are not Z1.

[0234] In some embodiments the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ia-1):(Ia-1) wherein: R1is selected from –OH, –OC(O)R, -C(O)NHR, –Z1–*, and optionally substituted triazole, where R is optionally substituted C1-6alkyl or optionally substituted aryl; R2is selected from–NHCOCH3, –NHCOCF3,–NHCOCH2CF3, –OH, optionally substituted triazole, and –Z1–*; R3is selected from –H, –OH, –CH3, –OCH3, –OCH2CH=CH and –Z1–*; one of R1to R3is –Z1–*, wherein “ * ” represents a point of attachment of Z1to the linker (L); R4and R5are each independently selected from H, and a promoiety (e.g., an ester promoiety); Z1is a linking moiety selected from Z11, optionally substituted Z11-heteroaryl, optionally substituted Z11-aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z11is selected from -O-, -S-, NR21-, and -C(R22)2, 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.

[0235] In some embodiments of formula (Ia-1): i) when n is 3, R1is OH, R2is –NHCOCH3,R4-R5are H, and R3is Z1, then Z1is not O; ii) when n is 2 or 3, R1is OAc, R2is –NHCOCH3,R4-R5are Ac, and R3is Z1, then Z1is not O; iii) when n is 2 or 3, R1is OBz, R2is –NHCOCH3,R4-R5are Bz, and R3is Z1, then Z1is not O; iv) when n is 3, R1is OH, R2is –NHCOCH3,R4-R5are H, and R3is Z1, and Z1is O, then L comprises a backbone of at least 16 consecutive atoms to a branching point; and / or v) when n is 3, R1is Z1, where Z1is O, and R4-R5are H, then R3is not -CH3.

[0236] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ib):wherein R1, R2, R4, R5and Z1are as defined herein. In some embodiments of formula (Ib), R1is selected from –OH, –OC(O)R, and -C(O)NHR; and R2is selected from –NHCOCH3, –NHCOCF3, and – NHCOCH2CF3

[0237] In some embodiments of Formula (Ib), Z1is in an alpha configuration.

[0238] In some embodiments of Formula (Ib), Z1is in an alpha configuration and X is of the following formula:.

[0239] In some embodiments of Formula (Ib), Z1is in an alpha configuration and X is of the following formula:.

[0240] In some embodiments of Formula (Ib), Z1is in an alpha configuration and X is of the following formula:.

[0241] In some embodiments of Formula (Ib), Z1is in an alpha configuration and X is of the following formula:.

[0242] In some embodiments of Formula (Ib), Z1is in an alpha configuration and X is of the following formula:.

[0243] In some embodiments of Formula (Ib), Z1is in a beta configuration.

[0244] In some embodiments of Formula (Ib), Z1is in a beta configuration and X is of the following formula:.

[0245] In some embodiments of Formula (Ib), Z1is in a beta configuration and X is of the following formula:.

[0246] In some embodiments of Formula (Ib), Z1is in a beta configuration and X is of the following formula:.

[0247] In some embodiments of Formula (Ib), Z1is in a beta configuration and X is of the following formula:.

[0248] In some embodiments of Formula (Ib), Z1is in a beta configuration and X is of the following formula:.

[0249] In certain embodiments of formula (Ib), Z1is Z11-Ar , wherein Ar is or optionally substituted heteroaryl or optionally substituted aryl. In certain embodiments, Ar is an optionally substituted heteroaryl. In certain embodiments, the heteroaryl is a 5 or 6-membered heteroaryl. In certain embodiments, the heteroaryl is a 5-membered heteroaryl. In certain embodiments, the 5-membered heteroaryl is a triazole. In certain embodiments, the triazole is a 1,2,3-triazole moiety. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -NR21, where R21is H or (C1-3)alkyl. In certain embodiments, Z1is -C(R22)2-triazole-. In certain * * embodiments, Z1is:. In certain embodiments, Z1is:.

[0250] In certain embodiments of formula (Ib), Z1is Z11. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -NR21, where R21is H or (C1-3)alkyl.

[0251] In certain embodiments of formula (Ib), Z1is monocyclic 5 or 6-membered heteroaryl or aryl. In certain embodiments, Z1is. In certain embodiments, Z1

[0252] In certain embodiments of formula (Ib), Z1is selected from -O-, -S-, -C(R22)2-, -NR21-, -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.

[0253] In certain embodiments of formula (Ib), Z1is optionally substituted (C1-C6)alkyl. In certain embodiments of Z1the alkyl is methyl. In certain embodiments of Z1, the alkyl is ethyl. In certain embodiments of Z1, the alkyl is propyl. In certain embodiments of Z1, the alkyl is butyl. In certain embodiments of Z1, the alkyl is pentyl. In certain embodiments of Z1, the alkyl is hexyl.

[0254] In certain embodiments, the compound of formula (Ib) is selected from one of the following structures:wherein R5is independently H or a promoiety.

[0255] In some embodiments, the compound of formula (Ib) is selected from one of the following structures:wherein R5and R4independently H or a promoiety, or R5and R4are cyclically linked to form a promoiety; and n1 is an integer from 1 to 6.

[0256] In certain embodiments, the compound of formula (Ib) is selected from one of the following structures:.

[0257] In some embodiments, at least one of R4-R5is of the formula -COCH3, -COCH(CH3)2or - COC(CH3)3. In certain embodiments, at least one of R4-R5is of the formula -CH2OCOC(CH3)3. In certain embodiments, at least one of R4-R5is of the formula -COC(CH3)3or -CH2OCOC(CH3)3. In certain embodiments, R4is H and R5is selected from -COCH3, -COCH(CH3)2, -COC(CH3)3and - CH2OCOC(CH3)3. In certain embodiments, R4is H and R5is -COC(CH3)3. In certain embodiments, R4is H and R5is -CH2OCOC(CH3)3. In some embodiments, the compound of formula (Ib) is selected from one of the following structures:wherein n2 is an integer from 1 to 6.

[0258] In some embodiments of the compound of formula (Ib), R5and R4are cyclically linked to form a promoiety. In certain embodiments , the compound of formula (Ib) is selected from one of the following structures:wherein n2 is an integer from 1 to 6; and Y4is a suitable counterion.

[0259] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ic):wherein R2-R5and Z1are as defined herein.

[0260] In certain embodiments of formula (Ic), Z1is selected from -O-, -S-, -CONR21-, and optionally substituted –(C(R22)2)q-heteroaryl, wherein q is 0 or 1. In certain embodiments, Z1is -O-. In certain other cases, Z1is optionally substituted –(C(R22)2)q-triazole wherein q is 0 or 1. In certain embodiments,

[0261] In certain embodiments of formula (Ic), Z1is Z11-Ar , wherein Ar is or optionally substituted heteroaryl or optionally substituted aryl. In certain embodiments, Ar is an optionally substituted heteroaryl. In certain embodiments, the heteroaryl is a 5 or 6-membered heteroaryl. In certain embodiments, the heteroaryl is a 5-membered heteroaryl. In certain embodiments, the 5-membered heteroaryl is a triazole. In certain embodiments, the triazole is a 1,2,3-triazole moiety. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -NR21, where R21is H or (C1-3)alkyl. In certain embodiments, Z1is -C(R22)2-triazole-. In certain embodiments, Z1is:.

[0262] In certain embodiments of formula (Ic), Z1is Z11. In certain embodiments, Z11is -C(R22)2. In certain embodiments, at least one R22is H. In certain embodiments, both R22are H, and Z11is -CH2-. In certain cases Z11is -O-. In certain embodiments, Z11is -S-. In certain other cases, Z11is -NR21, where R21is H or (C1-3)alkyl.

[0263] In certain embodiments of formula (Ic), Z1is monocyclic 5 or 6-membered heteroaryl or aryl. In certain embodiments,

[0264] In certain embodiments of formula (Ic), Z1is selected from -O-, -S-, -C(R22)2-, -NR21-, -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.

[0265] In certain embodiments, the compound of formula (Ic) is the following structure:.

[0266] In certain embodiments, the compound of formula (Ic) is the following structure:.

[0267] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Id):wherein R1, R3-R5and Z1are as defined herein.

[0268] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Id’):

[0269] In some embodiments, Z1is selected from optionally substituted –(C(R22)2)q-heteroaryl, and

[0270] In some embodiments, Z1is optionally substituted –(C(R22)2)q-triazole wherein q is 0 or 1.

[0271] In some embodiments, Z1is. In some embodiments, Z1.

[0272] In some embodiments,, wherein R23is H, or C(1-3)-alkyl.

[0273] In some embodiments, Z1is -NR23CO-, wherein R23is H or C(1-3)-alkyl.

[0274] In certain embodiments of formula (Id), Z1is selected from optionally substituted – (C(R22)2)q-heteroaryl,, wherein q is 0 or 1.

[0275] In certain embodiments of formula (Id), Z1is optionally substituted –(C(R22)2)q-triazole wherein q is 0 or 1. In certain embodiments,

[0276] In certain embodiments,, wherein R23is H, or C(1-3)-alkyl.

[0277] In certain embodiments, Z1is -NR23CO-, wherein R23is H or C(1-3)-alkyl.

[0278] In certain embodiments of formula (Id), Z1is monocyclic 5 or 6-membered heteroaryl or aryl. In certain embodiments,

[0279] In certain embodiments of formula (Id), Z1is a monocyclic 5 or 6-memebered heteroaryl of one of the following structures:

[0280] In certain embodiments of formula (Id), Z1is of one of the following structures:

[0281] In certain embodiments of formula (Id), Z1is selected from -O-, -S-, -C(R22)2-, -NR21-, -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.

[0282] In certain embodiments, the compound of formula (Id) is selected from one of the following structures:wherein R6is independently H or (C1-3)alkyl.

[0283] In some embodiments of the compound of formula (Id) R3is H, such that the compound of formula (Id) has no non-hydrogen substituents at the 1-position of the sugar ring.

[0284] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ie’):wherein: R1, R4, R5and R11are as defined herein; Z2is absent or selected from -O-, -S-, NR25-, and -C(R22)2, and optionally substituted Z12-alkyl; ring A is absent or selected from a 5 or 6-membered optionally substituted aryl and a 5 or 6- membered optionally substituted heteroaryl; Z3is a linking moiety selected from Z12, optionally substituted alkyl, optionally substituted Z12- alkyl, optionally substituted Z12-heteroaryl, optionally substituted Z12-aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; and Z12is selected from -CH2O-, -O-, -S-, -NR26-, and -C(R22)2-; R25and R26are each independently selected from H, optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl), and optionally substituted acyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl.

[0285] In some embodiments of formula (Ie’), the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ie’’):

[0286] In some embodiments of formula (Ie’), the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (Ie):wherein:R1, R4, R5and R11are as defined herein; Z2is absent or selected from -O-, -S-, NR25-, and -C(R22)2, and optionally substituted Z12-alkyl; ring A is absent or selected from a 5 or 6-membered optionally substituted aryl and a 5 or 6- membered optionally substituted heteroaryl; Z3is a linking moiety selected from Z12, optionally substituted alkyl, optionally substituted Z12- alkyl, optionally substituted Z12-heteroaryl, optionally substituted Z12-aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; and Z12is selected from -CH2O-, -O-, -S-, -NR26-, and -C(R22)2-; R25and R26are each independently selected from H, optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl), and optionally substituted acyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl.

[0287] In some embodiments Z2is absent. In some embodiments, Z2is C(R22)2where R22is H or optionally substituted (C1-C3)alkyl. In some embodiments, Z2is -CH2-. In some embodiments, Z2is NR25where R25is selected from H, optionally substituted (C1-C3)alkyl and optionally substituted acyl. In some embodiments, Z2is -N(COCH3)-. In some embodiments, Z2is -NH-. In some embodiments, Z2is - S-. In some embodiments, Z2is O.

[0288] In some embodiments, the compound of formula (Ie) is of any one of formulae (If)-(Ii):wherein the A ring, R1, R4, R5, R11, Z3and R25are as defined herein.

[0289] In some embodiments of any one of formulae (Ie)-(Ii), the A ring is a 5 or 6-membered aryl or heteroaryl. In certain embodiments, the A ring is a 5-membered heteroaryl selected from selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In certain embodiments, the A ring is a 6-membered heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In certain embodiments, the A ring is triazole. In certain embodiments, the A ring is pyridine. In certain embodiments, the A ring is pyrimidine. In certain embodiments, the A ring is thiadiazole.

[0290] In some embodiments of any one of formulae (Ie)-(Ii), the A ring is absent.

[0291] In some embodiments of any one of formulae (Ie)-(Ii), the A ring is phenyl or substituted phenyl.

[0292] In some embodiments of formula (If), the A ring is a 5 or 6-membered heteroaryl. In certain cases of formula (If), the A ring is a 5-membered heteroaryl. In certain embodiments of formula (If), the A ring is triazole. In certain embodiments of (If), the A ring is absent.

[0293] In some embodiments of formula (Ig), the A ring is a 5 or 6-membered heteroaryl and R25is H. In certain embodiments of formula (Ig), the A ring is triazole. In certain embodiments of formula (Ig), the A ring is pyridine. In certain cases of formula (Ig), the A ring is pyrimidine. In certain cases of formula (Ig), the A ring is thiadiazole. In some embodiments of formula (Ig), the A ring is absent and R25is H or optionally substituted acyl. In certain embodiments, R25is -COCH3. In certain embodiments, R25is H.

[0294] In some embodiments of formula (Ih), the A ring is a 5 or 6-membered heteroaryl. In certain cases of formula (Ih), the A ring is a 5-membered heteroaryl. In certain embodiments of formula (Ih), the A ring is triazole. In certain embodiments of (Ih), the A ring is absent.

[0295] In some embodiments of formula (Ii), the A ring is a 5 or 6-membered heteroaryl. In certain cases of formula (Ii), the A ring is a 5-membered heteroaryl. In certain embodiments of formula (Ii), the A ring is triazole. In certain embodiments of (Ii), the A ring is absent.

[0296] In certain embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by any one of formulae (Ij)-(Im):(Il), and (Im) wherein: R1, R4, R5, R11, Z3and R25are as defined herein. Y1-Y3are each independently N or CR27; and R24and R27are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen.

[0297] In some embodiments of any one of formulae (Ie)-(Im), Z3is selected from -O-, -CH2O-, - OCH2-, optionally substituted -OCH2-heteroaryl, optionally substituted -OCH2-aryl, optionally substituted -CH2O-heteroaryl, and optionally substituted -CH2O-aryl.

[0298] In some embodiments, Z3is selected from:

[0299] In some embodiments of any one of formulae (Ie)-(Im), Z3is selected from -C(R22)2-, optionally substituted alkyl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea. In some embodiments, Z3is -CH2-. In some embodiments, Z3is -CH2CH2-. In some embodiments, Z3is -CH2CH2CH2-. In some embodiments, Z3is -NHSO2-(C1-3-alkyl). In some embodiments, Z3is -N(Ac)-(C1-3-alkyl).

[0300] In some embodiments of any one of formulae (Ie)-(Im), Z3is selected from -S- and -NR26-, where R26is selected from H and optionally substituted (C1-C3)alkyl.

[0301] In some embodiments of formula (Ik) at least one of Y1to Y3is N. In certain embodiments, at least two of Y1to Y3are N. In certain embodiments, Y1and Y3are N and Y2is CR25. In certain embodiments, Y1and Y2are N and Y3is CR25. In certain embodiments, Y1and Y2are CR25and Y3is N. In certain embodiments, R25is H. In certain embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3.

[0302] In certain embodiments of any one of formulae (Ie)-(Im) R1is OH.

[0303] In some embodiments of any one of formulae (Ie)-(Im), R4and R5are each H. In certain embodiments, at least one of R4-R5is a promoiety. In certain embodiments, R4and R5are cyclically linked to form a promoiety (e.g., as described herein).

[0304] In certain embodiments, the compound of formula (Ie) is selected from one of the following structures:

[0305] In certain embodiments, the compound of formula (Ie) is selected from one of the following structures:.

