ASGPR-binding compounds and conjugates

Abstract

The present disclosure provides a class of compounds comprising a ligand moiety that specifically binds to the cell surface asialoglycoprotein receptor (ASGPR). Cell surface ASGPR-binding compounds can stimulate the receptor to internalize the bound compound within the cell. The ligand moieties of the present disclosure can be linked to various moieties of interest without affecting their specific binding to the cell surface ASGPR receptor and function. Also provided are compounds that are conjugates of the ligand moiety attached to a biomolecule, such as an antibody, which can utilize a cellular pathway to remove a specific protein of interest from the cell surface or extracellular environment. Also provided herein are methods for using the conjugates to target a polypeptide of interest for sequestration and / or lysosomal degradation.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Nos. 63 / 439,811, filed January 18, 2023, and 63 / 518,532, filed August 9, 2023, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Many therapeutic drugs act by binding to functionally important sites in target proteins to modulate their activity or by recruiting immune effectors to act on target proteins, as with many monoclonal antibody drugs. However, there is an untapped reservoir of medically important human proteins that are considered "undruggable" because they do not easily fit into currently available therapeutic targeting approaches. Therefore, there is a need for therapeutics that can target a broader range of proteins.

[0003] The asialoglycoprotein receptor (ASGPR), also known as the Ashwell-Morrell receptor, is a transmembrane glycoprotein receptor present primarily in hepatocytes that plays a key role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine (GalNAc) residues. The ASGPR cycles between endosomes and the cell surface.

[0004] Alternative ligands that bind to cell surface ASGPRs and subsequently transport across the plasma membrane are of great interest. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides a class of compounds comprising a ligand moiety that specifically binds to the cell surface asialoglycoprotein receptor (ASGPR). Cell surface ASGPR-binding compounds can stimulate the receptor to internalize the bound compound within the cell. The ligand moieties of the present disclosure can be linked to various moieties of interest without affecting their specific binding to the cell surface ASGPR receptor and function. Also provided are compounds that are conjugates of the ligand moiety attached to a biomolecule, such as an antibody, which can utilize a cellular pathway to remove a specific protein of interest from the cell surface or extracellular environment. For example, the conjugates described herein can sequester and / or degrade a target molecule of interest in the lysosomes of a cell. Also provided herein are compositions comprising such conjugates, methods for using the conjugates to target a polypeptide of interest for sequestration and / or lysosomal degradation, and methods for using the conjugates to treat a disorder or disease.

[0006] These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and accompanying drawings. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 shows a graph of cellular fluorescence (MFI) versus antibody conjugate concentration ([Ab]) demonstrating that various antibody conjugates of exemplary ASGPR-binding compounds and an example M6PR-binding compound (520) show comparable potent uptake into HepG2 cells after 1 hour of incubation. [Figure 2A] 1 shows a graph of cell fluorescence versus antibody conjugate concentration demonstrating that various antibody conjugates of an exemplary ASGPR binding compound exhibit strong uptake into HepG2 cells after 1 hour of incubation. [Figure 2B]1 shows a graph of cell fluorescence versus antibody conjugate concentration demonstrating that various antibody conjugates of an exemplary ASGPR binding compound exhibit strong uptake into HepG2 cells after 1 hour of incubation. [Figure 2C] 1 shows a graph of cell fluorescence versus antibody conjugate concentration demonstrating that various antibody conjugates of an exemplary ASGPR binding compound exhibit strong uptake into HepG2 cells after 1 hour of incubation. [Figure 2D] 1 shows a graph of cell fluorescence versus antibody conjugate concentration demonstrating that various antibody conjugates of an exemplary ASGPR binding compound exhibit strong uptake into HepG2 cells after 1 hour of incubation. [Figure 3] Fluorescence polarization screening results of exemplary trivalent compounds (1901 (I-171), 1902 (I-172), XB32, and 2101) are shown. [Figure 4] The binding of exemplary monovalent compounds (591, XB20, XB23, XB21, 592 and 593) is shown as a percentage of the activity of the reference compound XB149. [Figure 5] Fluorescence polarization screening results for exemplary monovalent compounds (XB20, XB21, 592, XB23, 591) are shown. [Figure 6] 1 shows a graph of the cellular uptake of various conjugates of OMA (anti-IgE) including exemplary compounds I-160 to I-163 and I-141 bound to Alexa488-labeled target IgE in HepG2 cells. [Figure 7] Figure 1 shows the affinity-dependent clearance of OMA-exemplary compounds (I-160 to I-163) compared to OMA (reference). [Figure 8] FIG. 1 shows dose titration of OMA-I-163 IgE clearance. [Figure 9] Figure 1 shows the affinity-dependent clearance of OMA-exemplary compounds (I-160 to I-163) compared to hIgE (reference). DETAILED DESCRIPTION OF THE INVENTION

[0008] As summarized above, the present disclosure provides a class of compounds that include a ligand moiety that specifically binds to an ASGPR on a cell of interest.

[0009] The present disclosure provides a compound of formula (I) [ka] or a prodrug thereof, or a salt thereof, wherein: X is a moiety (e.g., as described herein) that binds to an ASGPR cell surface receptor; n is 1 to 500; L is a linker (e.g., monovalent or multivalent of defined length as described herein); Y is a moiety of interest (e.g., as described herein).

[0010] Also provided herein are conjugates comprising a moiety X that binds to such ASGPR-internalizing cell surface receptors, e.g., for sequestration and / or lysosomal degradation. Thus, the present disclosure provides conjugates of formula (I): [ka] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: X is a moiety (e.g., as described herein) that binds to an ASGPR cell surface receptor; 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 to an extracellular target molecule.

[0011] In some embodiments, the target-binding conjugate has formula (II'): [ka] or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 3; m is 1 to 3; X and Y are each independently as defined herein; L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5.

[0012] The ASGPR-binding compounds and conjugates, and methods of the present disclosure are described in further detail below. The linkers (L) and moieties of interest (Y) used in the ASGPR-binding compounds, and biomolecular conjugates are also described. Methods in which the compounds and conjugates of the present disclosure can be used are also described.

[0013] ASGPR ligand As summarized above, the present disclosure provides a class of compounds comprising a ligand moiety that specifically binds to cell surface ASGPR. The ASGPR ligand moiety of the present disclosure can be linked to various moieties of interest without affecting the specific binding and function of cell surface ASGPR. In certain embodiments, the compounds of the present disclosure can utilize the function of cell surface ASGPR in biological systems, such as, for example, the internalization and sequestration of the compound into lysosomes of cells, and in certain embodiments, subsequent lysosomal degradation. The compounds of the present disclosure can be used in various applications.

[0014] The term "asialoglycoprotein receptor" (ASGPR), also known as the Ashwell-Morrell receptor, refers to a transmembrane glycoprotein receptor present primarily in hepatocytes that plays a key 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 certain embodiments, the ASGPR is Homo sapiens asialoglycoprotein receptor 1 (ASGR1) (see, e.g., NCBI Reference Sequence: NM_001197216).

[0015] Compounds comprising such an ASGPR-binding moiety (X) (e.g., as described herein) may bind to other receptors, or may bind with lower affinity, e.g., as determined by immunoassays or other assays known in the art. In certain embodiments, X, or a compound described herein comprising such X, specifically binds to a cell surface ASGPR with an affinity of at least 2, 2.5, 3, 4, or more logs greater than the affinity with which X or the compound or conjugate binds to another cell surface receptor. In certain embodiments, X, or a compound described herein comprising X, specifically binds to a cell surface ASGPR with an affinity (K d ) specifically binds to ASGPR. In certain embodiments, such binding is d ) 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 "bind," "bind," "specifically bind," or "specifically bind to" are used interchangeably.

[0016] The ASGPR-binding compounds of the present disclosure comprise a moiety (X) that specifically binds to the cell surface receptor ASGPR. ASGPR-binding compounds can be monovalent or multivalent (e.g., bivalent or trivalent or higher), where a monovalent compound contains a single ASGPR ligand moiety and a multivalent compound contains two or more such moieties.

[0017] In certain embodiments, the ASGPR-binding moiety X can bind to a specific cell-surface ASGPR and direct (or target) the molecule to this receptor. In certain embodiments, the ASGPR-binding moiety X can bind to an ASGPR and direct (or target) a compound or conjugate described herein to the lysosome for internalization and sequestration and / or subsequent lysosomal degradation.