[0306] In certain embodiments, the compound of formula (Ie) is:.

[0307] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (In’):wherein: R1, R4, R5and Z1are as defined herein; Y1and Y2are each independently selected from -O-, -S-, NR28-, and -C(R22)2; R28is 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 (In’), Y1is connected to the sugar ring via an alpha configuration. In some embodiments of formula (In’), Y1is connected to the sugar ring via a beta configuration.

[0308] In some embodiments, the ASGPR binding moiety (X) of the compounds of this disclosure can be described by formula (In):wherein: R1, R4, R5and Z1are as defined herein; Y1and Y2are each independently selected from -O-, -S-, NR28-, and -C(R22)2; R28is 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.

[0309] In some embodiments of formula (In)-(In’) Y1is O. In certain embodiments, Y1is S. In certain embodiments, Y1is -NR28-. In certain embodiments, Y1is -C(R22)2and each R22is H.

[0310] In some embodiments of formula (In)-(In’) Y2is -NR28- where R28is H. In certain embodiments, Y2is -NR28- where R28is -C(O)R22. In certain embodiments, R22is methyl.

[0311] In some embodiments of formula (In)-(In’) the B ring is a 5 or 6-membered heterocycle. In certain embodiments, the B ring is a 5-membered heterocycle. In certain embodiments, the B ring is a 6- membered heterocycle.

[0312] In some embodiments of formula (In)-(In’) Z1is Z11, where Z11is selected from -O-, -S-, NR21-, and -C(R22)2. In certain embodiments, Z1is -O-. In certain embodiments, Z1is -S-. In certain embodiments, Z1is NR21where R21is H. In certain embodiments, Z1is -C(R22)2where each R22is H.

[0313] In some embodiments of formula (In)-(In’) Z1is optionally substituted Z11-heteroaryl or optionally substituted Z11-aryl. In some embodiments, Z1is CH2-heteroaryl or CH2-aryl. In some embodiments of formula (In)-(In’) Z1is optionally substituted amide. In some embodiments of formula (In)-(In’) Z1is optionally substituted sulfonamide. In some embodiments of formula (In)-(In’) Z1is optionally substituted urea or optionally substituted thiourea.

[0314] In some embodiments, the compound of formula (In)-(In’) has one of the following structures:.

[0315] In certain embodiments of any one of formulae (Ia)-(In), n is 1, and L comprises a linear linker having a backbone of 20 or more consecutive atoms covalently linking X to Y via Z1, such as a backbone of 25 or more consecutive atoms, or 30 or more consecutive atoms, and in certain embodiments, up to 100 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 20 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (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 certain embodiments, linker L separates X and Y (or Z1) by a chain of 30 to 60 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 31 to 60 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 32 to 60 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 33 to 60 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 34 to 60 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 35 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 36 to 50 consecutive atoms. In certain embodiments, linker Lseparates X and Y (or Z1) by a chain of 41 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 46 to 50 consecutive atoms.

[0316] In certain embodiments of any one of formulae (Ia)-(In), n is 2 or more, and L is a branched linker that covalently links 2 or more X moieties to Y via the linking moiety Z1.

[0317] In certain embodiments of any one of formulae (Ia)-(In), n is 2 or more and each branch of L comprises a linear linker of 14 or more consecutive atoms to covalently link via Z1each X moiety to a branching point of the linker L, such as 15 or more consecutive atoms, 16 or more consecutive atoms, or 17 or more consecutive atoms, and in certain embodiments, up to 50 consecutive atoms. In certain embodiments, each branch of L comprises a linear linker of 14 to 50 consecutive atoms, such as 14 to 45, 14 to 40, 14 to 35 or 14 to 30 consecutive atoms. In certain embodiments, each branch of L comprises 14 to 30 consecutive atoms, such as 14 to 29, 14 to 28, 14 to 27, 14 to 26, 14 to 25, 14 to 24, 14 to 23, 14 to 22, 14 to 21, or 14 to 20 consecutive atoms. In certain embodiments, L comprises more than 14 consecutive atoms covalently linking each X moiety (via each Z1group) to a branching point of the linker. In certain embodiments, L comprises 15 consecutive atoms separating each Z1group from a branching point of L. In certain embodiments, L comprises 16 consecutive atoms separating each Z1group from a branching point of L. In certain embodiments, L comprises 17 consecutive atoms separating each Z1group from a branching point of L. In certain embodiments, L comprises 18 consecutive atoms separating each Z1group from a branching point of L. In certain embodiments, L comprises 19 consecutive atoms separating each Z1group from a branching point of L. In certain embodiments, L comprises 20 consecutive atoms separating each Z1group from a branching point of L. In certain other cases, L comprises a liner linker of 20 or more consecutive atoms separating each Z1group from a branching point L.

[0318] In certain embodiments of any one of formulae (Ia)-(In), n is 2, and L comprises a branched linker having 14 or more consecutive atoms separating each Z1group of X from a branching point of L.

[0319] In certain embodiments of any one of formulae (Ia)-(In), n is 3, and L comprises a branched linker having 14 or more consecutive atoms separating each Z1group of X from a branching point of L.

[0320] In certain embodiments of any one of formulae (Ia)-(In), the linker L is of the formula (II) (e.g., as described herein).

[0321] In certain embodiments of any one of formulae (Ia), (Ib) or (Id)-(In), R1is OH. In certain other cases, R1is -OC(O)R. In certain embodiments, R1is -C(O)NHR, where R is an optionally substituted alkyl. In certain embodiments, R terminates in an alkenyl or an alkynyl group. In certain other cases R1is optionally substituted triazole. In certain embodiments, the triazole is of the following structure:.

[0322] In certain embodiments of (Ia)-(Ic), R2is -NHCOCH3. In certain other embodiments, R2is – NHCOCF3. In certain other embodiments, R2is –NHCOCH2CF3. In certain embodiments, R2is –OH.In certain other cases, R2is an optionally substituted triazole. In certain embodiments, the triazole in of the following structure:.

[0323] In certain embodiments when R1or R2is a substituted triazole. The triazole is a 1,2,3-trizole, and the substituent is at the 4 or 5-position. In certain embodiments, 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.

[0324] In certain embodiments of any one of formulae (Ia)-(In), at least one of R4-R5is a promoiety. In certain embodiments, the promoiety is an ester. In certain embodiments the ester of the formula - OCOCH3, -OCOCH(CH3)2or -OCOC(CH3)3. In certain embodiments, at least one of R4-R5is of the formula -COCH3, -COCH(CH3)2or -COC(CH3)3. In certain embodiments, at least one of R4-R5is of the formula -CH2OCOC(CH3)3In certain embodiments, R4is a promoiety and R5is H. In certain other cases, R5is H and R4is a promoiety. In certain embodiments, both R4and R5are both promoieties. In certain embodiments, R4and R5are cyclically linked to form a promoiety. In certain embodiments, R4and R5are cyclically linked to form a promoiety of formulae (Io) or (Ip):wherein R1-R3and Y4are as defined herein.

[0325] In certain embodiments of any one of formulae (Ia)-(In), both R4and R5are H.

[0326] In certain embodiments of formula (I), n is 2 or 3, and X is selected from one of thewherein R5and R23are independently H or (C1-3)alkyl.

[0327] In certain embodiments of formula (I), n is 1, 2 or 3, and X is selected from one of the following structures:

[0328] wherein R5and R4independently H or a promoiety, or R5and R4are cyclically linked to form a promoiety; n1 and n2 are each independently an integer from 1 to 6; and Y4is a suitable counterion. In some embodiments, Y4is sodium.

[0329] In certain embodiments of formula (I), n is 1, 2 or 3, and X is selected from one of the following structures:.

[0330] In certain embodiments of formula (I), n is 1, 2 or 3, and X is selected from one of the following structures:

[0331] In certain embodiments of formula (I), n is 1, 2 or 3, and X is selected from one of the following structures:.

[0332] In certain embodiments of formula (I), n is 1, 2 or 3, and X is the following structure:.

[0333] In certain embodiments of formula (I), n is 1, 2 or 3, and X is the following structure:.

[0334] In certain embodiments of formula (I), n is 1 and X is.

[0335] In certain embodiments of any one of formulae (Ia)-(Ip), -Z1- is linked to an -L1- moiety (e.g., of the linker of any of formulae (II), (IIa) or (IIb) described herein). In some embodiments, the subject compounds comprise a -Z1-L1- group 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.

[0336] In certain embodiments, the Z1-L1- group is, and o is 1 or 2.

[0337] In certain embodiments, the Z1-L1- groupeach R22is H, and p is 1 or 2.

[0340] In certain embodiments, the Z1-L1- group is, where r is 1-3.

[0341] In certain embodiments, the Z1-L1- groupare each independently 1-3.

[0342] In certain embodiments, the Z1-L1- group

[0343] In certain embodiments, the Z1-L1- group iare each independently is 1-3.

[0344] In certain embodiments, the Z1-L1- group is, where x is 0-3.

[0345] In certain embodiments, the Z1-L1- group-3.R21

[0346] In certain embodiments, the Z1-L1- group i, where R21is H, and z is 1-4. R21

[0347] In certain embodiments, the Z1-L1- group is, where R21is H, and z1 is 1-4.

[0348] In certain embodiments, the Z1-L1- group iis 1-3.

[0349] In certain embodiments, the Z1-L1- group i, where q is 1-3.

[0350] In certain embodiments, the subject compounds comprise a -Z1-L- group selected from:

[0351] In certain embodiments, the Z1-L1- group is, where q is 1-3. In certainembodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0352] In certain embodiments, the Z1-L1- group i.

[0353] In certain embodiments, the Z1-L1- group i.

[0354] In certain embodiments, the Z1-L1- group is.

[0355] In certain embodiments, -Z1-L1- comprises an optionally substituted -NH-heteroaryl-. In certain embodiments the heteroaryl is a triazole. In certain embodiments, the heteroaryl is pyridine. In certain embodiments the heteroaryl is pyrimidine In certain cases the heteroaryl is thiadiazole

[0356] In certain embodiments, the -Z1-L1- comprises a group selected from:wherein each R24is independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen; and each R25is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl. In certain embodiments, R25is H. In certain embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3. Exemplary ASGPR Ligands

[0357] Exemplary moieties that bind ASGPR, and synthons which can be utilized in the preparation of compounds of this disclosure that include the ASGPR ligand of interest are shown in Tables 1-5.

[0358] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1:

[0359] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1A:

[0360] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1B:

[0361] In certain embodiments, the compound of formula (Ic) is a compound shown in Table 2a:

[0362] In certain embodiments, the compound of formula (Id) is a compound shown in Table 3a:

[0363] In certain embodiments, the compound of formula (Id) is a compound shown in Table 4:

[0364] In certain embodiments, the compound of formula (Id’) is a compound shown in Table 5:

[0365] Additional exemplary moieties that bind ASGPR, and synthons which can be utilized in the preparation of compounds of this disclosure that include the ASGPR ligand of interest are shown in the tables below. The building blocks described herein, in some embodiments, can be used to prepare the compounds disclosed herein. As is appreciated by one of skill in the art, reactive functional groups present on the building blocks described herein can be reacted with complimentary functional groups on a linker moiety to bond the ASGPR binding compound X to Y.

[0366] For example, compounds of this disclosure can be prepared using the building blocks described herein as exemplified in Scheme 1. In Scheme 1, compounds of formula (I):XnLmY (I) is represented by formula (II’):(II’) wherein: n is 1 to 3; m is 1 to 20; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; each L1to L6is independently a linking moiety which together provide a linear or branched linker between Z1and Y; and X and Y are as defined herein.

[0367] Scheme I is intended to be exemplary and in no way is intended to limit the scope of the disclosure. However, as can be appreciated by one of skill in the art, the compounds of this disclosure have various L moieties which may be constructed by coupling X to one or more first portions of the linker L (e.g., an -L1- moiety) via Z1to provide exemplary ASGPR binding compound X building blocks. In Scheme 1, RM1and RM2are each independently reactive functional groups for coupling reactions (e.g., alkyne, -N3, -C(O)OH, -NH2, etc.); and Y’ is Y or a chemoselective a chemoselective ligation group capable of conjugating to an amino acid residue(s) of Y. Scheme 1

[0368] Methods for the steps and exemplary reagents and starting materials (i.e., compounds of Formula 1-1, 1-2, 1-3) are described throughout or can be derived from the art.

[0369] Exemplary building blocks (e.g., compounds of formula 1-1, 1-2, or 1-3 in Scheme 1) are shown in the tables below.

[0370] Exemplary building blocks (e.g., compounds of formula 1-1, 1-2, or 1-3 in Scheme 1) that can be used in the preparation of compounds of this disclosure that include ASGPR ligands (X) of interest are shown in Table 6.

[0371] In some embodiments of the ASGPR ligand (X) building blocks that can be used in the preparation of compounds of this disclosure, R3is H such that the ASGPR ligand (X) includes CH2at the 1-position, and R2is a linking moiety, Z1. Exemplary building blocks that can be used in the preparation of compounds of this disclosure that include ASGPR ligands (X) of interest are shown in Table 7.

[0372] In some embodiments, the ASGPR ligand (X) building blocks that can be used in the preparation of compounds of this disclosure is a bicyclic structure. Exemplary building blocks that can be used in the preparation of compounds of this disclosure that include ASGPR ligands (X) of interest are shown in Table 8.

[0373] Other building blocks that can be used and / or modified to assemble ASGPR ligands of this disclosure are shown in Tables 8A-8B.

[0374] Table 8B: Monovalent binding examples, 2R or 6R modificationsProdrugs

[0375] Aspects of this disclosure include prodrugs of any of the ASGPR binding moieties described herein that are incorporated into the compounds and conjugates of this disclosure.

[0376] 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).

[0377] Prodrugs forms of any of the ASGPR binding 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.

[0378] Pro-drugs 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 isnot. The pro-drug may also have improved solubility in pharmacological compositions over the parent drug.

[0379] Prodrug derivative of a ASGPR binding moiety generally includes a promoiety substituent at a suitable labile site of the compound. The promoiety refers to the group that is removed by enzymatic or chemical reactions, when a prodrug is converted to the drug in vivo.

[0380] In some embodiments, the promoiety is a group attached via an ester linkage to a hydroxyl group of the compound or drug.

[0381] In some embodiments, a prodrug derivative of one or more of the hydroxyl groups of the sugar ring 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 sugar (e.g., as described herein). In some embodiments, the hydroxyl groups at the 3 and 4 positions of the sugar are cyclically linked to form a promoiety (e.g., as described herein). Linker Valency

[0382] 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 Y. 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.

[0383] 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 biomolecule (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 via a linking moiety at any of the 1-, 2- or 6-positions of X. In certain embodiments, the linker L includes a backbone of 20 to 100 consecutive atoms linking the ASGPR ligand (X) to Y, such as 25 to 80, 25 to 60, or 25 to 50 consecutive atoms.

[0384] 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 Y. In such cases, the multivalent linker (L) is a branched linker or a dendrimer linker. In certain embodiments, the bifunctional molecule has one or more divalent linkers (e.g., n is 2 in Formula (I)). In certain embodiments, the bifunctional molecule has one or more trivalent linkers (e.g., n is 3 in Formula (I)).

[0385] 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 ormore, 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. Linkers

[0386] 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 certain embodiments, the linker is divalent and connects two moieties. In certain embodiments, the linker is a branched linking group that is trivalent or of a higher multivalency. In certain embodiments, 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 embodiments, 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, urea, sulfonamide, thiourea, 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.

[0387] 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 conjugtaes 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.

[0388] 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 embodiments, the linker includes one or more heteroaryl cyclic structures, e.g., a triazole, such as a 1,2,3- traizole.

[0389] 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.

[0390] In certain embodiments, linker L separates X (or Z1) and Y by a chain of 10 to 100 consecutive atoms. In certain embodiments, linker L separates X (or Z1) and Y 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.

[0391] 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. The disclosure is meant to include all such configurations of ASGPR ligand moiety (X) and linker (L).

[0392] 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;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; 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.

[0393] 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):

[0394] 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:.