[0018] In some embodiments, the ASGPR-binding moiety X comprises an amino sugar ring derivative of galactose (e.g., N-acetylgalactosamine and its analogs) linked via a linking moiety to the 1-, 6-, or 2-position of the sugar ring. The linking moiety can be 1 to 10 atoms, e.g., 1 to 6, or 1 to 5, 1 to 4, or 1 to 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 at 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 at 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.

[0019] In some embodiments, the ASGPR-binding compound is monovalent (e.g., in Formula (I), n is 1), such that the ASGPR-binding compound comprises a single ASGPR ligand moiety (X) linked to a moiety of interest (Y) via a linking moiety at position 1, 6, or 2 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 that covalently bonds the ASGPR ligand (X) to Y via a linking moiety at either position 1, 2, or 6 of X. In certain embodiments, L is 20 to 100, e.g., 25 to 80, 25 to 60, or 25 to 50 consecutive atoms. In certain embodiments of Formula (I), n is 1 and L comprises a backbone of 25 or more consecutive atoms that covalently bonds the ASGPR ligand (X) to Y.

[0020] In some embodiments, the ASGPR-binding compound is multivalent (e.g., in Formula (I), n is 2 or greater, such that the ASGPR-binding compound comprises two or more ASGPR ligand-binding moieties (X), each covalently attached 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 bivalent (e.g., in Formula I, n is 2). In certain other cases, the ASGPR-binding compound is trivalent (e.g., in Formula I, n is 3). In certain embodiments, each branch of the branched linker is linked to a respective X to a branch point of the linker. In certain embodiments, each branch of the linker comprises 14 to 50 consecutive atoms, e.g., 14 to 40, 14 to 30, or 14 to 20 atoms. In certain embodiments, each branch of the linker comprises a linear linker of 20 or more consecutive atoms. In certain embodiments, the linker comprises 12 or more consecutive atoms covalently bonding the branch point of L to the moiety of interest (Y), e.g., a linear linker of 15 or more, 20 or more, 30 or more, or even more consecutive atoms covalently bonding the branch point of L to Y.

[0021] Exemplary ASGPR ligand moieties that can be adapted for use in the conjugates of the present disclosure are described in WO / 2023288033, filed July 14, 2022, the entire disclosure of which is incorporated herein by reference.

[0022] Particular ASGPR ligand moieties are described below.

[0023] In some embodiments, the ASGPR ligand portion of the bifunctional molecule (e.g., X n -L or (XL) n , and other formulas described herein) have an affinity (K d ) specifically binds to ASGPR. In this context, the terms "bind," "bind," "specifically bind," or "specifically bind to" are used interchangeably.

[0024] In some embodiments, Formula (I) [ka] or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 500; m is 1 to 20; Y is the desired part, L is a linker, X is a group represented by formula (II) [ka] an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R 1 -Z 1selected from -*, -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; R 2 -Z 1 -*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, -NHR, and optionally substituted triazole; R 6 -Z 1 -*, -OH, -OR, optionally substituted (C1-C6) alkyl, -OC(O)R, -C(O)NHR, -NR xx R yy , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, and -NRCOR; each R is independently an optionally substituted (C1-C6) alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can cyclize to form an optionally substituted heterocyclyl; In the formula, R 1 , R 2 , and R 6 One of them is -Z 1 -*, and "*" is Z 1 represents the connection point between the linker (L) and R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21 are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl.

[0025] In some embodiments, Z 1 -Z 11 -A 1 -and-A 2 A is a linking moiety selected from 1 -and-A 2 - is an optionally substituted heterocyclylene, or -A 2 - is an optionally substituted isoxazolyl.

[0026] In some embodiments, -LY is [ka] Contains R Y teeth, [ka] is.

[0027] In some embodiments, R 6 is -OR, optionally substituted (C1-C6) alkyl, -OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NR xx R yy , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, or -NRCOR, where heteroaryl is other than triazole, wherein each R is independently an optionally substituted (C1-C6) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can be cyclized to form an optionally substituted heterocyclyl.

[0028] In some embodiments, R 1 is an arbitrarily substituted C 2~6 alkyl, optionally substituted —S—(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, or optionally substituted —S-heteroaryl.

[0029] In some embodiments, at least one R 21 is -COR or optionally substituted heteroaryl.

[0030] In some embodiments, n is 1, 2, or 3 and m is 1-3.

[0031] In some embodiments, Formula (I) [ka] or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 500; m is 1 to 20; Y is the desired part, L is a linker, X is a group represented by formula (II) [ka] an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R 1 -Z 1 selected from -*, -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; R 2 -Z 1 -*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, -NHR, and optionally substituted triazole; R 6 -Z 1 -*, -OH, -OR, optionally substituted (C1-C6) alkyl, -OC(O)R, -C(O)NHR, -NR xx R yy , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, and -NRCOR; each R is independently an optionally substituted (C1-C6) alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can cyclize to form an optionally substituted heterocyclyl; In the formula, R 1 , R 2 , and R 6 One of them is -Z 1-*, and "*" is Z 1 represents the connection point between the linker (L) and R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z 11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21 are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; However, at least one of the following occurs: A)Z 1 -Z 11 -A 1 -and-A 2 A is a linking moiety selected from 1 -and-A 2- is an optionally substituted heterocyclylene, or -A 2 - is optionally substituted isoxazolyl; B) -LY is [ka] wherein R Y teeth, [ka] is; C)R 6 is -OR, optionally substituted (C1-C6) alkyl, -OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NR xx R yy , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, or -NRCOR, where heteroaryl is other than triazole, wherein each R is independently an optionally substituted (C1-C6) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can cyclize to form an optionally substituted heterocyclyl; D)R 1 is an arbitrarily substituted C 2~6 alkyl, 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 R 21 is -COR or optionally substituted heteroaryl.

[0032] In some embodiments, n is 1, 2, or 3 and m is 1-3.

[0033] In some embodiments, X is a group represented by formula (a-II): [ka] It is of the type.

[0034] In some embodiments, X is of formula (a-II), and R 1 is n-propyl, and R 2 -Z 1 -*.

[0035] In some embodiments, Z 1 -Z 11 -A 1 -and-A 2 A is a linking moiety selected from 1 -and-A 2 - is an optionally substituted heterocyclylene.

[0036] In some embodiments, Z 1 teeth, [ka] is.

[0037] In some embodiments, -LY is [ka] wherein R Y teeth, [ka] and R 16 is (C1-C6) alkyl or monocyclic heteroaryl.

[0038] In some embodiments, -LY is [ka] Contains R Y teeth, [ka] is.

[0039] In some embodiments, R 6 is -OR, optionally substituted (C1-C6) alkyl, -OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NR xx R yy , optionally substituted aryl, or optionally substituted heteroaryl, provided that heteroaryl is other than triazole; wherein R is optionally substituted (C1-C6) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can be cyclized to form an optionally substituted heterocyclyl.

[0040] In some embodiments, R 6 is -O-(C1-C6)alkyl, optionally substituted heterocyclyl, or -O-aryl.

[0041] In some embodiments, R 1 is an arbitrarily substituted C 2~6 alkyl, optionally substituted —S—(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, or optionally substituted —S-heteroaryl.

[0042] In some embodiments, R 1 is an arbitrarily substituted C 2~6 It is alkyl.

[0043] In some embodiments, at least one R 21 is -COR or optionally substituted heteroaryl.

[0044] In some embodiments, Y is an antibody or antibody fragment.

[0045] In some embodiments, Formula (I) [ka] or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 500; m is 1 to 20; L is a linker, X is a group represented by formula (II) [ka] an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R 1 -Z 1 selected from -*, -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; R 2 -Z 1 -*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, and optionally substituted triazole; R 6 is -Z1-*, -OH, -OR, optionally substituted (C1-C6) alkyl, -OC(O)R, -C(O)NHR, -NR xx R yy , optionally substituted aryl, and optionally substituted heteroaryl; R is an optionally substituted (C1-C6) alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and Ryy can cyclize to form an optionally substituted heterocyclyl; In the formula, R 1 , R 2 , and R 6 One of them is -Z 1 -*, and "*" is Z 1 represents the connection point between the linker (L) and R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z 11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21 are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; R 3 and R4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z 11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21 are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; Y is a chemoselective ligation group.

[0046] In some embodiments, n is 1, 2, or 3 and m is 1-3.

[0047] 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 α-leaving 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.

[0048] In some embodiments, the chemoselective ligation group is [ka] is selected from.

[0049] In some embodiments, at least one of the following occurs: A)Z 1 -Z 11 -A 1 -and-A 2 A is a linking moiety selected from 1 -and-A 2 - is an optionally substituted heterocyclylene, or -A 2 - is optionally substituted isoxazolyl; B) -LY is [ka] Contains; C)R 6 is -OR, optionally substituted (C1-C6) alkyl, -OC(O)-optionally substituted heteroaryl, -C(O)NH-optionally substituted heteroaryl, -NR xx R yy, optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, or -NRCOR, where heteroaryl is other than triazole, wherein each R is independently an optionally substituted (C1-C6) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can cyclize to form an optionally substituted heterocyclyl; D)R 1 is an arbitrarily substituted C 2~6 alkyl, 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 R 21 is -COR or optionally substituted heteroaryl.

[0050] In some embodiments, the compound of formula (II) has the formula (a-II): [ka] It is expressed as:

[0051] In some embodiments, R 1 -Z 1 -*, -H, or (C1-C6) alkyl.

[0052] In some embodiments, R 2 is Z 1 -* or -NHCOCH3.

[0053] In some embodiments, R 3 and R 4 are -H, respectively.

[0054] In some embodiments, R 6-OH, -OC(O)R, -NR xx R yy or aryl, R is (C1-C6) alkyl, and R xx and R yy cyclizes to form an optionally substituted heterocyclyl.

[0055] In some embodiments, -Z 1 -* is -S-, -CH2-, [ka] and "*" is Z 1 and the linker (L).

[0056] In some embodiments, R 1 -Z 1 -*.

[0057] In some embodiments, R 2 -Z 1 -*.

[0058] In some embodiments, L contains 10 to 60 consecutive linear or branched atoms.

[0059] In some embodiments, L is a group of formula (IIb'): [ka] wherein: L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y.

[0060] In some embodiments of Formula (IIb'), n is 1 to 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.

[0061] In some embodiments, L is a group of formula (IIb'): [ka] wherein: n is 1, 2, or 3; L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y.

[0062] In some embodiments, formula (II') [ka] or a prodrug thereof, or a salt thereof, During the ceremony, 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; L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; X and Y are each independently as defined herein.

[0063] In some embodiments, formula (II') [ka] or a prodrug thereof, or a salt thereof, During the ceremony, 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; L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; Y is as defined herein; Each X is a group represented by formula (a-II) [ka] an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R 1 -Z 1 selected from -*, -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; R 2 -Z 1 -*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, and optionally substituted triazole; R 6 -Z 1 -*, -OH, -OR, optionally substituted (C1-C6) alkyl, -OC(O)R, -C(O)NHR, -NR xx R yy , optionally substituted aryl, and optionally substituted heteroaryl; R is an optionally substituted (C1-C6) alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R xx and R yy are independently H, optionally substituted (C1-C6) alkyl, or R xx and R yy can cyclize to form an optionally substituted heterocyclyl; In the formula, R 1 , R 2 , and R 6 One of them is -Z 1 -*, and "*" is Z 1 represents the connection point between the linker (L) and R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z 11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z 11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R 21 are independently selected from H, optionally substituted (C1-C6) alkyl, -COR, and optionally substituted heteroaryl; Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl.

[0064] In some embodiments, L 1 ~L 5Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C 1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -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, an amino acid residue, -NH-, and -NMe-; 1 ~L 5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 -C 1~20 -Alkylene-, -NR 16 C(O)-C 1~6 -Alkylene-, -C(O)NR 16 -C 1~6 -Alkylene-, -NR 16 -C 1~6 -Alkylene-, -NR 16 C(O)NR 16 -C 1~6 -Alkylene-, -NR 16 C(S)NR 16 -C 1~6 -Alkylene-, -C 1~6 -Alkylene-NR 16 C(O)-, -C 1~6 -Alkylene-C(O)NR 16 -, -C 1~6 -Alkylene-NR16 -, -C 1~6 -Alkylene-NR 16 C(O)NR 16 -, -C 1~6 -Alkylene-NR 16 C(S)NR 16 -, -O(CH2) p -, -(OCH2CH2) p -, -NR 16 C(O)-, -C(O)NR 16 a linking group comprising one or more linking moieties independently selected from -, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, an amino acid residue, or -NR16-; Each R 16 is independently —H, (C1-C6) alkyl, or monocyclic heteroaryl.

[0065] In some embodiments, each R 16 is independently (C1-C6) alkyl, or monocyclic heteroaryl. In some embodiments, each R 16 are independently R'.

[0066] In some embodiments, L 1 ~L 5 Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C 1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -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, an amino acid residue, -NH-, and -NMe-; 1 ~L 5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 teeth, [ka] where R z teeth, [ka] and R 16 is (C1-C6) alkyl or monocyclic heteroaryl.

[0067] In some embodiments, each L 1 ~L 5 Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C 1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -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, an amino acid residue, -NH-, and -NMe-; 1 ~L 5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 teeth, [ka] In the formula, R z teeth, [ka] is.

[0068] In some embodiments, L 1 ~L 5 Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C 1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -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, an amino acid residue, -NH-, and -NMe-; 1 ~L5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 teeth, [ka] and In the formula, R z teeth, [ka]

[0069] In some embodiments of Formula (II'), n is 1.

[0070] In some embodiments of Formula (II'), n is 2.

[0071] In some embodiments of Formula (II'), n is 3.

[0072] At least one L 1 is -C optionally substituted with 1 to 5 halo 1~20 -alkylene-.

[0073] In some embodiments, at least one L 1 is -CF2CH2-.

[0074] In some embodiments, at least one L 2 is -(OCH2CH2) p -It is.

[0075] In some embodiments, p is 2-3.

[0076] In some embodiments, at least one L 3 NHCONH-C 1~6 -alkylene-.

[0077] In some embodiments, at least one L 4-C 1~6 -alkylene-NHCONH-.

[0078] In some embodiments, at least one L 5 is -(OCH2CH2) p -It is.

[0079] In some embodiments, the lysosome-targeting bifunctional molecules of the present disclosure (e.g., those of formula (I)-(Ia)) can be prepared by the steps of: [ka] wherein: R 3 -Z 1 selected from -*, -H, -OH, -CH3, -OCH3, and -OCH2CH=CH; R 2 -Z 1 -*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, and optionally substituted triazole; R 6 -Z 1 -*, -OH, -OC(O)R, -C(O)NHR, and optionally substituted triazole, wherein R is an optionally substituted (C1-C6) alkyl or an optionally substituted aryl; In the formula, R 1 , R 2 , and R 6 One of them is -Z 1 -*, and "*" is Z 1 represents the connection point between the linker (L) and R 3 and R 4 are each independently H, or a pro-moiety, or R 3 and R 4 are linked in a ring to form a pro-moiety, R 11 is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z 1 -Z 11 -, -Z11 -A 1 -, -A 2 -, -NR 21 CO-, -CONR 21 -, -NR 21 SO2-, -SO2NR 21 -, -NR 21 C(=O)NR 21 -, and -NR 21 C(=S)NR 21 - a linking moiety selected from -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted arylene or an optionally substituted heteroarylene; Each R 21 are independently selected from H and optionally substituted (C1-C6) alkyl; Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0080] In some embodiments of Formula (II), n is 3, R 6 OH, R 2 -NHCOCH3, R 3 ~R 4 H, R 1 Z 1 In the case of Z 1 is not O, ii) n is 2 or 3, R 6 OAc, R 2 -NHCOCH3, R 3 ~R 4 is Ac, R 1 Z 1 In the case of Z 1 is not O, iii) n is 2 or 3, R 6 Ga-OBz, R 2 -NHCOCH3, R 3 ~R 4 Bz, R1 Z 1 In the case of Z 1 is not O, iv) n is 3, R 6 OH, R 2 -NHCOCH3, R 3 ~R 4 H, R 1 Z 1 , Z 11 is O, L comprises a backbone of at least 16 contiguous atoms at the branch points; v) n is 3, R 6 Z 1 (Z 1 O), R 3 ~R 4 If H, then R 1 is neither -CH3-OCH3 nor -OCH2CH=CH, vi)R 11 is a group of formula -CH2O- bridging (i.e., cyclically linking) the 1-position carbon atom of the sugar ring, R 2 is -NHCOCH3, and R 3 ~R 4 is H and R 1 and R 3 is Z 1 isn't it.