[0395] In certain embodiments, the linear linker of formula (Xia) has a backbone of 10 or more consecutive atoms covalently linking X to Y 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 certain embodiments, up to 100 consecutive atoms. In certain embodiments of formula (Xia), the linear linker separates X (or Z1) and Y by a chain of 20 to 50 consecutive atoms. In certain embodiments of formula (Xa), the linear linker separates X (or Z1) and Y by a chain of 30 to 60 consecutive atoms.

[0396] 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):

[0397] 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):

[0398] 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 L1is 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–, arylene, heteroarylene, heteroalkylene, cycloalkylene, –NH–, –N(C1-6-alkyl)–, and –N(CH3)–, wherein each L10to L19of each L1is independently optionally substituted with one or more halo (e.g., 1 to 3, or 1 to 5); and 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.

[0399] 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 L1is independently selected from –C1-6-alkylene–,-CF2-, –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.

[0400] 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.

[0401] In certain embodiments, the linking moiety of formula (XII) includes one or repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In certain embodiments, 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.

[0402] 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:

[0403] 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.

[0404] 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.

[0405] 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).

[0406] 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.

[0407] 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.

[0408] In some embodiments of L2A, Z2is –O–, y is 0 and the linking moiety is of the structure L2Ai:

[0409] In some embodiments of L2B, Z2is –O– or –CO–, and the linking moiety is of the structure L2Bi or L2Bii:

[0410] In some embodthe linking moiety is of the structure L2Ci, L2Cii, L2Ciii, or L2Civ:

[0411] In some embodiments of L2D, Z2is absent and the linking moiety is of the structure L2Di:

[0412] In some embodiments, of any one of formulae L2A-L2Di, x is 1 to 6. In certain embodiments, x is 1 to 3. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3.

[0413] In some embodiments of any one of formulae L2A-L2Di, y is 0 to 6. In certain embodiments, y is 0 to 3. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3.

[0414] In certain embodiments of formula (XI), b is 1 and the linking moiety L2is selected from:

[0415] 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.

[0416] 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.

[0417] 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 fromLys, Orn, Asp, Glu, Ser, and Cys (e.g., where the sidechain, amino and carboxylic acid are each linked to an adjacent moiety).

[0418] 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; 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 –NMe–, wherein each p is independently 1 to 50.

[0419] 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.

[0420] In certain embodiments, the linking moiety of formula (XVI) includes repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In certain embodiments, 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.

[0421] 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 embodiments, 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).

[0422] 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.

[0423] 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.

[0424] 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. 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.

[0425] In some embodiments, the thiol-reactive group comprises:

[0427] 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. 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).

[0428] 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).

[0429] 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.

[0430] 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.

[0431] 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.

[0432] In some embodiments of any one of formulae (XVII) or (XVIIIa)-(XVIIIc), r is 1. In some embodiments, r is 2.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 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.

[0447] In some embodiments, the linker L includes LA:(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).

[0448] In some embodiments of LA, Z4is -NHC(O)NH-. In certain embodiments, Z4is -NHC(O)-. In certain embodiments, Z4is -C(O)NH-. In certain embodiments, Z4is -O-. In certain embodiments, Z4is -NH-.

[0449] 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.

[0450] 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.

[0451] 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).

[0452] 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.

[0453] 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.

[0454] 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).

[0455] 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.

[0456] 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.

[0457] 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.

[0458] In certain embodiments, the Z1-L1- group is, and o is 1 or 2.

[0459] In certain embodiments, the Z1-L1- group22each R is H, and p is 1 or 2.

[0462] In certain embodiments, the Z1-L1- group is, where r is 1-3.

[0463] In certain embodiments, the Z1-L1- groupare each independently 1-3.

[0464] In certain embodiments, the Z1-L1- group i

[0465] In certain embodiments, the Z1-L1- group iare each independently is 1-3.O

[0466] In certain embodiments, the Z -L - group isNN N11, where x is 0-3.

[0467] In certain embodiments, the Z1-L1- groupR21

[0468] In certain embodiments, the Z1-L1- group is, where R21is H, and z is 1-4. R21

[0469] In certain embodiments, the Z1-L1- group is, where R21is H, and z1 is 1-4.

[0470] In certain embodiments, the Z1-L1- group is, where each R22is H, and q is 1-3.

[0471] In certain embodiments, the Z1-L1- group i, where q is 1-3.

[0472] 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.

[0473] In certain embodiments, the -Z1-L1- group is, where q is 1-3. In certainembodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0474] In certain embodiments, the -Z1-L1- group is H .

[0475] In certain embodiments, -Z1-L1- includes an optionally substituted -NH-heteroarylene-. In certain embodiments, the heteroarylene is a triazole. In certain embodiments, the heteroarylene is pyridine. In certain embodiments, the heteroarylene is pyrimidine. In certain embodiments, the heteroarylene is thiadiazole.

[0476] 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 embodiments, R21is H. In certain embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3. In certain embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In certain embodiments, the fluoroalkyl is CF3.

[0477] 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 certain embodiments, 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) including a polypeptide that specifically binds an autoantibody

[0478] In some embodiments, a “linker” or linking moiety is derived from a molecule with two reactive termini, one for conjugation to a moiety of interest (Y), e.g., a biomolecule (e.g., an antibody) and the other for conjugation to a moiety (noted as X) that binds to a ASGPR cell surface receptor. When Y is a polypeptide, the polypeptide conjugation reactive terminus of the linker is in some cases a site that is capable of conjugation to the polypeptide through a cysteine thiol or lysine amine group on thepolypeptide, and so is can be a thiol-reactive group such as a maleimide or a dibromomaleimide, or as defined herein, or an amine-reactive group such as an active ester (e.g., perfluorophenyl ester or tetrafluorophenyl ester), or as defined herein.

[0479] In certain embodiments of the formula described herein, the linker L comprises 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 comprises one or more of carbon atoms, nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. In certain embodiments, the linker comprises 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 comprises a linear structure. In certain embodiments, the linker comprises a branched structure. In certain embodiments, the linker comprises a cyclic structure. In certain embodiments, the linker comprises one or more heteroaryl cyclic structures, e.g., a triazole, such as a 1,2,3-traizole.

[0480] In certain embodiments, L is between about 10 Å and about 20 Å in length. In certain embodiments, L is between about 15 Å and about 20 Å in length. In certain embodiments, L is about 15 Å in length. In certain embodiments, L is about 16 Å in length. In certain embodiments, L is about 17 Å in length.

[0481] 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, L is between about 10 Å and about 20 Å, between about 20 Å and about 30 Å, between about 30 Å and about 40 Å, between about 40 Å and about 50 Å, between about 50 Å and about 60 Å, between about 60 Å and about 70 Å, between about 70 Å and about 80 Å, between about 80 Å and about 90 Å, or between about 90 Å and about 100 Å. In certain embodiments, L is a linker between about 5 Å and about 500 Å, which comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an alkylene group linked to X, or a heteroatom linked to X. In certain embodiments, L is a linker between about 10 Å and about 500 Å, which comprises an optionally substituted arylene linked to X, or optionally substituted heteroarylene linked to X, an alkylene group linked to X, or a heteroatom linked to X. In certain embodiments, L is a linker between about 10 Å and about 400 Å, which comprises an optionally substituted arylene linked to X, or optionally substituted heteroarylene linked to X, an alkylene group linked to X, or a heteroatom linked to X. In certain embodiments, L is a linker between about 10 Å and about 200 Å, which comprises an optionally substituted arylene linked to X, or optionally substituted heteroarylene linked to X, an alkylene group linked to X, or a heteroatom linked to X.

[0482] In certain embodiments, linker L separates X and Y (or Z1) by a chain of 4 to 500 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 4 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) 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. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 6 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 11 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 16 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 21 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 26 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 31 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 36 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 41 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z1) by a chain of 46 to 50 consecutive atoms.

[0483] In certain embodiments, linker L separates X and Y (or Z1) by a chain of 4 or 5 consecutive atoms, by a chain of 6 to 10 consecutive atoms, by a chain of 11 to 15 consecutive atoms, by a chain of 16 to 20 consecutive atoms, by a chain of 21 to 25 consecutive atoms, by a chain of 26 to 30 consecutive atoms, by a chain of 31 to 35 consecutive atoms, by a chain of 36 to 40 consecutive atoms, by a chain of 41 to 45 consecutive atoms, or by a chain of 46 to 50 consecutive atoms.

[0484] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X.

[0485] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an alkylene, a heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an alkylene, a heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z1) andwhich comprises an comprises an alkylene, a heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z1) and which comprises an alkylene, a heteroatom, or optionally substituted heteroarylene linked to X.

[0486] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted triazole linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted triazole linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted triazole linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z1) and which comprises an optionally substituted triazole linked to X.

[0487] In certain embodiments, linker L is a chain of 16 to 400 consecutive atoms separating X and Y (or Z) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or a heteroatom linked to X.

[0488] It is understood that the linker may be considered as connecting directly to a Z1group of a ASGPR binding moiety (X) (e.g., as described herein). In some embodiments of any of formulae (Ia)- (Ip), 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. The disclosure is meant to include all such configurations of ASGPR binding moiety (X) and linker (L).

[0489] In some embodiments of formula (I)-(Ia), L is a linker of formula (II):wherein L1and L3are independently a linker, 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; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y; wherein: when n is 1, a is 1, and b is 0; when n is >1, a is 1, and b is 1.

[0490] In certain 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 –Nme–, wherein each p is independently1 to 50.

[0491] In certain embodiments of the linker of formula (II), any of L1-L3comprises repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In certain 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.

[0492] In certain 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 certain embodiments, the one or more 1,2,3-triazole 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).

[0493] In certain embodiments of the linker of formula (II), n is 1, such that b is 0, and the linker is of the formula (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.

[0494] In certain embodiments of the linker of formula (IIa), the linear linker has a backbone of 20 or more consecutive atoms covalently linking X to Y via Z1, such as a backbone of 25 or more consecutive atoms, or 30 or more consecutive atoms, and in certain embodiments, up to 100 consecutive atoms. In certain embodiments of formula (IIa), the linear linker separates X and Y (or Z1) by a chain of 20 to 50 consecutive atoms. In certain embodiments, the linear linker separates X and Y (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 to50 consecutive atoms, or by a chain of 29 to 50 consecutive atoms. In certain embodiments of formula (IIa), the linear linker separates X and Y (or Z1) by a chain of 30 to 60 consecutive atoms. In certain embodiments, the linear linker separates X and Y (or Z1) by a chain of 31 to 60 consecutive atoms. In certain embodiments, the linear linker separates X and Y (or Z1) by a chain of 32 to 60 consecutive atoms. In certain embodiments, the linear linker separates X and Y (or Z1) by a chain of 33 to 60 consecutive atoms. In certain embodiments, the linear linker separates X and Y (or Z1) by a chain of 34 to 60 consecutive atoms. In certain embodiments, the linear linker L separates X and Y (or Z1) by a chain of 35 to 50 consecutive atoms. In certain embodiments, the linear linker L separates X and Y (or Z1) by a chain of 36 to 50 consecutive atoms. In certain embodiments, the linear linker L separates X and Y (or Z1) by a chain of 41 to 50 consecutive atoms. In certain embodiments, the linear linker L separates X and Y (or Z1) by a chain of 46 to 50 consecutive atoms.

[0495] In certain other embodiments of formula (II), n is 2 or more, such that L1to L3together provide a branched linker between X and Y.

[0496] In certain embodiments of formula (II), n is 2 or more, and L2is selected from:wherein each x and y are independently 1 to 10.

[0497] In certain embodiments of formula (II), 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.

[0498] In certain embodiments of formula (II) or (IIa), 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, L comprises of 12 to 70, 12 to 60, 12 to 50, or 10 to 60 consecutive linear or branched chain atoms.

[0499] In certain embodiments of formula (II) or (IIa), 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.

[0500] In certain embodiments, L is of formula (Iib):wherein each L1to L5is independently a linking moiety which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 0, 1, or 2; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y; wherein: when n is 1, a is 1, and c is 0; and when n is >1, a is 1, and c is 1.

[0501] In some embodiments, L is of formula (IIb’):wherein: 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 to L1of X via Z1; and *** represents the point of attachment to Y.

[0502] In certain embodiments, L is of formula (IIb’):wherein: 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 to L1of X via Z1; and *** represents the point of attachment to Y.

[0503] In certain 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–, –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(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 acidresidue, –NH–, and –NMe–; 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, (C1-C6)alkyl, or monocyclic heteroaryl.

[0504] In certain 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(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 –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo;

[0505] In certain embodiments of the linker of formula (Iib) or (IIb’), 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 –Nme–, wherein each p is independently1 to 50.

[0506] In certain embodiments of formula (Iib) or (IIb’), -(L1)a- comprises an optionally substituted alkyl or ethylene glycol linking moiety. In certain embodiments, L1comprises an optionally substituted -C1-6-alkylene–. In certain embodiments, L1comprises an ethylene glycol linking moiety.

[0507] In certain embodiments of formula (Iib), 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 R4is independently selected from H, and optionally substituted (C1-C6)alkyl. In certain embodiments, L1is -C1-6-alkylene–, such as -C1-3-alkylene–. In certain embodiments, 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 certain embodiments, L1is –-C1-6-alkylene-NR4CO–. In certain embodiments, L1is –C1-6-alkyleneCONH–. In certain embodiments, L1is or OCH2.

[0508] In some embodiments of formula (Iib) or (IIb’), one or more L1is independently –CH2O–; –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; each r independently 0 to 20, and any of the L1moieties are optionally further substituted.

[0509] In certain embodiments of formula (Iib) or (IIb’), L2is independently selected from:is 1 to 10, u is 0 to 10, w is 1 to 10, and R4’is independently selected from H, and optionally substituted (C1-C6)alkyl. In certain embodiments, L2is –NR4’CO-C1-6-alkylene–. In certain embodiments, L2is – CONR4’-C1-6-alkylene.

[0510] In certain embodiments,

[0511] In certain embodiments,

[0512] In certain embodiments,is 1.

[0513] In certain embodiments,

[0514] In certain embodiments,

[0515] In certain embodiments, L2is -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 certain embodiments, q is 2 to 8, such as 2 to 6 , 4 to 6, or 2 to 4.

[0516] In certain embodiments of formula (Iib), L4is absent or independently selected from -C1-6-alkylene–, –(CH2CH2O)t–, –-C1-6-alkylene-NHCO–, –C1-6-alkyleneCONH–,or OCH2, wherein t is 1 to 20. In certain embodiments, L4is absent.

[0517] In certain embodiments, L4is -C1-6-alkylene–. In certain embodiments, L4is –(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 certain embodiments, L4is –-C1-6-alkylene-NHCO–. In certain embodiments, L4is –C1-6-alkyleneCONH–. In certain embodiments, L4is OCH2.

[0518] In some embodiments of the subject compounds, n is 1 and L3in formula (Iib) is absent.

[0519] In certain embodiments of the subject compounds, n is 2 or more, and L3of formula (Iib) is a branched linking moiety.

[0520] Accordingly, in some embodiments of formula (Iib) or (IIb’), L3is a branched linking moiety, e.g., a divalent, or a trivalent linking moiety. For example, an L3linking moiety can be of the one of the following general formula:.

[0521] In some embodiments of formula (Iib) or (IIb’), the branched linking moiety can be of higher valency and be described by one of the one of the following general formula:where any two L3groups can be directed linked or connected via optional linear linking moieties (e.g., as described herein).

[0522] In some embodiments of formula (Iib) or (IIb’), the branched linking moiety can include one, two or more L3linking moieties, each being trivalent moieties, which when linked together can provide for multiple branching points for covalent attachment of the ligands and be described by the following general formula:where t is 0 to 500, such as 0 to 100, 0 to 20, or 0 to 10.

[0523] In some embodiments, the branched linking moiety (e.g., L3) comprises one or more of: an amino acid residue (e.g., Asp, Lys, Orn, Glu), N-substituted amido (-N(-)C(O)-), tertiary amino, polyol (e.g., O-substituted glycerol), and the like.