[0081] 1. Linked ASGPR Ligand Moiety In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Iia): [ka] where R 2 , R 3 , R 4 , R 6 and Z 1 is as defined herein. In some embodiments of Formula (Iia), R 6 is selected from -OH, -OC(O)R, and -C(O)NHR, and R 2 is selected from -NHCOCH3, -NHCOCF3, and -NHCOCH2CF3.

[0082] In some embodiments of Formula (II), Z 1 is in the β configuration, and the formula (Iia-1) [ka] It can be described as:

[0083] In some embodiments of Formula (II), Z 1 is in the α configuration, and the formula (Iia-2) [ka] It can be described as:

[0084] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z 1 -Z 11 -A 1 - in which A 1 - is an optionally substituted arylene or an optionally substituted heteroarylene. 1 is 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.

[0085] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (IIIa) or (IIIb): [ka] where: -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2-, wherein each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl; R21 is H or optionally substituted (C1-C6) alkyl; -A 1 - is arylene, substituted arylene, heteroarylene, or substituted heteroarylene.

[0086] In some embodiments of formula (IIIa) or (IIIb), Z 11 is -S-.

[0087] In some embodiments, Z 11 is -C(R 22 )2-. In some embodiments, Z 11 is -CH2-.

[0088] In certain embodiments, Z 11 is -C(R 22 )2, wherein at least one R 22 is H. In certain embodiments, both R 22 is H. In certain embodiments, Z 11 is —O—. In certain embodiments, Z 11 In certain embodiments, Z is -S-. 11 is -N(R 21 ) where R 21 is H or (C1-C3) alkyl.

[0089] In certain embodiments, A 1 is a triazole.

[0090] In certain embodiments, Z 1 is -C(R 22 ) 2-triazole. In certain embodiments, Z 1 teeth, [ka] In certain embodiments, Z 1 teeth, [ka] is.

[0091] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z 1 is Z 11 In certain embodiments, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H, Z 11 is -CH2-. In some cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -N(R 21 ) where R 21 is H or (C1-C3) alkyl.

[0092] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z 1 is a monocyclic 5- or 6-membered heteroaryl or aryl. In certain embodiments, Z 1 teeth, [ka] In certain embodiments, Z 1 teeth, [ka] is.

[0093] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z 1 -O-, -S-, -C(R 22 )2-, -NR 21 -,-CONR 21 - and [ka] is selected from: X 1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0094] In certain embodiments of formula (Iia), (Iia-1), or (Iia-2), Z 1 is an optionally substituted (C1-C6) alkyl. Z 1 In certain embodiments, alkyl is methyl. 1 In certain embodiments, alkyl is ethyl. 1 In certain embodiments, alkyl is propyl. 1 In certain embodiments, alkyl is butyl. 1 In certain embodiments, alkyl is pentyl. 1 In certain embodiments, alkyl is hexyl.

[0095] In certain embodiments, the ASGPR binding moiety (X) of formula (Iia-1) is selected from one of the following structures: [ka]

[0096] In some embodiments of formula (Iia-2), Z 1 is in the β configuration, and X is represented by the formula (IIIb-2) [ka] wherein -A1 - is arylene, substituted arylene, heteroarylene, or substituted heteroarylene.

[0097] In some embodiments of formula (IIIb-2), A 1 In some embodiments of formula (IIIb-2), X is a group represented by formula (X A -4).

[0098] In some embodiments of formula (Iia-1), Z 1 is in the alpha configuration at the 1 carbon of the galactosamine ring. In some embodiments of formula (Iia-1), Z 1 is S, and each X is a function of the formula (X A In some embodiments of formula (Iia-1), each X is of formula (X A In some embodiments of formula (Iia-1), each X is of formula (X A In some embodiments of formula (Iia-1), each X is of formula (X A In some embodiments of formula (Iia-1), each X is of formula (X A -5).

[0099] In certain embodiments, the compound of formula (Iia-2) is selected from one of the following structures: [ka] (X B -1), (X B -2), (X B -3), (X B -4), and.

[0100] In some embodiments of formula (Iia-2), each X is a group represented by the formula (X B -1).

[0101] In some embodiments of formula (Iia-2), each X is a group represented by the formula (X B -2).

[0102] In some embodiments of formula (Iia-2), each X is a group represented by the formula (X B -3).

[0103] In some embodiments of formula (Iia-2), each X is a group represented by the formula (X B -4).

[0104] In some embodiments of formula (Iia-2), Z 1 is in the α configuration, and X is represented by the formula (IIIb-1) [ka] wherein -A 1 - is arylene, substituted arylene, heteroarylene, or substituted heteroarylene.

[0105] In certain embodiments of Formula (IIIb-1), A 1 is 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.

[0106] In certain embodiments, X in formula (IIIb-1) is selected from one of the following structures: [ka]

[0107] In some embodiments of formula (IIIb-1), each X is a group represented by the formula (X C -1).

[0108] In some embodiments of formula (IIIb-1), each X is a group represented by the formula (X C -2).

[0109] Exemplary ligand moieties that bind to ASGPR and their synthons that can be utilized in compounds of the present disclosure are shown in Tables 1-5. In certain embodiments, the compound of formula (Iia) is a compound shown in Table 1. [Table 1-1]

[0110] In some embodiments of any one of X1 to X5.1, Z 1 is in the α-configuration, so that the ASGPR binding moieties X1 to X5.1 are represented by the formula (Iia-2): [ka] is derived from

[0111] Two linked ASGPR ligand moieties In some embodiments, the ASGPR binding moiety (X) is linked to the 2-position of the sugar analog. In some embodiments, the ASGPR binding moiety (X) has a reduced ring carbon at the 1-position relative to the galactosamine-derived sugar. In some embodiments, the ASGPR binding moiety (X) of the bifunctional molecules of the present disclosure has formula (Iib): [ka] where R 1 , R 3 , R 4 , R 6 , R 11 and Z 1 is as defined herein.

[0112] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (Iib'): [ka] where R 3 ~R 4 , R 6 , and Z1 is as defined herein.

[0113] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (Iva): [ka] where R 1 , R 11 , and Z 1 is as defined herein.

[0114] In some embodiments of Formula (Iib), (Iib') or (Iva), Z1 is an optionally substituted -(C(R 22 )2) q heteroarylene, and [ka] wherein q is 0 or 1.

[0115] In some embodiments of formula (Iib), (Iib') or (Iva), Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, where q is 0 or 1.

[0116] In some embodiments of formula (Iib), (Iib') or (Iva), Z 1 teeth, [ka] In some embodiments, Z 1 teeth, [ka] is.

[0117] In some embodiments of formula (Iib), (Iib') or (Iva), Z 1 teeth, [ka] where R 23 is H or C (1~3) - alkyl.

[0118] In some embodiments of formula (Iib), (Iib') or (Iva), Z 1 is -NR 23 CO—, where R 23 is H or C (1~3) - alkyl.

[0119] In certain embodiments of formula (Iib), (Iib') or (Iva), Z 1 is an optionally substituted -(C(R 22 )2) q heteroaryl, and [ka] wherein q is 0 or 1.

[0120] In certain embodiments of formula (Iib), (Iib') or (Iva), Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, where q is 0 or 1. In certain embodiments, Z 1 teeth, [ka] is.

[0121] In certain cases of formula (Iib), (Iib') or (Iva), Z 1 teeth, [ka] where R 23 is H or C (1~3) - alkyl.

[0122] In certain cases of formula (Iib), (Iib') or (Iva), Z 1 is -NR 23 CO—, where R 23 is H or C (1~3) - alkyl.

[0123] In certain embodiments of formula (Iib), (Iib') or (Iva), Z 1 is a monocyclic 5- or 6-membered heteroarylene or arylene. In certain embodiments, Z 1 teeth, [ka] is.

[0124] In certain embodiments of formula (Iib), (Iib'), or (Iva), Z 1 -O-, -S-, -C(R 22 )2-, -NR 21 -,-CONR 21 - and [ka] is selected from: X 1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0125] In certain embodiments, the compound of formula (Iib), (Iib') or (Iva) is selected from one of the following structures: [ka] In the formula, R 1A are independently H or (C 1~3 ) alkyl.

[0126] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ivb) or (Ivc): [ka] where: -Z 11 - is -O-, -S-, -N(R 21 )-, or -C(R 22 )2, -A 1 -and-A 2 - is an optionally substituted arylene or an optionally substituted heteroarylene; Each R 21 are independently selected from H and optionally substituted (C1-C6) alkyl; Each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl. In some embodiments of formula (Ivb) or (Ivc), R 1 is H.

[0127] In some embodiments, R 2 -Z 1 -* and R 11 is a group of formula -CH2O- that bridges (i.e., cyclically joins) the 1-carbon atom of the sugar ring.

[0128] In some embodiments, -Z 1 -* or -Z 1 -L- is [ka] Includes:

[0129] In certain embodiments of Formula (Iib), R 11 is H and the compounds are those in Table 2. [Table 2]

[0130] In certain embodiments, the compound of formula (Iib) is a compound shown in Table 3. In certain embodiments, the compound of formula (Iib), C1 (i.e., R 1 In certain embodiments, the configuration in the compound of formula (Iib), C1 (i.e., R 1 ) is configured as β. [Table 3-1] [Table 3-2]

[0131] In certain embodiments, the compound of formula (Id') is a compound shown in Table 4. [Table 4-1]

[0132] In some embodiments, the ASGPR binding moiety (X) of a compound of the present disclosure has formula (Ivb-1) or (Ivc-1): [ka] where R 11 is the bridging moiety connecting the 5 carbon to the 1 carbon.

[0133] In some embodiments of formula (Ivb), or (Ivb-1), Z 11 is -C(R 22 )2-. In certain embodiments, at least one R22 is H. In certain embodiments, both R 22 is H. In certain embodiments, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain embodiments, Z 11 is -N(R 21 ) where R 21 is H or (C1-C3) alkyl.

[0134] In certain embodiments of formula (Ivb), (Ivc), (Ivb-1) or (Ivc-1), -A 1 -and-A 2 Each - is 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.

[0135] In some embodiments of formula (Ivb) or (Ivb-1), A 1 The ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. 1 The ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. 1 The ring is a triazole. 1 The ring is pyridine. 1 The ring is pyrimidine. 1 In certain embodiments, the ring is a thiadiazole. 1 The ring is a 5- or 6-membered arylene or heteroarylene, further substituted with one or more substituents. 1The ring is further substituted with one or more substituents selected from halogen, (C1-C6) alkyl, and substituted (C1-C6) alkyl (eg, CF3).

[0136] In some embodiments of any one of formulas (Ivc) or (Ivc-1), A 2 The ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. 2 The ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. 2 The ring is a triazole. 2 The ring is pyridine. 2 The ring is pyrimidine. 2 In certain embodiments, the ring is a thiadiazole. 2 The ring is a 5- or 6-membered arylene or heteroarylene, further substituted with one or more substituents. 2 The ring is further substituted with one or more substituents selected from halogen, (C1-C6) alkyl, and substituted (C1-C6) alkyl (eg, CF3).

[0137] In certain embodiments of formula (Ivb) or (Ivb-1), -Z 11 -A 1 - is a monocyclic 5- or 6-membered heteroarylene of one of the following structures: [ka]

[0138] In certain embodiments of formula (Ivc) or (Ivc-1), -A 2 - is the following structure [ka] is a monocyclic 5- or 6-membered heteroarylene of the formula:

[0139] Specific -Z 11 -A 1 It is understood that a variety of substituents can be utilized to connect the - group to the adjacent linker. In certain embodiments of formula (Ivb) or (Ivb-1), -Z 11 -A 1 - is a monocyclic 5- or 6-membered heteroarylene attached to a linking moiety as shown in one of the following structures: [ka]

[0140] In certain embodiments of formula (Ivc) or (Ivc-1), -Z 11 -A 1 - is a monocyclic 5- or 6-membered heteroarylene attached to a linking moiety as shown in one of the following structures: [ka]

[0141] In some embodiments of the compound of formula (Iib), or (Iva)-(Ivc), R 1 is H, and as a result, the compounds of formula (Iib) or (Iva) to (Ivc) have no substituent other than hydrogen at the 1-position of the sugar ring.

[0142] In some embodiments, the compound of Formula (Iib) is any one of Formulas (Ivd)-(Ivg): [ka] In the formula, A 1 Ring and A 2 Ring, R 6 , R 4 , R 3 , R 11 , and R 21is as defined herein.

[0143] In some embodiments of any one of formulas (Ivd)-(Ivg), A 1 The ring is a 5- or 6-membered arylene or heteroarylene. 1 The ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, imidazole, and furan. 1 The ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. 1 The ring is a triazole. 1 The ring is pyridine. 1 The ring is pyrimidine. 1 In certain embodiments, the ring is a thiadiazole. 1 The ring is pyrazine. 1 The ring is a 5- or 6-membered arylene or heteroarylene, further substituted with one or more substituents. 1 The ring is further substituted with one or more substituents selected from halogen, (C1-C6) alkyl, and substituted (C1-C6) alkyl (eg, CF3).

[0144] In some embodiments of any one of formulas (Ivd)-(Ivg), A 2 The ring is a 5- or 6-membered arylene or heteroarylene. 2 The ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. 2The ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. 2 The ring is a triazole. 2 The ring is pyridine. 2 The ring is pyrimidine. 2 In certain embodiments, the ring is a thiadiazole. 2 The ring is a 5- or 6-membered arylene or heteroarylene, further substituted with one or more substituents. 2 The ring is further substituted with one or more substituents selected from halogen, (C1-C6) alkyl, and substituted (C1-C6) alkyl (eg, CF3).

[0145] In some embodiments of any one of formulas (Ivd)-(Ivg), A 1 Ring or A 2 There is no ring.

[0146] In some embodiments of any one of formulas (Ivd)-(Ivg), A 1 Ring or A 2 The ring is phenylene or substituted phenylene.

[0147] In some embodiments of Formula (Ivd), A 2 The ring is a 5- or 6-membered heteroarylene. In certain cases of formula (Ivd), A 2 The ring is a 5-membered heteroarylene. In certain embodiments of Formula (Ivd), A 2 In certain embodiments of (Ivd), A 2 There is no ring.

[0148] In some embodiments of Formula (Ive), A 1 The ring is a 5- or 6-membered heteroarylene, and R 21is H. In certain embodiments of Formula (Ive), the A ring is triazole. In certain cases of Formula (Ive), A 1 In certain cases of formula (Ive), A 1 In certain cases of formula (Ive), A 1 In some embodiments of Formula (Ive), A 1 The ring is absent, and R 21 is H or optionally substituted acyl. In certain embodiments, R 21 is —COCH. In certain embodiments, R 21 is H.

[0149] In some embodiments of Formula (Ivf), A 1 The ring is a 5- or 6-membered heteroarylene. In certain cases of formula (Ivf), A 1 The ring is a 5-membered heteroarylene. In certain embodiments of Formula (Ivf), A 1 In certain embodiments of (Ivf), A 1 There is no ring.

[0150] In some embodiments of Formula (Ivg), A 2 The ring is a 5- or 6-membered heteroarylene. In certain cases of formula (Ivg), A 2 The ring is a 5-membered heteroarylene. In certain embodiments of Formula (Ivg), A 2 The ring is a triazole. (In certain embodiments of Ivdg, A 2 There is no ring.

[0151] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure is represented by formula (Ivh)-(Ivk): [ka] wherein: R 6 , R 4 , R3 , and R 21 is as defined herein; Y 1 ~Y 3 are each independently N or CR 25 and R 24 and R 25 are H, optionally substituted C (1~6) -alkyl, optionally substituted fluoroalkyl, and halogen.

[0152] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure is represented by the formula ((Ivl)-(Ivm): [ka] wherein: R 6 , R 4 , R 3 , and R 21 is as defined herein; Y 1 ~Y 3 are each independently N or CR 25 and Y 4 is N or CR 24 and Y 5 is S, O, or NH, R 24 and R 25 are H, optionally substituted C (1~6) -alkyl, optionally substituted fluoroalkyl, and halogen.

[0153] In some embodiments of Formula (Ivi), Y 1 ~Y 3 At least one of is N.

[0154] In certain embodiments, Y 1 ~Y 3 At least two of the are N.

[0155] In certain embodiments, Y 1 and Y 4 is N.

[0156] In certain embodiments, Y 1 and Y 3 is N, Y 2 is CR 25 is.

[0157] In certain embodiments, Y 1 and Y 2 is N, Y 3 is CR 25 is.

[0158] In certain embodiments, Y 1 and Y 2 is CR 25 , Y 3 is N.

[0159] In certain embodiments of any one of Formulas (Ivd)-(Ivk), or (Ivd)-(Ivm), R 6 is H.