[0524] In some embodiments of formula (Iib) or (IIb’), one or more L4is a branching 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 certain embodiments, each x is 1, 2 or 3, e.g., 2.

[0525] In some embodiments of formula (Iib) or (IIb’), L5is selected from –CH2O–; –(CH2CH2O)t–,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 L5moieties are optionally further substituted.

[0526] In certain embodiments, L5is –CH2O–. In certain embodiments, L5is –(CH2CH2O)t–, where t is 1 to 20, such as 1-15, 1-12, 1-10, 1-8, 1-6, or 1 to 4. In certain embodiments, L5is –NR4CO–, where R4is H, or optionally substituted (C1-C6)alkyl. In certain embodiments, L5is -C1-6-alkylene–.

[0527] In certain embodiments, L5is, where r is 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0528] In certain embodiments,each r is independently 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5 and R13is H, or optionally substituted (C1-C6)alkyl.

[0529] In certain embodiments,20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5 and R13is H, or optionally substituted (C1-C6)alkyl.

[0530] In certain embodiments,20, such as 0 to 15, 0 to10, 0 to 8, or 0 to 5, and R13is H, or optionally substituted (C1-C6)alkyl.

[0531] In certain embodiments,20, such as 0 to 15, 0 to 10,0 to 8, or 0 to 5, and R13is H, or optionally substituted (C1-C6)alkyl.

[0532] In certain embodiments,each r is independently 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0533] In certain embodiments, L5is , where each r is independently 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0534] In certain embodiments, L5is, where each r is independently 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0535] In certain embodiments, L5is, where each r is independently 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0536] In certain embodiments, L5is, where r is 0 to 20, such as 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0537] In some embodiments of formula (Iib) or (IIb’), L5comprises 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.

[0538] In some embodiments of formula (Iib) or (IIb’), L1-L5comprises one or more of the following units: Ra, where Rais (C1-C6)alkyl or substituted (C1-C6)alkyl, e.g., a (C1-C6)alkyl optionally substituted with amine, a tertiary amine, optionally substituted alkoxy, optionally substituted carboxyl, optionally substituted aryl, or optionally substituted heteroaryl. It is understood that Racan be linked to a M6PR binding moiety.

[0539] 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 ASGPR binding moiety (e.g., as described herein). It is understood that ASGPR 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 certain embodiments, 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.

[0540] In certain embodiments of formula (Iib) or (IIb’), a is 1. In certain embodiments, at least one of b, c, d, and e is not 0. In certain embodiments, b is 1 or 2. In certain embodiments, c is 1 or 2. In certain embodiments, e is 1 or 2. In certain embodiments, b, d and e are independently 1 or 2. In certain embodiments, a, b, d, and e are each 1, and c is 0.

[0541] In certain embodiments of formula (II), (IIa) or (Iib), 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 certain 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.

[0542] In certain embodiments of formula (II), (IIa) or (Iib), 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 certain embodiments of formula (II), (IIa) or (Iib), 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.

[0543] In certain embodiments, ASGPR binding compounds of this disclosure having a particular configuration with a linker of desired valency and length can specifically bind with high affinity to both the ASGPR and a target simultaneously, and exhibit high uptake activity of a target. The conjugates of this disclosure can thus provide for sequestering of a target protein in the cell’s lysosome and degrading of the target protein. For example, conjugates of trivalent ASGPR binding compounds with 14 or more atoms between the ASGPR binding moiety (e.g., Z1group) and the branching point of the linker can exhibit superior uptake of cells as compared to conjugates of trivalent ASGPR binding compounds with shorter linkers (e.g., linkers less than 14 atoms) between the ASGPR binding compound (e.g., Z1group) and the branching point. For example, In certain embodiments, a conjugate having a 1-triazole moiety and a short linkage (e.g., 6 atoms) from the ASGPR ligand to the branching point of the ligand (I-157, linker length of 6 atoms to branching point) exhibited less uptake activity in HepG2 cells than the conjugate having a 1-triazole moiety and a longer linkage (e.g., 14 atoms) from the ASGPR ligand to the branching point (I-143, length of 14 atoms) (see, e.g., FIG.2A). Based on this discovery, described herein are multivalent ASGPR binding compounds having a certain linker length range between the ASGPR binding moiety and the linker branching point which provides desirable binding and cellular uptake of a bound target.

[0544] Further, conjugates of trivalent ASGPR binding compounds (e.g., compounds of formula (I) where n = 3) can exhibit superior uptake activity in cells as compared to conjugates of divalent or monovalent ASGPR binding compounds (e.g., compounds of formula (I) where n = 2 or 1). In certain embodiments, conjugate (I-124, n = 3) showed superior uptake activity in HepG2 cells as compared to the divalent conjugate (I-144, n = 2) (see, e.g., FIG.2B).

[0545] Still further, conjugates of multivalent ASGPR binding compounds with 12 or more atoms between the branching point of the linker and the Y moiety of interest can exhibit superior uptake of cells as compared to conjugates of multivalent ASGPR binding compounds with shorter linkers (e.g., linkers less than 12 atoms) between the branching point of the linker and the Y moiety of interest. In certain embodiments, conjugates of ASGPR binding compounds having more than 12 atoms between the branching point of the linker and Y exhibit comparable uptake activity. For example, it was observed that conjugates having longer linkers between the ASGPR linker and Y (e.g., conjugates of compounds I-137, having 81 atoms between the branching point and Y; and I-129, having 33 atoms between the branching point and Y) exhibit comparable activity to a reference conjugate (e.g., conjugate of compound I-124, having 12 atoms between the branching point and Y) (see, e.g., FIG.2B).

[0546] As such, in certain embodiments where the linker of formula (II), or (IIb’), or (Iib) is a branched linker, each branch of the linker comprises a linear linker of 14 or more consecutive atoms to covalently link via Z1each X moiety to a branching point of the linker. In certain embodiments, each branch of the linker comprises a linear linker of 15 or more consecutive atoms to the branching point. In certain embodiments, each branch of the linker comprises a linear linker of 16 or more consecutive atoms to the branching point. In certain embodiments, each branch of the linker comprises a linear linker of 17 or more consecutive atoms to the branching point. In certain embodiments, each branch of the linker comprises a linear linker of 18 or more consecutive atoms to the branching point. In certain embodiments, each branch of the linker comprises a linear linker of 19 or more consecutive atoms to the branching point.

[0547] In certain embodiments of formula (II) , or (IIb’), or (Iib), the linker is a branched linker comprising branches covalently linking via Z1each X moiety to a branching point of the linker, and a linear linker covalently linking the branching point to Y. In certain embodiments, the linear linker covalently linking the branching point to Y is 12 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 15 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 20 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 25 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 30 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 40 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 50 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 60 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 70 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branching point to Y is 80 or more consecutive atoms. Exemplary linkers and linking moieties

[0548] Exemplary linkers and linking moieties that can be utilized in the preparation of compounds of this disclosure (e.g., that link the ASGPR ligand (X) to the moiety of interest (Y)) are shown in Tables 9-11.

[0549] In certain embodiments, the linker is a linear linker or linking moiety as shown in Table 9.

[0550] Table 10 includes various linker component synthetic precursors (e.g., linear and branched linker precursors) that can be utilized in the preparation of the subject compounds.

[0551] In certain embodiments, the linker is a branched linker or linking moiety as shown in Table 11.Chemoselective ligation group

[0552] In certain embodiments of formula (I), Y is a chemoselective ligation group, or a precursor thereof. A chemoselective ligation group is a group having a reactive functionality or function group capable of conjugation to a compatible group of a second moiety. 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), amine-active ester coupling, 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.

[0553] 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 or PFP ester or thioester), haloacetamide (e.g., iodoacetamide or bromoacetamide), chloroacetyl, bromoacetyl, bromomethyl-aryl, chloromethyl-aryl, bromomethyl- heteroaryl, chloromethyl-heteroaryl, 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.

[0554] In some instances, 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 (e.g., copper catalyzed Click chemistry conditions).

[0555] 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.

[0556] In some instances, Y is a precursor of the reactive functionality or function group capable of conjugation to a compatible group of a second moiety. For example, a carboxylic acid is a precursor of an active ester chemoselective ligation group.

[0557] In certain embodiments of formula (I), Y is a reactive moiety capable forming a covalent bond to a polypeptide (e.g., with an amino acid sidechain of a polypeptide having a compatible reactive group). The reactive moiety can be referred to as a chemoselective ligation group.

[0558] In certain embodiments of formula (I), Y is a thio-reactive chemoselective ligation group (e.g., as described in Table 12). In certain embodiments, Y can produce a residual moiety Z resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of a protein, e.g., Ab.

[0559] In certain embodiments of formula (I), Y is a Cys-reactive chemoselective ligation group (e.g., a maleimide derivative as described in table 12). In certain embodiments, the Cys-reactive chemoselective ligation group includes a maleimide group. In some embodiments, the chemoselective ligation group includes a maleimide group of Table 12, e.g., mal-1 to mal-7.

[0560] In certain embodiments of formula (I), Y is an amino-reactive chemoselective ligation group (e.g., as described in Table 12). In certain embodiments, Y can produce a residual moiety Z resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) a protein, e.g., Ab.

[0561] In certain embodiments of formula (I), Y is a Lys-reactive chemoselective ligation group (e.g., an active ester as described in table 12). In some embodiments the Lys-reactive chemoselective ligation group is a PFP ester.

[0562] Exemplary chemoselective ligation groups, and synthetic precursors thereof, which may be adapted for use in the compounds of this disclosure are shown in Table 12.

[0563] In Table 12, the can represent a point of attachment of Y to a linking moiety or a linked X moiety.

[0564] Table 12a shows exemplary residual moieties, wherein the “***” indicates the point of attachment of Y.Exemplary Compounds with Chemoselective Ligation Group

[0565] This disclosure includes compounds of formula (I) which can include: (1) one or more particular ASGPR ligand (X) (e.g., as described herein, such as ligands X1-X20 of Tables 1-4) or a particular ASGPR ligand (X) (e.g., as described herein), (2) a linker including one or more linking moieties (e.g., as described herein, such as any one or more of the linking moieties of Tables 8 to 10); and (3) a chemoselective ligation group (Y) e.g., as described herein, such as any one of the groups of Table 12).

[0566] In some embodiments, the chemoselective ligation group can be tailored to provide linkages which confer additional benefits, such as, but not limited to, stability of the conjugate.

[0567] In some embodiments, the chemoselective ligation group comprises:

[0568] Table 13 illustrates various monovalent ligand-linker compounds for use in conjugates of the disclosure.

[0569] Tables 14 illustrates various multivalent ligand-linker compounds for use in conjugates of the disclosure.

[0570] In some embodiments, the compound of formula (I) is an ASGPR binding compound as described in International Application No. WO / 2023288033, filed July 14, 2022, and the disclosure of which is herein incorporated by reference in its entirety.

[0571] The following Tables 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 13-23. For example, conjugates where the chemoselective ligation group has been conjugated to a different Y, such as a biomolecule or a small molecule ligand for a target protein.

[0572] 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.

[0573] 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. Other Exemplary Compounds

[0574] Table 19 illustrates exemplary ASGPR binding compounds of this disclosure that include a binding moiety, or a precursor thereof.

[0575] Table 20 illustrates exemplary trivalent ASGPR binding intermediate compounds of this disclosure including X groups of formula (Ie).

[0576] Table 21 illustrates exemplary monovalent ASGPR binding intermediate compounds of this disclosure that include a promoiety and X groups that are of formula (Ib).

[0577] Table 22 illustrates exemplary ASGPR binding intermediate compounds of this disclosure that include X groups that are of formula (In).

[0578] Table 23 illustrates exemplary ASGPR binding intermediate compounds.

[0579] 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. Conjugates with Moiety of Interest

[0580] The compounds of this disclosure can be referred to as a conjugate, e.g., when the moiety of interest (Y) is a molecule (e.g., as described herein). Such conjugates can be prepared by conjugation of a chemoselective ligation group of any one of the compounds described herein with a compatible reactive group of a molecule Y. The compatible group of the molecule Y can be introduced by modification prior to conjugation, or can be a group present in the molecule. Alternatively, such conjugates can be preparedde novo, e.g., via modification of a Y molecule of interest starting material to introduce a linker, e.g., to which a ligand X can be attached.

[0581] In some embodiments, the moiety of interest to which the ASGPR binding moiety is linked is a biomolecule. In some embodiments, the moiety of interest is a biomolecule. In some embodiments, the biomolecule is selected from peptide, protein, polynucleotide, polysaccharide, glycan, glycoprotein, lipid, enzyme, antibody, and antibody fragment. In some embodiments, the moiety of interest Y is selected from small molecule, small molecule drug, chemotherapeutic agent, cytotoxic agent, diagnostic agent, dye, fluorophore, and the like.

[0582] In preferred embodiments, the moiety of interest is a molecule that specifically binds to a target of interest, i.e., a target-binding moiety. In such embodiments, the conjugates of this disclosure can provide for cellular uptake of the target after it non-covalently binds to the conjugate, and / or degradation. In certain embodiments, conjugates of this disclosure having a particular configuration of ASGPR binding moiety of a desired affinity, with a linker of desired valency and length can specifically bind with high affinity to both the ASGPR and the target simultaneously. The conjugates of this disclosure can thus provide for sequestering of a target protein in the cell’s lysosome and degrading of the target protein.

[0583] In some embodiments, the moiety of interest is a molecule that does not bind to an extracellular target, but rather is a molecule that is itself desirable to deliver intracellularly. In some embodiments, the moiety of interest is selected from enzymes (e.g., lysosomal enzyme), a nanoparticle, a viral composition (e.g., viral particle), therapeutic protein, therapeutic antibodies and cytotoxic agents.

[0584] In some embodiments, the moiety of interest is a lysosomal enzyme for delivery to a cell for use in enzyme replacement therapy, such as acid alpha-glucosidase (GAA). Lysosomal enzymes of interest that may be adapted for use in conjugates of this disclosure include, but are not limited to, acid alpha-glucosidase, acid beta-galactosidase-1, acid sphingomyelinase, alpha-D-mannosidase, alpha- fucosidase, alpha-galactosidase A, alpha-glucosaminide acetyltransferase, alpha-glucosidase, alpha-L- iduronidase, alpha-N-acetylgalactosaminidase, alpha-acetylglucosaminidase, alpha-D-neuraminidase, arylsulfatase A, arylsulfatase B, beta-galactosidase, beta-glucuronidase, beta-mannosidase, cathepsin D, cathepsin K, ceramidase, cystinosine, ganglioside activator GM2, galactocerebrosidase, glucocerebrosidase, heparan sulfatase, hexosaminidase A, hexosaminidase B, hyaluronidase, iduronate-2- sulfatase, LAMP2, lysosomal acid lipase, N-acetylglucosamine-1-phosphotransferase, N- acetylgalactosamine 6-sulfatase, N-acetylglucosamine-1-phosphotransferase, N-acetylglucosamine-6- sulfate sulfatase, N-aspartyl-beta-glucosaminidase, palmitoyl-thioesterase-1, acid phosphatase, protected protein / cathepsin A (PPCA), sialin, tripeptidyl-peptidase 1.

[0585] Aspects of this disclosure include compounds of formula (I) where the moiety of interest Y is a selected from small molecule, dye, fluorophore, monosaccharide, disaccharide, trisaccharide, and biomolecule. In some embodiments, Y is a small molecule that specifically binds to a target molecule, such as a target protein.

[0586] In some embodiments of the compounds of this disclosure, Y is a biomolecule. In some embodiments, the biomolecule is selected from protein, polynucleotide, polysaccharide, peptide, glycoprotein, lipid, enzyme, antibody, and antibody fragment. In some embodiments, Y is a biomolecule that specifically binds to a target molecule, such as a target protein.