[0160] In some embodiments of any one of Formulas (Ivd)-(Ivk), or (Ivd)-(Ivm), R 4 and R 3 are each H. In certain embodiments, R 4 ~R 3 At least one of R is a pro-moiety. 4 and R 3 are cyclically linked to form a promoiety (eg, as described herein).

[0161] In some embodiments, the compound of formula (Ivi) has the formula (Ivi-1): [ka] It is of

[0162] In the formula, R 24 and R 25 is independently selected from H, halogen, (C1-C6) alkyl, and substituted (C1-C6) alkyl (e.g., CF3). In some embodiments of Formulas (Ivi)-(Ivi-1), R 25 is H. In certain embodiments, R 25 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF. In some embodiments of Formula (Ivi) or (Ivi-1), R 24 is H. In certain embodiments, R 24 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF.

[0163] In some embodiments, the compound of formula (Ivi-1) is a compound of formula (X D ) [ka] It is of the type.

[0164] In some embodiments, the compound of formula (Ivk-1) is a compound of formula (X E ) [ka] It is of the type.

[0165] In certain embodiments, the compound of formula (Ivl) has the formula (Ivl-1): [ka] wherein: R 6 , R 4 , R 3 , and R 21 is as defined herein; Y 1~Y 4 are each independently N or CR 25 and Y 5 is S, O, or NH, Each R 25 is H, optionally substituted C (1~6) -alkyl, optionally substituted fluoroalkyl, and halogen.

[0166] In certain embodiments, each R 25 is H.

[0167] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure can be described by one of the following structures: [ka]

[0168] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure can be described by one of the following structures: [ka]

[0169] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure can be described by one of the following structures: [ka]

[0170] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure can be described by one of the following structures: [ka]

[0171] In certain embodiments of Formula (Iib), R 1 R 3 , R 4, and R 11 is H, R 6 is OH, [ka] In the formula, Z 1 is -NH-, -CH2-, -S- or -O-.

[0172] In certain embodiments of Formula (Iib′), R 3 , R 4 is H, R 6 is OH, [ka] In the formula, Z 1 is -NH-, -CH2-, -S-, -O-, triazole, e.g. [ka] is.

[0173] 6-linked ASGPR ligand moiety In some embodiments, the ASGPR binding moiety (X) is linked to position 6 of the sugar analog. In some embodiments, the ASGPR binding moiety (X) has a reduced ring carbon at position 1 relative to the galactosamine-derived sugar.

[0174] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Iic): [ka] where R 1 ~R 4 , and Z 1 is as defined herein.

[0175] In certain embodiments of Formula (Iic), Z 1 -O-, -S-, -CONR 21 - and optionally substituted -(C(R 22)2) q -heteroarylene, where q is 0 or 1. In certain embodiments, Z 1 is -O-. In certain other cases, Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, and q is 0 or 1.

[0176] In certain embodiments, Z 1 teeth, [ka] is.

[0177] In certain embodiments of Formula (Iic), Z 1 -Z 11 -A 1 - in which -A 1 - is an optionally substituted -A 1 - or optionally substituted arylene. In certain embodiments, -A 1 - is an optionally substituted heteroarylene. In certain embodiments, the heteroarylene is a 5- or 6-membered heteroarylene. In certain embodiments, the heteroarylene is a 5-membered heteroarylene. In certain embodiments, the 5-membered heteroarylene is a triazole. In certain embodiments, the triazole is a 1,2,3-triazole moiety. In certain embodiments, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H. In certain cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -N(R 21 ) where R 21 is H or (C1-C3) alkyl. In certain embodiments, Z1 is -C(R 22 ) 2-triazole. In certain embodiments, Z 1 teeth, [ka] is.

[0178] In certain embodiments of Formula (Iic), Z 1 is Z 11 In certain embodiments, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H, Z 11 is -CH2-. In some cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -N(R 21 ) where R 21 is H or (C1-C3) alkyl.

[0179] In certain embodiments of Formula (Iic), Z 1 is a monocyclic 5- or 6-membered heteroarylene or arylene. In certain embodiments, Z 1 teeth, [ka] is.

[0180] In certain embodiments of Formula (Iic), Z1 is -O-, -S-, -C(R22)2-, -N(R21)-CON(R 21 )-, and [ka] is selected from: X 1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0181] In certain embodiments, the compound of formula Iic) has the following structure: [ka]

[0182] In certain embodiments, the compound of formula Iic) has the following structure: [ka]

[0183] In certain embodiments of Formula (Iic), R 11 is H and the compounds are those in Table 5. [Table 5-1]

[0184] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (Iid): [ka] where: R 6 , R 4 , R 3 , and Z 1 is as defined herein; Y 6 and Y 5 are -O-, -S-, and NR, respectively. 21 - and -C(R22 )2 are independently selected from R 21 is H, optionally substituted (C1-C6) alkyl, and -C(O)R 22 is selected from Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; Ring B is a 5- or 6-membered optionally substituted cyclic group. In some embodiments of Formula (Iid), Y 5 is attached to the sugar ring via an α-configuration. In some embodiments of formula (Iid), Y 5 is connected to the sugar ring via a β configuration.

[0185] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (Iid'): [ka] where: R 6 , R 4 , R 3 , and Z 1 is as defined herein; Y 5 and Y 6 are -O-, -S-, and NR, respectively. 21 - and -C(R 22 )2 are independently selected from R 21 is H, optionally substituted (C1-C6) alkyl, and -C(O)R 22 is selected from Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; Ring B is a 5- or 6-membered optionally substituted cyclic group.

[0186] In some embodiments of formula (Iid)-(Iid′), Y 5 is O. In certain embodiments, Y 5is S. In certain embodiments, Y 5 is -NR 21 In certain embodiments, Y 5 is -C(R 22 )2, and each R 22 is H.

[0187] In some embodiments of formula (Iid)-(Iid′), Y 6 is -NR 21 -, wherein R 21 is H. In certain embodiments, Y 6 is -NR 21 -, wherein R 21 is -C(O)R 22 In certain embodiments, R 22 is methyl.

[0188] In some embodiments of Formula (Iid)-(Iid'), the B ring is a 5-membered 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.

[0189] In some embodiments of formulas (Iid)-(Iid′), Z 1 is Z 11 wherein Z 11 -O-, -S-, NR 21 - and -C(R 22 )2. In certain embodiments, Z 1 is —O—. In certain embodiments, Z 1 is -S-. In certain embodiments, Z 1 is NR 21 where R 21 , is H. In certain embodiments, Z 1 is -C(R 22 )2, wherein each R 22 is H.

[0190] In some embodiments of formulas (Iid)-(Iid′), Z 1 is an arbitrarily substituted Z11 -heteroarylene or optionally substituted Z 11 -arylene. In some embodiments, Z 1 is CH2-heteroarylene or CH2-arylene. In some embodiments of Formula (Iid)-(Iid'), Z 1 is an optionally substituted amide. In some embodiments of Formula (Iid)-(Iid'), Z 1 is an optionally substituted sulfonamide. In some embodiments of Formula (Iid)-(Iid'), Z 1 is an optionally substituted urea or an optionally substituted thiourea.

[0191] In some embodiments, the compound of Formula (Iid)-(Iid') has one of the following structures: [ka]

[0192] In certain embodiments of any one of formulas (Iia), (Iib), or (Iid), R 6 is OH. In certain other cases, R 6 is —OC(O)R. In certain embodiments, R 6 is —C(O)NHR, where R is an optionally substituted alkyl. In certain embodiments, R terminates in an alkenyl or alkynyl group. In certain other cases, R 6 is an optionally substituted triazole. In certain embodiments, the triazole has the structure [ka] It is of the type.

[0193] In certain embodiments of formula (Iia) and (Iic), R 2 is —NHCOCH. In certain other embodiments, R 2is -NHCOCF. In certain other embodiments, R 2 is —NHCOCH2CF3. In certain embodiments, R 2 is —OH. In certain other cases, R 2 is an optionally substituted triazole. In certain embodiments, the triazole has the structure [ka] It is of the type.

[0194] In certain embodiments, R 6 or R 2 When is a substituted triazole, the triazole is a 1,2,3-triazole and the substituent is at the 4- or 5-position. In certain embodiments, the substituent on the triazole moiety is optionally substituted (C 1~6 ) alkyl, optionally substituted (C 1~6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkaryl, and optionally substituted alkylheteroaryl. It will be understood that any convenient substituent can be included in the triazole moiety. See, for example, the triazole moieties disclosed in Mamidayala et al., J. Am. Chem. Soc. 2012, 134, 1978-1981.

[0195] Z 1 , Z 11 , and Z 11 It is understood that the -Ar linking moiety can be considered part of the X group of formula (I). In the ASGPR binding moieties (X) described herein, -Z 1 - can be connected to -L (e.g., in a linker described herein) via various bonds and linking moieties depending on the method of preparation. 1 In some embodiments, the subject compound can be linked to a - moiety. [ka] Selected from -Z 1 -L 1 - includes parts, In the formula, each R 21 is independently selected from H, and optionally substituted (C-C) alkyl, and each R 22 are 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 0-6.

[0196] In some embodiments, the subject compound is [ka] Selected from -Z 1 -L 1 - includes parts, In the formula, each R 21 is independently selected from H, and optionally substituted (C-C) alkyl, and each R 22 are 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.

[0197] In certain embodiments, Z 1 -L 1 -The base is [ka] and o is 1 or 2.

[0198] In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and p is 1 or 2.

[0199] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0200] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0201] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0202] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein s and t each independently represent an integer of 1 to 3.

[0203] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein u is 1 to 3.

[0204] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, v and w each independently represent an integer of 1 to 3.

[0205] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, x is 0 to 3.

[0206] In certain embodiments, Z 1 -L 1 -The base is [ka] where y is 1 to 3.

[0207] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H and z is 1 to 4.

[0208] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H, and z1 is 1 to 4.

[0209] In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and q is 0 to 3. In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and q is 1 to 3.

[0210] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0211] In some embodiments, the subject compound is [ka] Selected from -Z 1 Contains the -L- group.

[0212] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0213] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0214] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0215] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0216] In certain embodiments, -Z 1 -L 1 - includes optionally substituted -NH-heteroarylene-. In certain embodiments, a heteroarylene is triazole. In certain embodiments, a heteroarylene is pyridine. In certain embodiments, a heteroarylene is pyrimidine. In certain embodiments, a heteroarylene is thiadiazole.

[0217] In certain embodiments, -Z 1 -L 1 -teeth, [ka] wherein each R 21 are independently selected from H, optionally substituted (C-C) alkyl, and optionally substituted acyl; R 24 and R 25 are H, optionally substituted C, (1~6) -alkyl, optionally substituted fluoroalkyl, and halogen.

[0218] In certain embodiments, -Z 1 -L 1 -teeth, [ka] wherein R 24 and R 25 are H, optionally substituted C, (1~6) - independently selected from alkyl, optionally substituted fluoroalkyl, and halogen; 21 are independently selected from H, optionally substituted (C1-C6) alkyl, and optionally substituted acyl.

[0219] In certain embodiments, R 21 is H. In certain embodiments, R 24 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF. In certain embodiments, R 25 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF.

[0220] In certain embodiments, -Z 1 -L 1 -teeth, [ka] is.

[0221] 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, the linking moiety of the linker comprises a triazole derived from a click chemistry bond. In certain embodiments, the ASGPR ligand moiety (X) is attached to the linking moiety as shown in any one of the following structures: [ka]

[0222] In certain embodiments of Formula (Iib), R 1 R 3 , R 4 , and R 11 is H, R 6 is OH, [ka] In the formula, Z 1 is triazole, -NH-heteroaryl (e.g., -NH- attached to pyridine, pyrazine, or pyrimidine), -NH-, -O-, or -CH2-, and / or Z 1 is attached to a linking moiety as shown in one of the following structures: [ka]

[0223] In certain embodiments of Formula (Iib), R 1 R 3 , R 4 , and R 11 is H, R 6 is OH, [ka] In the formula, Z 1 is attached to a linking moiety as shown in one of the following structures: [ka]

[0224] Further exemplary ASGPR binding moieties The ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ia): [ka] where: R 1 -OH, -OC(O)R, -C(O)NHR, -Z 1-*, and optionally substituted triazole, wherein R is an optionally substituted C 1~6 alkyl or optionally substituted aryl; R 2 is -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, optionally substituted triazole, and -Z 1 - Selected from *, R 3 are -H, -OH, -CH3, -OCH3, -OCH2CH=CH and -Z 1 - Selected from *, R 1 ~R 3 One of them is -Z 1 -*, where "*" represents Z 1 represents the point of attachment of the linker (L) to the R 4 and R 5 are each independently selected from H and pro moieties; or R 4 and R 5 are cyclically linked to form a pro-moiety, R 11 is H or a group that forms a bridge (e.g., a two-atom bridge connected in a ring) to the 1-position carbon atom, Z 1 is Z 11 , optionally substituted Z 11 -heteroaryl, optionally substituted Z 11 - a linking moiety selected from aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z 11 -O-, -S-, NR 21 - and -C(R 22 )2 is selected, Each R 21 are independently selected from H and optionally substituted (C1-C6) alkyl; Each R 22are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0225] In some embodiments of Formula (Ia), i) n is 3, R 1 OH, R 2 -NHCOCH3, R 4 ~R 5 H, R 3 Z 1 In the case of Z 1 is not O, ii) n is 2 or 3, R 1 OAc, R 2 -NHCOCH3, R 4 ~R 5 is Ac, R 3 Z 1 In the case of Z 1 is not O, iii) n is 2 or 3, R 1 OBz, R 2 -NHCOCH3, R 4 ~R 5 Bz, R 3 Z 1 In the case of Z 1 is not O, iv) n is 3, R 1 OH, R 2 -NHCOCH3, R 4 ~R 5 H, R 3 Z 1 , Z 11 is O, L comprises a backbone of at least 16 contiguous atoms at the branch points; v) n is 3, R 1 Z 1 (Z 1 O), R 4 ~R 5 If H, then R 3 is neither -CH3-OCH3 nor -OCH2CH=CH, vi)R 11 is a group of formula -CH2O- bridging (i.e., cyclically linking) the 1-position carbon atom of the sugar ring, R 2 is -NHCOCH3, and R 4 ~R5 is H and R 1 and R 3 is Z 1 isn't it.

[0226] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ia-1): [ka] where: R 1 -OH, -OC(O)R, -C(O)NHR, -Z 1 -*, and optionally substituted triazole, wherein R is an optionally substituted C 1~6 alkyl or optionally substituted aryl; R 2 is -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, optionally substituted triazole, and -Z 1 - Selected from *, R 3 are -H, -OH, -CH3, -OCH3, -OCH2CH=CH and -Z 1 - Selected from *, R 1 ~R 3 One of them is -Z 1 -*, where "*" represents Z 1 represents the point of attachment of the linker (L) to the R 4 and R 5 are each independently selected from H and a promoiety (e.g., an ester promoiety); Z 1 is Z 11 , optionally substituted Z 11 -heteroaryl, optionally substituted Z 11 - a linking moiety selected from aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z 11 -O-, -S-, NR21 - and -C(R 22 )2 is selected, Each R 21 are independently selected from H and optionally substituted (C1-C6) alkyl; Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0227] In some embodiments of Formula (Ia-1), i) n is 3, R 1 OH, R 2 -NHCOCH3, R 4 ~R 5 H, R 3 Z 1 In the case of Z 1 is not O, ii) n is 2 or 3, R 1 OAc, R 2 -NHCOCH3, R 4 ~R 5 is Ac, R 3 Z 1 In the case of Z 1 is not O, iii) n is 2 or 3, R 1 OBz, R 2 -NHCOCH3, R 4 ~R 5 Bz, R 3 Z 1 In the case of Z 1 is not O, iv) n is 3, R 1 OH, R 2 -NHCOCH3, R 4 ~R 5 H, R 3 Z 1 , Z 1 is O, L comprises a backbone of at least 16 consecutive atoms at the branch points; and / or v) n is 3, R 1 Z 1 (Z 1 O), R 4 ~R 5 If H, then R 3is not -CH3.

[0228] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ib): [ka] where R 1 , R 2 , R 4 , R 5 and Z 1 is as defined herein. In some embodiments of Formula (Ib), R 1 is selected from -OH, -OC(O)R, and -C(O)NHR, and R 2 is selected from -NHCOCH3, -NHCOCF3, and -NHCOCH2CF3

[0229] In some embodiments of Formula (Ib), Z 1 is the alpha configuration. [ka]

[0230] In some embodiments of Formula (Ib), Z 1 is the α configuration, and X is the following formula: [ka] It is of the type.