[0587] The compounds of this disclosure can, in certain embodiments, be referred to as a conjugate, e.g., when the moiety of interest (Y) is a molecule such as a biomolecule, where the conjugate can be derived from a conjugation or coupling reaction between a chemoselective ligation group and a compatible group on the biomolecule. In some embodiments, the biomolecule is conjugated via a naturally occurring group of the biomolecule. In some embodiments, the biomolecule is conjugated via a compatible functional group that is introduced into the biomolecule prior to chemoselective conjugation. In such embodiments, the linking moiety between X and Y incorporates the residual group (e.g., Z) that is the product of the chemoselective ligation chemistry.

[0588] Aspects of this disclosure include compounds of formula (I) where the moiety of interest Y is a moiety that specifically binds to a target molecule, such as a target protein. The target protein can be the target protein is a membrane bound protein or an extracellular protein. In some embodiments of the compounds of this disclosure, Y is a biomolecule that specifically binds to a target protein. This disclosure provides conjugates of the particular ASGPR binding compounds and conjugates. In some embodiments, the conjugate includes a moiety of interest Y that specifically binds a target protein, and can find use in methods of cell uptake or internalization of the target protein via binding to the cell surface receptor, and eventual degradation of the target protein.

[0589] In some embodiments, Y is an aptamer that specifically binds to a target molecule, such as a target protein. In some embodiments, Y is a peptide or protein (e.g., peptidic binding motif, protein domain, engineered polypeptide, or glycoprotein) that specifically binds to a target molecule, such as a target protein. In some embodiments, Y is an antibody or antibody fragment that specifically binds to a target molecule, such as a target protein. In some embodiments, Y is a polynucleotide or oligonucleotide that specifically binds to a target molecule, such as a target protein or a target nucleic acid.

[0590] In some embodiments, one Y biomolecule is conjugated to a single moiety (X) that specifically binds to the cell surface receptor (e.g., ASGPR) via a linker L. In some embodiments, one Y biomolecule is conjugated to one (Xn-L)- group, wherein when n =1 the (Xn-L)- group is referred to as monovalent, and when n > 1 the (Xn-L)- group is referred to as multivalent (e.g., bivalent, trivalent, etc.). It is understood that in some embodiments of formula (I), where Y is a biomolecule, Y can be conjugated to two or more (Xn-L)- groups, wherein each (Xn-L)- group may itself be monovalent or multivalent (e.g., bivalent, trivalent, etc.). In such embodiments, the ratio of linked (Xn-L)- groups to biomolecule can be referred to as 2 or more.

[0591] In some embodiments, Y is a moiety that specifically binds the target protein and the compound is a conjugate of formula (III’):wherein: n is 1 to 20; m is an average loading of 1 to 80; each X is a moiety that binds to a cell surface ASGPR; each L is a linker; each Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group to a compatible group of Y; and Y is a moiety of interest binds the target protein.

[0592] In some embodiments of formula (III’), Y is an antibody or an antibody fragment.

[0593] In some embodiments, Y is an antibody or antibody fragment that specifically binds the target protein and the compound is a conjugate of formula (III):wherein: n is 1 to 20; m is an average loading of 1 to 80; each X is a moiety that binds to a cell surface ASGPR; each L is a linker; each Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group to a compatible group of Ab; and Ab is the antibody or antibody fragment that specifically binds the target protein.

[0594] In certain embodiments of the conjugate of formula (III), n is 1 to 6. In certain cases, n is 1, such that the antibody is conjugated to a monovalent ligand and the linker is of the formula (IIa) (e.g., as described herein). In certain cases, n is at least 2, such that the antibody is conjugated to a multivalent ligand. In certain cases, n is 2. In certain cases n is 3.

[0595] In certain embodiments of the conjugate of formula (III), Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation moiety of Table 12 (e.g., Table 12a).

[0596] In certain embodiments of formula (III) or (III’), each X is independently of formula (Ib) (e.g., as described herein). In certain embodiments, each X is independently selected from a compound of Table 1. In certain embodiments, each X is independently selected from one of the following compounds:.

[0597] In certain embodiments of formula (III) or (III’), each X is independently selected from one of the following compounds:wherein R5and R4independently H or a promoiety, or R5and R4are cyclically linked to form a promoiety; n1 and n2 are each independently an integer from 1 to 6; and Y4is a suitable counterion. In some embodiments, Y4is sodium.

[0598] In certain embodiments of formula (III) or (III’), n is 1 and X is:.

[0599] In certain other embodiments of formula (III) or (III’), each X is independently of the formula (Ic) (e.g., as described herein). In certain embodiments, each X is independently selected from a compound of Table 2 or 2a.

[0600] In certain other embodiments of formula (III) or (III’), each X is independently of formula (Id) (e.g., as described herein). In certain embodiments, each X is independently selected from a compound of Table 3 or 3a. In certain embodiments, each X is independently selected from a compound of Table 4. In certain embodiments, each X is a compound of Table 5.

[0601] In certain embodiments of formula (III), each X is independently selected from one of the following compounds:

[0602] In certain embodiments of the conjugate of formula (III) or (III’), L is a linker of formula (II) (e.g., as described herein).

[0603] In certain embodiments of the conjugate of formula (III) or (III’), n is 1 to 6. In certain embodiments, n is 1, such that the antibody is conjugated to a monovalent ASGPR ligand and the linker is of the formula (IIa) (e.g., as described herein). In certain embodiments, n is at least 2, such that the antibody is conjugated to a multivalent ASGPR ligand. In certain embodiments, n is 2. In certain cases n is 3.

[0604] In certain embodiments of the conjugate of formula (III) or (III’), Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation moiety of Table 9.

[0605] In certain embodiments of the conjugate of formula (III) or (III’), 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 Ab. In certain embodiments, the thiol-reactive chemoselective ligation group is a maleimide derivative.

[0606] In certain other embodiments of the conjugate of formula (III), 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 Ab. In certain embodiments, the amine-reactive chemoselective ligation group is an active ester. In certain embodiments, the active ester is a PFP ester.

[0607] In certain embodiments, the conjugates with their linker structures described herein have weaker binding affinity to cell surface receptors. Without being bound to any particular mechanism or theory, such weaker binding affinity may be corrected to longer half-life of the conjugates, and may be useful for tuning (e.g., modifying) the pharmacokinetic properties of the conjugates described herein. In certain embodiments, such weaker binding conjugates still have sufficiently robust uptake.

[0608] Conjugates of a polypeptide, e.g., an antibody (Ab) and compound (Xn-L-Y) may be made using a variety of bifunctional protein coupling agents such as BMPS, EMCS, GMBS, HBVS, LC- SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate). The present disclosure further contemplates that the conjugates described herein may be prepared using any suitable methods as disclosed in the art (see, e.g., Bioconjugate Techniques (Hermanson ed., 2d ed.2008)).

[0609] In certain embodiments of the conjugates described herein, L is bonded through an amide bond to a lysine residue of the polypeptide. In certain embodiments of the conjugates described herein, L is bonded through a thioether bond to a cysteine residue of the polypeptide. In certain embodiments of the conjugates described herein, L is bonded through an amide bond to a lysine residue of Ab. In certain embodiments of the conjugates described herein, L is bonded through a thioether bond to a cysteine residue of Ab. In certain embodiments of the conjugates described herein, L is bonded through two thioether bonds to two cysteine residues of Ab, wherein the two cysteine residues are from an opened cysteine-cysteine disulfide bond in Ab. In certain embodiments, the opened cysteine-cysteine disulfide bond is an interchain disulfide bond.

[0610] In certain embodiments of the conjugates described herein, when L is bonded through an amide bond to a lysine residue of a polypeptide (e.g., an antibody), m is an integer from 1 to 80. In certain embodiments of the conjugates described herein, when L is bonded through a thioether bond to a cysteine residue of P, m is an integer from 1 to 8.

[0611] 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 antigen-binding or pharmacokinetics.In certain embodiments, for example, conjugation may comprise engineering of cysteine substitutions at positions on the polypeptide or antibody, e.g., on the heavy and / or light chains of an antibody that provide reactive thiol groups and do not disrupt polypeptide or antibody folding and assembly or alter polypeptide or antigen binding (see, e.g., Junutula et al., J. Immunol. Meth.2008; 332: 41-52; and Junutula et al., Nature Biotechnol.2008; 26: 925-32; see also WO2006 / 034488 (herein incorporated by reference in its entirety)). In another non-limiting approach, selenocysteine is cotranslationally 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.

[0612] Loading of the compounds of formula (I) to the polypeptides (e.g., antibodies) described herein is represented by “m” in formula (III), and is the average number of units of “Xn-L-” or “Xn-” per conjugate molecule. As used herein, the term “DAR” refers to the average value of “m” or the loading of the conjugate. The number of “X” moieties (e.g., folate moieties) per each unit of “Xn-L-” or “Xn-” is represented by “n” in formula (III). As used herein, the term “valency” or “valencies” refers to the number of “X” moieties per unit (“n”). It will be understood that loading, or DAR, is not necessarily equivalent to the number of “X” moieties per conjugate molecule. 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 four “Xn-L-” units per conjugate (m = 4), there will be 2 x 4 = 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. As used herein, the term “total valency” or “total valencies” refers to the total number of “X” moieties per conjugate molecule (n x m; total valency).

[0613] DAR (loading) may range from 1 to 80 units per conjugate. The conjugates provided herein may include collections of polypeptides, antibodies or antigen binding fragments conjugated with a range of units, e.g., from 1 to 80. The average number of units per polypeptide or antibody in preparations of the conjugate from conjugation reactions may be characterized by conventional means such as mass spectroscopy. The quantitative distribution of DAR (loading) in terms of m may also be determined. Insome instances, separation, purification, and characterization of homogeneous conjugate where m is a certain value may be achieved by means such as electrophoresis.

[0614] In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 80. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 70. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 60. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 50. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 40. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 35. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 30. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 25. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 20. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 18. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 15. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 4. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 3. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 4. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 4.

[0615] In certain embodiments, the DAR 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; 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.

[0616] In certain embodiments, the DAR 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 DAR 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.

[0617] In some embodiments, the DAR 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 DAR 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 DAR for a conjugate provided herein is about 1. In some embodiments, the DAR for a conjugate provided herein is about 2. In some embodiments, the DAR for a conjugate provided herein is about 3. In some embodiments, the DAR for a conjugate provided herein is about 4. In some embodiments, the DAR for a conjugate provided herein is about 3.8. In some embodiments, the DAR for a conjugate provided herein is about 5. In some embodiments, the DAR for a conjugate provided herein is about 6. In some embodiments, the DAR for a conjugate provided herein is about 7. In some embodiments, the DAR for a conjugate provided herein is about 8. In some embodiments, the DAR for a conjugate provided herein is about 9. In some embodiments, the DAR for a conjugate provided herein is about 10. In some embodiments, the DAR for a conjugate provided herein is about 11. In some embodiments, the DAR for a conjugate provided herein is about 12. In some embodiments, the DAR for a conjugate provided herein is about 13. In some embodiments, the DAR for a conjugate provided herein is about 14. In some embodiments, the DAR for a conjugate provided herein is about 15. In some embodiments, the DAR for a conjugate provided herein is about 16. In some embodiments, the DAR for a conjugate provided herein is about 17. In some embodiments, the DAR for a conjugate provided herein is about 18. In some embodiments, the DAR for a conjugate provided herein is about 19. In some embodiments, the DAR for a conjugate provided herein is about 20.

[0618] In some embodiments, the DAR for a conjugate provided herein is about 25. In some embodiments, the DAR for a conjugate provided herein is about 30. In some embodiments, the DAR for a conjugate provided herein is about 35. In some embodiments, the DAR for a conjugate provided herein is about 40. In some embodiments, the DAR for a conjugate provided herein is about 50. In some embodiments, the DAR for a conjugate provided herein is about 60. In some embodiments, the DAR for a conjugate provided herein is about 70. In some embodiments, the DAR for a conjugate provided herein is about 80.

[0619] In certain embodiments, fewer than the theoretical maximum of units are conjugated to the polypeptide, e.g., antibody, 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, antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug unit; indeed most cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, an antibody 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, an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groupssuch as lysine or cysteine. In some embodiments, the compound is conjugated via a lysine residue on the antibody. In some embodiments, the linker unit or a drug unit is conjugated via a cysteine residue on the antibody.

[0620] In certain embodiments, the amino acid that attaches to a unit is in the heavy chain of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the light chain of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the hinge region of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the Fc region of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the constant region (e.g., CH1, CH2, or CH3 of a heavy chain, or CH1 of a light chain) of an antibody. In yet other embodiments, the amino acid that attaches to a unit or a drug unit is in the VH framework regions of an antibody. In yet other embodiments, the amino acid that attaches to unit is in the VL framework regions of an antibody.

[0621] The DAR (loading) 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 (herein incorporated by reference in its entirety)).

[0622] 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 units attached to a polypeptide, for example, an antibody. 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 DAR (loading) value may be isolated from the conjugation mixture by electrophoresis or chromatography.

[0623] In certain embodiments of the conjugate of formula (III) m is 1 to 20, such as 2 to 10, 2 to 8, or 2 to 6. In certain embodiments, m is 10 or less. In certain embodiments, m is 2 to 8. In certain embodiments, m is 2 to 6. In certain embodiments, m is an average loading of about 4.

[0624] 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 units attached to a polypeptide, for example, an antibody. 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 DAR (loading) value may be isolated from the conjugation mixture by electrophoresis or chromatography. Target-binding Moieties

[0625] The target-binding moiety can be any moiety that has an affinity for the target of less than 1 µM, such as 300nM or less, 100nM or less, 30nM or less, 10nM or less, 3nM or less, or 1nM or less, e.g., as measured in an in vitro binding assay.

[0626] In some embodiments, the target-binding moiety is a biomolecule. In some embodiments, the target-binding moiety is a biomolecule that specifically binds to a target protein. In some embodiments, the biomolecule is selected from peptide, protein, polynucleotide, polysaccharide, glycan, glycoprotein, lipid, enzyme, antibody, and antibody fragment.

[0627] In some embodiments, the target-binding moiety is a polypeptide (e.g., peptide or protein binding motif, protein domain, engineered polypeptide, or glycoprotein) that specifically binds to a target molecule, such as a target protein. In some embodiments, the target-binding moiety of the bifunctional compound includes a polypeptide that binds to a soluble (e.g., secreted) target protein of interest. In some embodiments, the target-binding is a polypeptide ligand that includes a receptor ligand, or a receptor-binding portion or fragment of the receptor ligand, that binds a target cell surface receptor. Target-binding polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of naturally occurring amino acids, non-naturally occurring amino acids, and / or amino acid modifications or analogs known in the art. Useful modifications include, e.g., N-terminal acetylation, amidation, methylation, etc.

[0628] In some embodiments, the target-binding moiety is a polynucleotide that specifically binds to a target molecule, such as a target protein or a target nucleic acid. The terms polynucleotide and nucleic acid can be used interchangeably. In some embodiments, the target-binding moiety is a nucleic acid aptamer that specifically binds to a target molecule, such as a target protein.

[0629] In some embodiments, the target-binding moiety is a glycan. In some embodiments, the target-binding moiety is a glycan epitope for an autoantibody. Antibodies

[0630] In some embodiments, the target-binding moiety is an antibody or antibody fragment that specifically binds to a target moiety, such as a target protein.

[0631] The ASGPR binding moiety can be site-specifically covalently linked to the antibody or antibody fragment, via an optional linking moiety. ASGPR binding moiety can be covalently linked to the antibody or antibody fragment via a site-specific cysteine modification on the antibody or antibody fragment (e.g., L443C) and a thiol-reactive chemoselective ligation group. ASGPR binding moiety can be covalently linked to the antibody or antibody fragment via one or more lysine residues of the antibody or antibody fragment and an amine-reactive chemoselective ligation group.

[0632] In some embodiments, the bifunctional conjugate of this disclosure includes an antibody (Ab). In some embodiments, Ab is a monoclonal antibody. In some embodiments, Ab is a human antibody. In some embodiments, Ab is a humanized antibody. In some embodiments, Ab is a chimeric antibody. In some embodiments, Ab is a full-length antibody that includes two heavy chains and two light chains. In some embodiments, Ab is an IgG antibody, e.g., is an IgG1, IgG2, IgG3 or IgG4 antibody. In some embodiments, Ab is a single chain antibody. In some embodiments, the target- binding moiety is an antigen-binding fragment of an antibody, e.g., a Fab fragment.

[0633] In some embodiments, the antibody or antibody fragment specifically binds to a cancer antigen.

[0634] In some embodiments, the antibody or antibody fragment specifically binds to a hepatocyte antigen.

[0635] In some embodiments, the antibody or antibody fragment specifically binds to an antigen presented on a macrophage.

[0636] In some embodiments, the antibody or antibody fragment specifically binds to an intact complement or a fragment thereof. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within intact complement or a fragment thereof.

[0637] In some embodiments, the antibody or antibody fragment specifically binds to a cell surface receptor. In some embodiments, the antibody or antibody fragment specifically binds to a cell surface receptor ligand.

[0638] In some embodiments, the antibody or antibody fragment specifically binds to an epidermal growth factor (EGF) protein, e.g., a human EGF. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within an EGF protein.

[0639] In some embodiments, the antibody or antibody fragment specifically binds to an epidermal growth factor receptor (EGFR) protein, e.g., a human EGFR. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within an EGFR protein. In some embodiments, the antibody or antibody fragment comprises the CDRs present in cetuximab. In some embodiments, the antibody or antibody fragment includes the variable light chain and variable heavy chain present in cetuximab. In some embodiments, the antibody is cetuximab. In some embodiments, the antibody or antibody fragment includes the CDRs present in matuzumab. In some embodiments, the antibody or antibody fragment includes the variable light chain and variable heavy chain present in matuzumab. In some embodiments, the antibody is matuzumab.

[0640] In some embodiments, the antibody or antibody fragment specifically binds to vascular endothelial growth factor (VEGF) protein, e.g., human VEGF protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within a VEGF protein.

[0641] In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor receptor (VEGFR) protein, e.g., human VEGFR protein. In some embodiments, the antibody or antibody fragment specifically binds vascular endothelial growth factor receptor 2 (VEGFR2) protein, e.g., a human VEGFR2 protein. In some embodiments, the antibody or antibody fragment specifically binds a vascular endothelial growth factor receptor 3 (VEGFR3) protein, e.g., a human VEGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within a VEGFR protein, a VEGFR2 protein or a VEGFR3 protein.

[0642] In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor (FGF), e.g., a human FGF. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within a FGF protein.

[0643] In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor (FGFR), e.g., a human FGFR. In some embodiments, the antibody or antibody fragment specifically binds fibroblast growth factor receptor 2 (FGFR2) protein, e.g., a human FGFR2 protein, for example, a FGFR2b protein. In some embodiments, the antibody or antibody fragment specifically binds a fibroblast growth factor receptor 3 (FGFR3) protein, e.g., a human FGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within a FGFR protein, a FGFR2 protein or a FGFR3 protein.

[0644] In some embodiments, the antibody specifically binds to a receptor tyrosine kinase cMET protein. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within a receptor tyrosine kinase cMET protein.

[0645] In some embodiments, the antibody specifically binds to a CD47 protein, e.g., a human CD47 protein. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within a CD47 protein.

[0646] In some embodiments, the antibody specifically binds to an immune checkpoint inhibitor. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within an immune checkpoint inhibitor. In some embodiments, the antibody specifically binds to a programmed death protein, e.g., a human PD-1. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within PD-1 protein.

[0647] In some embodiments, the antibody specifically binds to a programmed death ligand-1 (PD- L1) protein, e.g., a human PD-L1. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within PD-L1 protein.

[0648] In some embodiments, the antibody binds to TIM3. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within TIM3.

[0649] In some embodiments, the antibody specifically binds to a lectin. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within a lectin. In some embodiments, the antibody binds to SIGLEC. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within SIGLEC. In some embodiments, the antibody binds to a cytokine receptor. In some embodiments, the antibody binds to a one or more immunodominant epitope(s) within cytokine receptor. In some embodiments, the antibody binds to sIL6R. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within sIL6R. In some embodiments, the antibody binds to a cytokine. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within a cytokine. In some embodiments, the antibody binds to MCP-1, TNF (e.g., a TNF- alpha), IL1a, IL1b, IL4, IL5, IL6, IL12 / IL23, IL13, IL17 or p40. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within MCP-1, TNF (e.g., a TNF-alpha), IL1a, IL1b, IL4, IL5, IL6, IL12 / IL23, IL13, IL17 or p40.

[0650] In some embodiments, the antibody binds to a major histocompatibility protein (e.g., a MHC class I or class II molecule). In some embodiments, the antibody binds to one or more immunodominant epitope(s) within a major histocompatibility protein (e.g., a MHC class I or class II molecule). In someembodiments, the antibody binds to beta 2 microglobulin. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within beta 2 microglobulin. Modified Viral Compositions

[0651] In specific embodiments, Y is a viral particle, viral capsid, a viral envelope or a viral protein. In some embodiments, the viral composition is a viral particle that comprises a transgene. In some embodiments, the viral protein is a viral capsid protein or a viral envelope protein.

[0652] In certain aspects, provided herein are modified viral compositions comprising a viral composition, for example, a virus particle, a virus capsid or a viral protein (e.g., a viral capsid protein or an envelope protein) attached to (e.g., conjugated to, directly or indirectly, for example via an intervening linker sequence) an ASGPR binding moiety that binds to a cell surface receptor. In certain embodiments, a modified viral composition comprises a virus particle that comprises a polynucleotide that optionally comprises a transgene, e.g., a transgene useful for therapeutic applications.

[0653] The modified viral compositions, e.g., viral conjugates, presented herein may comprise any viral composition described herein e.g., any virus particle, capsid or viral protein, for example capsid protein or envelope protein, or fragment thereof, as described herein.

[0654] In certain aspects, a viral composition described herein may comprise a virus particle. The terms “virus particle,” “viral particle,” “virus vector” or “viral vector” are used interchangeably herein. A “virus particle” refers to a virus capsid and a polynucleotide (DNA or RNA), which may comprise a viral genome, a portion of a viral genome, or a polynucleotide derived from a viral genome (e.g., one or more ITRs), which polynucleotide optionally comprises a transgene. In certain instances, a virus particle further comprises an envelope (which generally comprises lipid moieties and envelope proteins), surrounding or partially surrounding the capsid.

[0655] A viral particle may be referred to as a “recombinant viral particle,” or “recombinant virus particle,” which terms as used herein refer to a virus particle that has been genetically altered, e.g., by the deletion or other mutation of an endogenous viral gene and / or the addition or insertion of a heterologous nucleic acid construct into the polynucleotide of the virus particle. Thus, a recombinant virus particle generally refers to a virus particle comprising a capsid coat or shell (and an optional outer envelope) within which is packaged a polynucleotide sequence that comprises sequences of viral origin and sequences not of viral origin (i.e., a polynucleotide heterologous to the virus). This polynucleotide sequence is typically a sequence of interest for the genetic alteration of a cell.

[0656] In certain aspects, a viral composition described herein may comprise an “viral capsid,” “empty viral particle,” “empty virus particle,” or “capsid,” or “empty particle” when referred to herein in the context of the virus, which terms as used herein refer to a three-dimensional shell or coat comprising a viral capsid protein, optionally surrounded or partially surrounded by an outer envelope. In particular embodiments, the viral composition is a virus particle or a fragment thereof, virus capsid or fragment thereof, a viral protein, for example, a virus capsid protein or fragment thereof or envelope protein, or fragment thereof.

[0657] In some embodiments, the virus used in a modified viral composition provided herein is adenovirus (AV); adeno-associated virus (AAV); retroviruses (e.g., lentiviruses (LV), rhabdoviruses, murine leukemia virus); herpes simplex virus, coronavirus, reovirus, and the like. In some embodiments, the viral vector, viral particle or viral protein used in the present disclosure is derived from a non- enveloped virus, e.g., an adeno-associated virus (AAV).

[0658] In some embodiments, lentiviral vectors can be used for CAR-T gene delivery, vaccines, or research tools, e.g., to introduce genes into mature T cells to generate immunity to cancer through the delivery of chimeric antigen receptors (CARs) or cloned T-cell receptors.

[0659] Naturally occurring AAV forms a virus particle that comprises a three-dimensional capsid coat or shell (a “capsid”) made up of capsid proteins (VP1, VP2 and VP3) and, contained within the capsid, an AAV viral genome.

[0660] The modified AAV compositions, e.g., AAV conjugates or fusions, presented herein may comprise any AAV composition described herein, e.g., any AAV particle, capsid or capsid protein, or fragment thereof, as described herein. The term “AAV capsid protein” or “AAV cap protein” refers to a protein encoded by an AAV capsid (cap) gene (e.g., VP1, VP2, and VP3) or a variant or fragment thereof. The term includes a capsid protein expressed by or derived from an AAV, e.g., a recombinant AAV, such as a chimeric AAV. For example, the term includes but not limited to a capsid protein derived from any AAV serotype such as AAV1, AAV2, AAV2i8, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV rh10, AAV11, AAV12, AAV13, AAV-DJ, AAV3b, AAV LK03, AAV rh74, AAV Anc81, Anc82, Anc83, Anc84, Anc110, Anc113, Anc126, or Anc127, AAV_go.1, AAV hu.37, or AAV rh.8 or a variant thereof. Bridging Moieties that Bind Virus Composition

[0661] In some embodiments, Y is a bridging moiety that specifically binds to a viral composition, for example, a viral particle, viral capsid, viral envelope or viral protein (e.g., a viral capsid protein or envelope protein), wherein the binding is not via a covalent linkage.

[0662] Any suitable moiety that binds a viral particle, viral capsid, viral envelope or viral protein (e.g., a viral capsid protein or envelope protein) can be adapted for use in the conjugates of this disclosure.

[0663] In certain embodiments, a bridging moiety is a polypeptide that specifically binds a viral composition. In some embodiments, the bridging moiety is a polypeptide that binds to a viral composition, e.g., a virus particle, virus capsid, virus envelope, or a viral protein, for example, a viral capsid protein or viral envelope protein. In certain aspects, the bridging composition binds the viral capsid protein or a viral envelope protein, when the viral protein is part of a virus particle.

[0664] In certain embodiments, a bridging moiety is an antibody or antibody fragment (e.g., an antigen binding fragment of an antibody) that specifically binds a viral composition. In certain embodiments, a bridging moiety that binds a viral protein may also bind a viral particle, for example, via binding to the viral protein incorporated in a viral particle. Likewise, in certain embodiments, a bridging moiety that binds a viral particle may also bind a viral protein even if the viral protein is not incorporatedin a viral particle. The viral particle can be an AAV virus particle. The viral protein can be a AAV capsid protein.

[0665] In some embodiments, the bridging moieties of this disclosure specifically bind to an AAV composition, e.g., an AAV particle, AAV capsid, or AAV viral protein (e.g., an AAV capsid protein, for example, a VP1, VP2 or VP3 protein).

[0666] An antibody or antigen binding fragment that may be utilized in connection with the modified viral compositions provided herein, e.g., in connection with the bridging compositions and bridging moieties presented herein, includes, without limitation, monoclonal antibodies, antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity), formed from at least two intact antibodies, single chain antibodies, and fragments thereof (e.g., domain antibodies). Small Molecules

[0667] In some embodiments, the target-binding moiety of the bifunctional compound of this disclosure is a small molecule that specifically binds to a target molecule, such as a target protein. In some embodiments, the bifunctional compound includes a small molecule inhibitor or ligand of a target protein. A small molecule target-binding moiety can be covalently linked to one or more ASGPR binding moieties via a linker. The linker can be covalently attached to the small molecule via substitution at any suitable site of the small molecule such that binding to the target protein is substantially retained.

[0668] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of a target protein (e.g., as described herein). Any convenient small molecules known to bind a target of interest can be adapted for use in the subject compounds and conjugates.

[0669] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of VEGF.

[0670] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of PD-L1.

[0671] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of EGFR protein, a VEGFR protein, a FGFR2 protein or a FGFR3 protein.

[0672] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of TNF protein (e.g., TNF-alpha). TNF-alpha (TNFα) is a soluble cytokine produced by monocytes and macrophages as part of immune and inflammatory processes and is involved in a diverse range of cellular responses including differentiation, proliferation, inflammation, and cell death. TNFα is a type II transmembrane protein that can be cleaved and secreted as a soluble form. Both the transmembrane and soluble biologically active forms of TNFα are homotrimeric complexes that can signal through TNF receptors 1 and 2 (TNF-R1 and TNF-R2). TNFα is directly involved in systemic inflammation through the regulation of the intracellular NF-κB, JNK and p38-MAPK signaling pathways.

[0673] The TNFα binding moiety can be a TNFα inhibitor, such as a competitive inhibitor of TNF receptor binding or an allosteric inhibitor of TNF signaling. The compounds of this disclosure caninclude a potent TNFα inhibitor, e.g., an inhibitor having sub-micromolar inhibitory activity. In some embodiments, the TNFα inhibitor is an allosteric inhibitor. In some embodiments, the TNFα binding moiety is an allosteric desymmetrization TNFα inhibitor. An allosteric desymmetrization TNFα inhibitor refers to a compound that binds to an allosteric site within TNFα and stabilizes the trimeric unit in a nonsymmetrical conformation that allows the TNFα trimer to recruit only two out of the three copies of TNF Receptor (TNFR, e.g., TNFR1), leading to an incompetent TNFα-TNFR signaling complex.

[0674] See e.g., Xiao et al. in Journal of Medicinal Chemistry 202063 (23), 15050-15071, and McMillan et al. in Nature Communications (2021) 12:582, which discloses an analysis of the X-ray co- crystal structure of exemplary inhibitors bound to TNFα. An allosteric desymmetrization TNFα inhibitor can act via a particular mechanism of action to provide potent inhibitory activity. For example, (a) the TNFα inhibitor binding site is a cavity within the TNFα trimer created via movement of monomer A, (b) the inhibitor stabilizes the TNFα trimer in an inactive conformation by forming key π−π and hydrogen bonding interactions, (c) an allosteric desymmetrization TNFα inhibitor binds to TNFα trimer leading to major disruption of one TNFR binding site and minor disruption of a second site, while the third site remains unchanged, and (d) the allosteric desymmetrization TNFα inhibitor modulates TNF-R activity through an allosteric mechanism rather than direct competition with TNFR. Thus, the binding of an allosteric desymmetrization TNFα inhibitor to the symmetric TNFα trimer can lead to the formation of an asymmetric trimer which prevents the recruitment of three TNF receptor molecules that are necessary for signaling. Targets

[0675] As summarized above, the bifunctional compounds of this disclosure can include a moiety of interest (Y) that specifically binds a target molecule. The target molecule can be a cell surface molecule or an extracellular molecule.

[0676] In some embodiments of the compounds and methods of this disclosure, the target molecule is a cell surface molecule. By “cell surface molecule” is meant a target molecule associated with a cell membrane, e.g., because the molecule has a domain that inserts into or spans a cell membrane, e.g., a cell membrane- tethering domain or a transmembrane domain. The cell surface molecule may be any cell surface molecule which is desired for targeted degradation via the endosomal / lysosomal pathway. In some embodiments, the cell surface molecule is a cell surface receptor.

[0677] Cell surface receptors of interest include, but are not limited to, stem cell receptors, immune cell receptors, growth factor receptors, cytokine receptors, hormone receptors, receptor tyrosine kinases, a receptor in the epidermal growth factor receptor (EGFR) family (e.g., HER2 (human epidermal growth factor receptor 2), etc.), a receptor in the fibroblast growth factor receptor (FGFR) family, a receptor in the vascular endothelial growth factor receptor (VEGFR) family, a receptor in the platelet derived growth factor receptor (PDGFR) family, a receptor in the rearranged during transfection (RET) receptor family, a receptor in the Eph receptor family, a receptor in the discoidin domain receptor (DDR) family, and a mucin protein (e.g., MUC1 ). In some embodiments, the cell surface molecule is CD71 (transferrin receptor). In certain aspects, the cell surface receptor is an immune cell receptor selected from a T cellreceptor, a B cell receptor, a natural killer (NK) cell receptor, a macrophage receptor, a monocyte receptor, a neutrophil receptor, a dendritic cell receptor, a mast cell receptor, a basophil receptor, and an eosinophil receptor.

[0678] In some embodiments, the moiety of interest (Y) specifically binds a cell surface molecule which mediates its effect not through a specific molecular interaction (and therefore is not susceptible to blocking), but rather through bulk biophysical or aggregate effects. A non-limiting example of such a cell surface molecule is a mucin. Examples of mucins include, but are not limited to, MUC1 , MUC16, MUC2, MUC5AC, MUC4, CD43, CD45, GPIb, and the like.

[0679] In some embodiments, when the moiety of interest specifically binds a cell surface molecule, the cell surface molecule is present on a cancer cell. By “cancer cell” is meant a cell exhibiting a neoplastic cellular phenotype, which may be characterized by one or more of, for example, abnormal cell growth, abnormal cellular proliferation, loss of density dependent growth inhibition, anchorage- independent growth potential, ability to promote tumor growth and / or development in an immunocompromised non-human animal model, and / or any appropriate indicator of cellular transformation. “Cancer cell” may be used interchangeably herein with “tumor cell”, “malignant cell” or “cancerous cell”, and encompasses cancer cells of a solid tumor, a semi-solid tumor, a hematological malignancy (e.g., a leukemia cell, a lymphoma cell, a myeloma cell, etc.), a primary tumor, a metastatic tumor, and the like. In some embodiments, the cell surface molecule present on the cancer cell is a tumor-associated antigen or a tumor-specific antigen. In certain aspects, when the moiety of interest (Y) specifically binds a cell surface molecule, the cell surface molecule is present on an immune cell. In some embodiments, the cell surface molecule is present on an immune cell selected from a T cell, a B cell, a natural killer (NK) cell, a macrophage, a monocyte, a neutrophil, a dendritic cell, a mast cell, a basophil, and an eosinophil. In certain aspects, the cell surface molecule present on the immune cell is an inhibitory immune receptor. As used herein, an “inhibitory immune receptor” is a receptor present on an immune cell that negatively regulates an immune response. Examples of inhibitory immune receptors which may be inhibited according to the methods of the present disclosure include inhibitory immune receptors of the Ig superfamily, including but not limited to: CD200R, CD300a (IRp60; mouse MAIR-I), CD300f (IREM-1 ), CEACAM1 (CD66a), FcyRIIb, ILT-2 (LIR-1 ; LILRB1 ; CD85j), ILT-3 (LIR-5; CD85k; LILRB4), ILT-4 (LIR-2; LILRB2), ILT-5 (LIR-3; LILRB3; mouse PIR-B); LAIR-1 , PECAM-1 (CD31 ), PILR-a (FDF03), SIRL-1 , and SIRP-a. Further examples of inhibitory immune receptors which may be inhibited according to the methods of the present disclosure include sialic acid-binding Ig-like lectin (Siglec) receptors, e.g., Siglec 7, Siglec 9, and / or the like. Additional examples of inhibitory immune receptors which may be inhibited according to the methods of the present disclosure include C- type lectins, including but not limited to: CLEC4A (DCIR), Ly49Q and MICL. Details regarding inhibitory immune receptors may be found, e.g., in Steevels et al. (2011 ) Eur. J. Immunol.41 (3):575- 587. In some embodiments, the cell surface molecule present on the immune cell is a ligand of an inhibitory immune receptor. In certain aspects, the cell surface molecule present on the immune cell is an immune checkpoint molecule. Non-limiting examples of immune checkpoint molecules to which themoiety of interest (Y) may specifically bind include PD-1, PD-L1, CTLA4, TIM3, LAG3, TIGIT, and a member of the B7 family.

[0680] In some embodiments of the compounds and methods of this disclosure, the target molecule is an extracellular molecule. By “extracellular molecule” is meant a soluble molecule external to the cell membranes of any cells in the vicinity of the soluble molecule. The extracellular molecule may be any extracellular molecule which is desired for targeted degradation via the endosomal / lysosomal pathway.

[0681] In some embodiments, the extracellular molecule is a soluble target protein. In some embodiments, the extracellular molecule is a secreted protein that accumulates in disease (e.g., alpha- synuclein), a cholesterol carrier (e.g., ApoB), an infectious disease toxin (e.g., AB toxins, ESAT-6), an infectious particle (e.g., a whole virus, a whole bacterium, etc.), a clotting factor (e.g., Factor IX), the target of any FDA approved antibody that binds to an extracellular molecule (e.g., TNFalpha), any chemokine or cytokine (e.g., mediators of sepsis or chronic inflammation such at IL-1 ), a proteinaceous hormone (e.g., insulin, ACTH, etc.), a proteinaceous mediator of a mood disorder, a proteinaceous mediator of energy homeostasis (e.g., leptin, ghrelin, etc.), a proteinaceous allergen present in the bloodstream or an antibody against such an allergen (e.g., for peanut allergies), a proteinaceous toxin (e.g., snake venom hyaluronidase, etc.), an autoantibody, etc.

[0682] In some embodiments, the target molecule is an extracellular molecule that is an antibody, e.g., an antibody that specifically binds a cell surface molecule or different extracellular molecule. In some embodiments, the antibody is an autoantibody. In some embodiments, the target is a human immunoglobulin A(IgA). In some embodiments, the IgA is a particular antibody that plays a crucial role in the immune function of mucous membranes. In the blood, IgA interacts with an Fc receptor called CD89 expressed on immune effector cells, to initiate inflammatory reactions. Aberrant IgA expression has been implicated in a number of autoimmune and immune-mediated disorders. In some embodiments, the target is a human immunoglobulin G (IgG). The Fc regions of IgGs include a conserved N- glycosylation site at asparagine 297 in the constant region of the heavy chain. Various N-glycans can b eattached to this site. The N-glycan IgG composition has been linked to several autoimmune, infectious and metabolic diseases. In addition, overexpression of IgG4 has been associated with IG4-related diseases. In some embodiments, the target is human immunoglobulin E (IgE). IgE is a type of immunoglobulin that plays an essential role in type I hypersensitivity, which can manifest into various allergic diseases and conditions.

[0683] In some embodiments, the extracellular molecule is a ligand for a cell surface receptor. Cell surface receptor ligands of interest include, but are not limited to, growth factors (e.g., epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and the like), cytokines (e.g., an interleukin, an interferon, a tumor necrosis factor (TNF), a transforming growth factor b (TGF-b), including any particular subtypes of such cytokines), hormones, and the like. In certain aspects, the moiety of interest (Y) specifically binds apolipoprotein E4 (ApoE4). Pharmaceutical Compositions

[0684] In another embodiment, provided herein are pharmaceutical compositions comprising one or more conjugates disclosed herein and a pharmaceutically acceptable carrier.

[0685] 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.

[0686] 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.

[0687] The conjugates described herein can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients.

[0688] 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.

[0689] 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.

[0690] 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.

[0691] 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.

[0692] 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.

[0693] 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.

[0694] 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) 22nd ed., 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.

[0695] 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.

[0696] 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.

[0697] 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.

[0698] 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.

[0699] 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.

[0700] 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 asterile aqueous or oily solution or suspension containing a conjugate described herein injected as necessary to produce the desired pharmacological effect.

[0701] 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.

[0702] 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.

[0703] 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.

[0704] 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. Uses and Methods

[0705] In one aspect, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from a cell’s surface. In one aspect, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from the extracellular milieu. For example, in one embodiment, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from the surface of a cell by sequestering the target protein in the cell’s lysosome. In another embodiment, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from the extracellular space (the extracellular milieu) of a cell by sequestering the target protein in the cell’s lysosome. In another embodiment, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from the surface of a cell by sequestering the target protein in the cell’s lysosome and degrading the target protein. In anotherembodiment, provided herein are methods of using the conjugates described herein to remove a polypeptide of interest (a target protein) from the extracellular space (the extracellular milieu) of a cell by sequestering the target protein in the cell’s lysosome and degrading the target protein.

[0706] Removal of a target protein may refer to reduction, or depletion, of the target protein from the cell surface or from the extracellular space, or the extracellular milieu, that is, a reduction, or depletion, of the amount of the target protein on the cell surface or in the extracellular milieu.

[0707] In one aspect, provided herein are methods of using the conjugates described herein to sequester a polypeptide of interest (a target protein) in a cell’s lysosome. In one aspect, provided herein are methods of using the conjugates described herein to sequester a polypeptide of interest (a target protein) in a cell’s lysosome and to degrade the polypeptide of interest.

[0708] In one aspect, provided herein are methods of using the conjugates described herein to degrade a polypeptide of interest (a target protein).

[0709] In one aspect, provided herein are methods of depleting a polypeptide of interest (a target protein) described herein by degradation through a cell’s lysosomal pathway.

[0710] In another aspect, provided herein are methods of depleting a polypeptide of interest (a target protein) described herein by administering to a subject in need thereof an effective amount of aconjugate or pharmaceutically acceptable salt described herein,or a pharmaceutical compositiondescribed herein. In certain embodiments, the subject is a mammal (e.g., human).

[0711] In certain embodiments, the target protein is a VEGF protein, an EGFR protein, a VEGFR protein, a PD-L1 protein, an FGFR2 protein or an FGFR3 protein.

[0712] In another aspect, provided herein are methods of treating a disease or disorder byadministering to a subject, e.g., a human, in need thereof an effective amount of aconjugate orpharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0713] 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 a particular embodiment, administration is by intravenous infusion.

[0714] 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 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.

[0715] In certain embodiments, when the disorder or disease is cancer, “effective amount” or “therapeutically effective amount” mean that amount of a conjugate or pharmaceutical composition provided herein which, when administered to a human suffering from a cancer, is sufficient to effect treatment for the cancer. “Treating” or “treatment” of the cancer includes one or more of: (1) limiting / inhibiting growth of the cancer, e.g. limiting its development; (2) reducing / preventing spread of the cancer, e.g. reducing / preventing metastases; (3) relieving the cancer, e.g. causing regression of the cancer, (4) reducing / preventing recurrence of the cancer; and (5) palliating symptoms of the cancer.

[0716] 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 a specific embodiment, the subject is human.

[0717] The terms “therapies” and “therapy” can refer to any protocol(s), method(s), compositions, formulations, and / or agent(s) that can be used in the prevention, treatment, management, or amelioration of a disease or disorder or symptom thereof (e.g., a disease or disorder provided herein or one or more symptoms or condition associated therewith). In certain embodiments, the terms “therapies” and “therapy” refer to drug therapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, and / or other therapies useful in treatment, management, prevention, or amelioration of a disease or disorder or one or more symptoms thereof. In certain embodiments, the term “therapy” refers to a therapy other than a conjugate described herein or pharmaceutical composition thereof.

[0718] In certain embodiments, the disease or disorder is treated by depletion of the target protein by degradation through the lysosomal pathway.

[0719] In certain embodiments, the disease or disorder is treated by depletion of certain proteins, for example, soluble proteins, e.g., secreted proteins, cell surface proteins (for example, cell surface receptor proteins, e.g., tyrosine kinase receptors, soluble cytokine receptors, and immune checkpoint receptors, e.g., EGFR, VEGFR, FGFR, and PD-L1), lectins, complements, lipoproteins, transport proteins, MHC class I and class II molecules, cytokines, chemokines, and / or receptors , or fragments or subunits of any of the foregoing.

[0720] In certain embodiments, the disease or disorder is a cancer.

[0721] In certain embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, hepatocellular carcinoma, kidney cancer, melanoma, myeloid neoplasms, non-small cell lung cancer (NSCLC), Ewing’s sarcoma, and Hodgkin’s Lymphoma.

[0722] In certain embodiments, the cancer is a solid tumor.

[0723] In certain embodiments, the disease or disorder is an inflammatory or autoimmune disease.

[0724] In certain embodiments, the disease or disorder is an inflammatory disease.

[0725] In certain embodiments, the disease or disorder is an autoimmune disease. In certain embodiments, the disease or disorder is a viral disease. In certain embodiments, the viral disease is hepatitis B. Definitions

[0726] It is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0727] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of embodiments of the present disclosure.

[0728] It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes not only a single compound but also a combination of two or more compounds, reference to "a substituent" includes a single substituent as well as two or more substituents, and the like.

[0729] Certain terminology will be used in accordance with the definitions set out below. It will be appreciated that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall within the definition of more than one term.

[0730] 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.

[0731] 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. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0732] 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 ormodification. 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 comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. In some embodiments, proteins are antibodies, antibody fragments, biologically active portions thereof, and / or characteristic portions thereof.

[0733] The terms “antibody” and “immunoglobulin” are terms of art and can be used interchangeably herein in their broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope.

[0734] In a certain embodiments, an isolated antibody (e.g., monoclonal antibody) described herein, or an antigen-binding fragment thereof, which specifically binds to a protein of interest, for example, EGFR, is conjugated to one or more lysosomal targeting moieties, for example, via a linker.

[0735] An “antigen” is a moiety or molecule that contains an epitope to which an antibody can specifically bind. As such, an antigen is also is specifically bound by an antibody. In a specific embodiment, the antigen, to which an antibody described herein binds, is a protein of interest, for example, EGFR (e.g., human EGFR), or a fragment thereof, or for example, an extracellular domain of EGFR (e.g., human EGFR).

[0736] 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 comprise amino acids from two or more non-contiguous regions of the antigen.

[0737] The terms “binds,” “binds to,” “specifically binds” or “specifically binds to” in the context of antibody binding refer to antibody binding to an antigen (e.g., epitope) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen may bind to other polypeptides, generally with lower affinity as determined by, e.g., immunoassays, Biacore™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specificembodiment, molecules that specifically bind to an antigen bind to the antigen with an affinity (Kd) thatis at least 2 logs, 2.5 logs, 3 logs, 4 logs lower (higher affinity) than the Kdwhen the molecules bind to another antigen. In another specific embodiment, molecules that specifically bind to an antigen do not cross react with other proteins. In another specific embodiment, where EGFR is the protein of interest, molecules that specifically bind to an antigen do not cross react with other non-EGFR proteins.

[0738] An antibody specifically includes, but is not limited to, full length antibodies (e.g., intact immunoglobulins), antibody fragments, monoclonal antibodies, polyclonal antibodies,, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, anantibody light chain / antibody heavy chain pair, an antibody with two light chain / heavy chain pairs (e.g., identical pairs), intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, bivalent antibodies (including monospecific or bispecific bivalent antibodies), single chain antibodies, or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, F(ab’) fragments, F(ab’)2fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), and epitope-binding fragments of any of the above.

[0739] Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class, (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, antibodies described herein are IgG antibodies (e.g., human IgG), or a class (e.g., human IgG1, IgG2, IgG3 or IgG4) or subclass thereof.

[0740] In a particular embodiment, an antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs, wherein the amino acid sequences of the H chains are identical and the amino acid sequences of the L chains are identical. In a specific embodiment, the H and L chains comprise constant regions, for example, human constant regions. In a yet more specific embodiment, the L chain constant region of such antibodies is a kappa or lambda light chain constant region, for example, a human kappa or lambda light chain constant region. In another specific embodiment, the H chain constant region of such antibodies comprise a gamma heavy chain constant region, for example, a human gamma heavy chain constant region. In a particular embodiment, such antibodies comprise IgG constant regions, for example, human IgG constant regions.

[0741] The term “constant region” or “constant domain” is a well-known antibody term of art (sometimes referred to as “Fc”), and refers to an antibody portion, e.g., a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The terms refer to a portion of an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0742] The term “heavy chain” when used in reference to an antibody can refer to any distinct types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3and IgG4.

[0743] The term “light chain” when used in reference to an antibody can refer to any distinct types, e.g., kappa (κ) of lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.

[0744] The term “monoclonal antibody” is a well-known term of art that refers to an antibody obtained from a population of homogenous or substantially homogeneous antibodies. The term “monoclonal” is not limited to any particular method for making the antibody. Generally, a population of monoclonal antibodies can be generated by cells, a population of cells, or a cell line. In specific embodiments, a “monoclonal antibody,” as used herein, is an antibody produced by a single cell (e.g.,hybridoma or host cell producing a recombinant antibody), wherein the antibody specifically binds to an epitope as determined, e.g., by ELISA or other antigen-binding or competitive binding assay known in the art or in the Examples provided herein. In particular embodiments, a monoclonal antibody can be a chimeric antibody or a humanized antibody. In certain embodiments, a monoclonal antibody is a monovalent antibody or multivalent (e.g., bivalent) antibody. In particular embodiments, a monoclonal antibody is a monospecific or multispecific antibody (e.g., bispecific antibody).

[0745] The terms “variable region” or “variable domain” refer to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 100 amino acids in the mature light chain. Variable regions comprise complementarity determining regions (CDRs) flanked by framework regions (FRs). Generally, the spatial orientation of CDRs and FRs are as follows, in an N-terminal to C-terminal direction: FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4. Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with antigen and for the specificity of the antibody for an epitope. In a specific embodiment, numbering of amino acid positions of antibodies described herein is according to the EU Index, as in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242. In certain embodiments, the variable region is a human variable region.

[0746] In certain aspects, the CDRs of an antibody can be determined according to (i) the Kabat numbering system (Kabat et al. (1971) Ann. NY Acad. Sci.190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242); or (ii) the Chothia numbering scheme, which will be referred to herein as the “Chothia CDRs” (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196: 901-917; Al- Lazikani et al., 1997, J. Mol. Biol., 273: 927-948; Chothia et al., 1992, J. Mol. Biol., 227: 799-817; Tramontano et al., 1990, J. Mol. Biol.215(1):175-82; U.S. Patent No.7,709,226; and Martin, A., “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422-439, Springer-Verlag, Berlin (2001)); or (iii) the ImMunoGeneTics (IMGT) numbering system, for example, as described in Lefranc, 1999, The Immunologist, 7: 132-136 and Lefranc et al., 1999, Nucleic Acids Res., 27: 209-212 (“IMGT CDRs”); or (iv) the AbM numbering system, which will be referred to herein as the “AbM CDRs”, for example as described in MacCallum et al., 1996, J. Mol. Biol., 262: 732-745. See also, e.g., Martin, A., “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422-439, Springer-Verlag, Berlin (2001); or (v) the Contact numbering system, which will be referred to herein as the “Contact CDRs” (the Contact definition is based on analysis of the available complex crystal structures (bioinf.org.uk / abs) (see, e.g., MacCallum et al., 1996, J. Mol. Biol., 262:732-745)).

[0747] The terms “full length antibody,” “intact antibody” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, and are not antibody fragments as defined below. The terms particularly refer to an antibody with heavy chains that contain the Fc region.

[0748] “Antibody fragments” comprise only a portion of an intact antibody, wherein the portion retains at least one, two, three and as many as most or all of the functions normally associated with that portion when present in an intact antibody. In one aspect, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. In another aspect, an antibody fragment, such as an antibody fragment that comprises the Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody. Such functions may include FcRn binding, antibody half life modulation, conjugate function and complement binding. In another aspect, an antibody fragment is a monovalent antibody that has an in vivo half life substantially similar to an intact antibody. For example, such an antibody fragment may comprise on antigen binding arm linked to an Fc sequence capable of conferring in vivo stability to the fragment. Antibody fragments suitable for use in the compounds of this disclosure include, for example, Fv fragments, Fab fragments, F(ab’)2fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0749] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, control regions, isolated RNA of any sequence, nucleic acid probes, and primers. The nucleic acid molecule may be linear or circular. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. The nucleic acid molecule may be an aptamer.

[0750] The term “purified” refers to isolation of a substance (compound, polynucleotide, protein, polypeptide, polypeptide composition) such that the substance of interest comprises the majority percent of the sample in which it resides. Typically in a sample a substantially purified component comprises 50%, 80%-85%, 90-99%, such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the sample. Techniques for purifying polynucleotides, polypeptides and virus particles of interest are well- known in the art and include, for example, ion-exchange chromatography, affinity chromatography and sedimentation according to density.

[0751] The terms “treatment,” “treating,” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect, such as reduction of tumor burden. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” asused herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCV infection); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease (e.g., reduction in of tumor burden).

[0752] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to an animal, including, but not limited to, human and non-human primates, including simians and humans; rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like. "Mammal" means a member or members of any mammalian species, and includes, by way of example, canines; felines; equines; bovines; ovines; rodentia, etc. and primates, e.g., non-human primates, and humans. Non-human animal models, e.g., mammals, e.g. non-human primates, murines, lagomorpha, etc. may be used for experimental investigations.

[0753] A "therapeutically effective amount" or "efficacious amount" means the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to effect such treatment for the disease, condition, or disorder. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0754] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers, are intended to be encompassed within the scope of the claimed subject matter. For example, when a compound is described as a particular optical isomer D- or L-, it is intended that both optical isomers be encompassed herein. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. The compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configurations, or may be a mixture thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0755] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),13C,14C,15N,17O,18O,18F,36Cl,82Br,123I,124I,125I,129I and131I. Particular isotopic variants of a compound according to the present disclosure, especially those inwhich one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with3H,14C and / or18F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance. Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and / or starting compounds therein.

[0756] Thus, any of the embodiments described herein are meant to include a salt, a single stereoisomer, a mixture of stereoisomers and / or an isotopic form of the compounds.

[0757] 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.

[0758] 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, intracheal, intramuscular, subcutaneous, and the like.

[0759] 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.

[0760] 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

[0761] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)- , heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the “acetyl” group CH3C(O)-

[0762] The term "alkyl" refers to a branched or unbranched saturated hydrocarbon group (i.e., a mono-radical) typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although not necessarily, alkyl groups herein may contain 1 to about 18 carbon atoms, and such groups may contain 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and this includes instances wherein two hydrogen atoms from the same carbon atom in an alkyl substituent are replaced, such as in a carbonyl group (i.e., a substituted alkyl group may include a -C(O)- moiety). The terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl substituent in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0763] The term “substituted alkyl” is meant to include an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -O- , -N-, -S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NRaRb, wherein R’ and R” may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0764] The term "alkenyl" refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Generally, although again not necessarily, alkenyl groups herein may contain 2 to about 18 carbon atoms, and forexample may contain 2 to 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of 2 to 6 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkenyl" and "lower alkenyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl, respectively.

[0765] 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.

[0766] The term "alkoxy" refers to an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. A "lower alkoxy" group refers to an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc. Substituents identified as "C1-C6 alkoxy" or "lower alkoxy" herein may, for example, may contain 1 to 3 carbon atoms, and as a further example, such substituents may contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0767] The term “substituted alkoxy” refers to the groups substituted alkyl-O-, substituted alkenyl- O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0768] The term "aryl", unless otherwise specified, refers to an aromatic substituent generally, although not necessarily, containing 5 to 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Aryl groups may, for example, contain 5 to 20 carbon atoms, and as a further example, aryl groups may contain 5 to 12 carbon atoms. For example, aryl groups may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc.). Examples include phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. Aryl is intended to include stable cyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated C3-C14moieties, exemplified but not limited to phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazoyl, pyrimidinyl, and oxazoyl; which may further besubstituted with one to five members selected from the group consisting of hydroxy, C1-C8alkoxy, C1-C8branched or straight-chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halogen, trifluoromethyl, cyano, and carboxyl (see e.g. Katritzky, Handbook of Heterocyclic Chemistry). If not otherwise indicated, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0769] The term "aralkyl" refers to an alkyl group with an aryl substituent, and the term "alkaryl" refers to an aryl group with an alkyl substituent, wherein "alkyl" and "aryl" are as defined above. In general, aralkyl and alkaryl groups herein contain 6 to 30 carbon atoms. Aralkyl and alkaryl groups may, for example, contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.

[0770] The term "alkylene" refers to a multi-valent (e.g., di-radical alkyl group, tri-radical alkyl group, tetra-radical alkyl group, etc.) . Unless otherwise indicated, such groups include saturated hydrocarbon chains containing from 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may be heteroatom-containing. "Lower alkylene" refers to alkylene linkages containing from 1 to 6 carbon atoms. Examples include, methylene (--CH2--), ethylene (--CH2CH2--), propylene (--CH2CH2CH2--), 2-methylpropylene (--CH2--CH(CH3)--CH2--), hexylene (-- (CH2)6--) and the like.

[0771] Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and "alkarylene" refer to di-radical alkenyl, alkynyl, aryl, aralkyl, and alkaryl groups, respectively.

[0772] In some embodiments, such as in branched constructs, the "alkylene" refers to a multi-valent (e.g., di-valent alkyl group, tri-valent alkyl group, tetra-valent alkyl group, etc.). Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and "alkarylene" can refer to multi-valent alkenyl, multi-valent alkynyl, multi-valent aryl, multi-valent aralkyl, and multi-valent alkaryl groups, respectively.

[0773] 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.

[0774] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.

[0775] “Carboxyl,” “carboxy” or “carboxylate” refers to –C(O)OH or salts thereof.

[0776] “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, adamantyl, 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 adamantanyl, and the like.

[0777] The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-substituted alkyl, -S(O)-aryl, -S(O)-heteroaryl, - S(O)2-alkyl, -S(O)2-substituted alkyl, -S(O)2-aryl and -S(O)2-heteroaryl.

[0778] The term "heteroatom-containing" as in a "heteroatom-containing alkyl group" (also termed a "heteroalkyl" group) or a "heteroatom-containing aryl group" (also termed a "heteroaryl" group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the term "heterocycloalkyl" refers to a cycloalkyl substituent that is heteroatom-containing, the terms "heterocyclic" or “heterocycle” refer to a cyclic substituent that is heteroatom-containing, the terms "heteroaryl" and "heteroaromatic" respectively refer to "aryl" and "aromatic" substituents that are heteroatom-containing, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl- substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl, etc.

[0779] “Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, - SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.

[0780] The terms “heterocycle,” “heterocyclic” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiroring systems, and having from 3 to 15 ring atoms, including 1 to 4 hetero atoms. These ring heteroatoms are selected from nitrogen, sulfur and oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or –SO2- moieties.

[0781] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0782] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO- aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0783] "...

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 500; m is 1 to 20; Y is a moiety of interest; L is a linker; and 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; provided at least one of the following occurs: A) Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and -A2- are optionally substituted heterocyclylene; or -A2- is optionally substituted isoxazolyl; B) -L-Y comprises:C) R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, - C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, optionally substitutedheteroaryl–NHCOR, or –NRCOR, provided the heteroaryl is other than triazole; where 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; D) R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl; or E) at least one R21is -COR or optionally substituted heteroaryl.

2. The compound of claim 1, wherein X is of formula (a-II):(a-II).

3. The compound of claim 1 or 2, wherein Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and -A2- are optionally substituted heterocyclylene.

4. The compound of any preceding claim, wherein5. The compound of any preceding claim, wherein -L-Y comprises:

6. The compound of any preceding claim, wherein R6is -OR, optionally substituted (C1-C6)alkyl, – OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, or optionally substituted heteroaryl, provided the heteroaryl is other than triazole; where R is 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.

7. The compound of any preceding claim, wherein R6is -O-(C1-C6)alkyl, optionally substituted heterocyclyl, or -O-aryl.

8. The compound of any preceding claim, wherein R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl 9. The compound of any preceding claim, wherein R1is optionally substituted C2-6alkyl.

10. The compound of any preceding claim, wherein at least one R21is -COR or optionally substituted heteroaryl.

11. The compound of any preceding claim, wherein Y is an antibody or antibody fragment.

12. A compound of formula (I):or a prodrug thereof, or a salt thereof, wherein: n is 1 to 500; m is 1 to 20; L is a linker; and 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, 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, and optionally substituted heteroaryl, R is 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; 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; and Y is a chemoselective ligation group; wherein at least one of the following occurs: A) Z1is a linking moiety selected from -Z11-A1- and -A2-; and -A1- and -A2- are optionally substituted heterocyclylene; or -A2- is optionally substituted isoxazolyl; B) -L-Y comprises:C) R6is -OR, optionally substituted (C1-C6)alkyl, –OC(O)-optionally substituted heteroaryl, - C(O)NH-optionally substituted heteroaryl, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl–NHCOR, or –NRCOR, provided the heteroaryl is other than triazole; where 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; D) R1is optionally substituted C2-6alkyl, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl; or E) at least one R21is -COR or optionally substituted heteroaryl.

13. The compound of claim 12, wherein the compound of formula (II) is represented by formula (a- II):(a-II).

14. The compound of any one of claims 1-13, wherein R1is –Z1–*, –H, or (C1-C6)alkyl.

15. The compound of any one of claims 1-13, wherein R2is –Z1–* or –NHCOCH3.

16. The compound of any preceding claim, wherein R3and R4are each –H.

17. The compound of any preceding claim, wherein R6is –OH, –OC(O)R, -NRxxRyy, or aryl; R is (C1-C6)alkyl; and Rxxand Ryycyclize to form an optionally substituted heterocyclyl.

18. The compound of any preceding claim, wherein –Z1–* is -S-, -CH2-,, ,19. The compound of claim 18, wherein R1is –Z1–*.

20. The compound of claim 18, wherein R2is –Z1–*.

21. The compound of any preceding claim, wherein L comprises of 10 to 60 consecutive chain atoms.

22. The compound of any preceding claim, wherein L is of formula (IIb’):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 to L1of X via Z1; and *** represents the point of attachment to Y.

23. The compound of claim 22, wherein 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–, –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(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 cycloalkyl, amino acid residue, –NH–, and –NMe–; 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, (C1-C6)alkyl, or monocyclic heteroaryl.

24. The compound of claim 22, wherein 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(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 cycloalkyl, amino acid residue, –NH–, and –NMe– ; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and L6is25. The compound of any one of claims 22-24, wherein n is 1.

26. The compound of any one of claims 22-24, wherein n is 2.

27. The compound of any one of claims 22-24, wherein n is 3.

28. The compound of any one of claims 22-27, wherein at least one L1is –C1-20-alkylene– optionally substituted with one to five halo.

29. The compound of any one of claims 22-28, wherein at least one L1is -CF2CH2-.

30. The compound of any one of claims 22-29, wherein at least one L2is –(OCH2CH2)p–.

31. The compound of claim 30, wherein p is 2-3.

32. The compound of any one of claims 22-31, wherein at least one L3is NHCONH-C1-6-alkylene–.

33. The compound of any one of claims 22-32, wherein at least one L4is –C1-6-alkylene–NHCONH-.

34. The compound of any one of claims 22-33, wherein at least one L5is –(OCH2CH2)p–.

35. A pharmaceutical composition comprising the compound of any one of claims 1-34 and one or more pharmaceutically acceptable excipients.

36. A method of internalizing a target molecule in a cell comprising a cell surface asialoglycoprotein receptor (ASGPR), the method comprising: contacting a cellular sample comprising the cell and the target molecule with an effective amount of a compound according to any one of claims 1 to 34, wherein the compound specifically binds the target protein and specifically binds the ASGPR to facilitate cellular uptake of the target protein.

37. The method of claim 36, wherein the target molecule is a membrane bound protein.

38. The method of claim 37, wherein the target molecule is an extracellular protein.

39. A method of reducing levels of a target molecule in a biological system, the method comprising: contacting the biological system with an effective amount of a compound according to any one of claims 1 to 34, wherein the compound specifically binds the target protein and specifically binds a ASGPR of cells in the biological system to facilitate cellular uptake and degradation of the target protein.

40. The method of claim 39 wherein the biological system is a human subject. 41 The method of claim 39, wherein the biological system is an in vitro cellular sample.

42. The method of any one of claims 36 to 41, wherein the target molecule is a membrane bound protein.

43. The method of any one of claims 36 to 41, wherein the target molecule is an extracellular protein.

Images