[0231] In some embodiments of Formula (Ib), Z 1 is the α configuration, and X is the following formula: [ka] It is of the type.

[0232] In some embodiments of Formula (Ib), Z 1 is the α configuration, and X is the following formula: [ka] It is of the type.

[0233] In some embodiments of Formula (Ib), Z 1 is the α configuration, and X is the following formula: [ka] It is of the type.

[0234] In some embodiments of Formula (Ib), Z 1 is the α configuration, and X is the following formula: [ka] It is of the type.

[0235] In some embodiments of Formula (Ib), Z 1 is the β configuration. [ka]

[0236] In some embodiments of Formula (Ib), Z 1 is in the β configuration and X is of the formula: [ka]

[0237] In some embodiments of Formula (Ib), Z 1 is in the β configuration and X is of the formula: [ka]

[0238] In some embodiments of Formula (Ib), Z 1 is in the β configuration and X is of the formula: [ka]

[0239] In some embodiments of Formula (Ib), Z 1 is in the β configuration and X is of the formula: [ka]

[0240] In some embodiments of Formula (Ib), Z 1 is in the β configuration and X is of the formula: [ka]

[0241] In certain embodiments of Formula (Ib), Z 1 is Z 11 -Ar, where Ar is an optionally substituted heteroaryl or an 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, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H. In certain cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -NR 21 where R 21 is H or (C 1~3 ) alkyl. In certain embodiments, Z 1 is -C(R22 ) 2-triazole. In certain embodiments, Z 1 teeth, [ka] In certain embodiments, Z 1 teeth, [ka] is.

[0242] In certain embodiments of Formula (Ib), Z 1 is Z 11 In certain embodiments, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H, Z 11 is -CH2-. In some cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -NR 21 where R 21 is H or (C1-3) alkyl.

[0243] In certain embodiments of Formula (Ib), Z 1 is a monocyclic 5- or 6-membered heteroaryl or aryl. In certain embodiments, Z 1 teeth, [ka] In certain embodiments, Z 1 teeth, [ka] is.

[0244] In certain embodiments of Formula (Ib), Z 1 -O-, -S-, -C(R 22 )2-, -NR 21 -,-CONR 21 - and [ka] is selected from: X 1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0245] In certain embodiments of Formula (Ib), Z 1 is an optionally substituted (C1-C6) alkyl. Z 1 In certain embodiments, alkyl is methyl. 1 In certain embodiments, alkyl is ethyl. 1 In certain embodiments, alkyl is propyl. 1 In certain embodiments, alkyl is butyl. 1 In certain embodiments, alkyl is pentyl. 1 In certain embodiments, alkyl is hexyl.

[0246] In certain embodiments, the compound of formula (Ib) is selected from one of the following structures: [ka] In the formula, R 5 are independently H or a pro moiety.

[0247] In some embodiments, the compound of Formula (Ib) is selected from one of the following structures: [ka] In the formula, R 5 and R 4 are independently H or a pro-moiety, or R 5 and R 4 are linked in a ring to form a pro moiety, and n1 is an integer of 1 to 6.

[0248] In certain embodiments, the compound of formula (Ib) is selected from one of the following structures: [ka]

[0249] In some embodiments, R 4 ~R 5 At least one of R is of formula -COCH, -COCH(CH), or -COC(CH). 4 ~R 5 At least one of R is of the formula -CHOCOC(CH). 4 ~R 5 At least one of R is of formula -COC(CH) or -CHOCOC(CH). 4 is H and R 5 is selected from -COCH, -COCH(CH), -COC(CH), and -CHOCOC(CH). In certain embodiments, R 4 is H and R 5 is —COC(CH). In certain embodiments, R 4 is H and R 5 is -CHOCOC(CH) In some embodiments, the compound of Formula (Ib) is selected from one of the following structures: [ka] In the formula, n2 is an integer of 1 to 6.

[0250] In some embodiments of compounds of Formula (Ib), R 5 and R 4 are linked in a cyclic fashion to form a promoiety. In certain embodiments, the compound of formula (Ib) is selected from one of the following structures: [ka] In the formula, n2 is an integer of 1 to 6, and Y 4 is a suitable counterion.

[0251] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ic): [ka] where R 2 ~R 5 , and Z 1 is as defined herein.

[0252] In certain embodiments of (Ic), Z 1 -O-, -S-, -CONR 21 - and optionally substituted -(C(R 22 )2) q -heteroaryl, where q is 0 or 1. In certain embodiments, Z 1 is -O-. In certain other cases, Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, and q is 0 or 1. In certain embodiments, Z 1 teeth, [ka] is.

[0253] In certain embodiments of Formula (Ic), Z 1 is Z 11 -Ar, where Ar is an optionally substituted heteroaryl or an 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, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H. In certain cases, Z 11 is —O—. In certain embodiments, Z 11 is -S-. In certain other cases, Z 11 is -NR 21 where R 21 is H or (C1-3) alkyl. In certain embodiments, Z 1 is -C(R 22 ) 2-triazole. In certain embodiments, Z 1 teeth, [ka] is.

[0254] In certain embodiments of Formula (Ic), Z 1 is Z 11 In certain embodiments, Z 11 is -C(R 22 )2. In certain embodiments, at least one R 22 is H. In certain embodiments, both R 22 is H, Z 11 is -CH2-. In some cases, Z 11 is —O—. In certain embodiments, Z11 is -S-. In certain other cases, Z 11 is -NR 21 where R 21 is H or (C 1~3 ) alkyl.

[0255] In certain embodiments of Formula (Ic), Z 1 is a monocyclic 5- or 6-membered heteroaryl or aryl. In certain embodiments, Z 1 teeth, [ka] is.

[0256] In certain embodiments of Formula (Ic), Z 1 -O-, -S-, -C(R 22 )2-, -NR 21 -,-CONR 21 - and [ka] is selected from: X 1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0257] In certain embodiments, the compound of formula (Ic) has the following structure: [ka]

[0258] In certain embodiments, the compound of formula (Ic) has the following structure: [ka]

[0259] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Id): [ka] where R 1 ~R 3 , R 5 , and Z 1 is as defined herein.

[0260] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Id'): [ka] It can be described as:

[0261] In some embodiments, Z 1 is an optionally substituted -(C(R 22 )2) q heteroaryl, and [ka] wherein q is 0 or 1.

[0262] In some embodiments, Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, where q is 0 or 1.

[0263] In some embodiments, Z 1 teeth, [ka] [ka]

[0264] In some embodiments, Z 1 teeth, [ka] where R 23 is H or C (1~3) - alkyl.

[0265] In some embodiments, Z 1 is -NR 23 CO—, where R 23 is H or C (1~3) - alkyl.

[0266] In certain embodiments of Formula (Id), Z 1 is an optionally substituted -(C(R 22 )2) q heteroaryl, and [ka] wherein q is 0 or 1.

[0267] In certain embodiments of Formula (Id), Z 1 is an optionally substituted -(C(R 22 )2) q -triazole, where q is 0 or 1. In certain embodiments, Z 1 teeth, [ka] is.

[0268] In certain embodiments, Z 1 teeth, [ka] where R 23 is H or C (1~3) - alkyl.

[0269] In certain embodiments, Z 1 is -NR 23 CO—, where R 23 is H or C (1~3) - alkyl.

[0270] In certain embodiments of Formula (Id), Z 1 is a monocyclic 5- or 6-membered heteroaryl or aryl. In certain embodiments, Z 1 teeth, [ka] is.

[0271] In certain embodiments of Formula (Id), Z 1 is a monocyclic 5- or 6-membered heteroaryl of one of the following structures: [ka]

[0272] In certain embodiments of Formula (Id), Z 1 is one of the following structures: [ka]

[0273] In certain embodiments of Formula (Id), Z 1 -O-, -S-, -C(R 22 )2-, -NR 21 -,-CONR 21 - and [ka] is selected from: X1 is O or S, t is 0 or 1, R 21 and each R 23 is H, and optionally substituted (C1-C6) alkyl (e.g., C such as methyl). (1~3) alkyl), Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0274] In certain embodiments, the compound of formula (Id) is selected from one of the following structures: [ka] In the formula, R 6 are independently H or (C 1~3 ) alkyl.

[0275] In some embodiments of compounds of Formula (Id), R 3 is H, so that compounds of formula (Id) have no substituents other than hydrogen at the 1-position of the sugar ring.

[0276] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has formula (Ie′): [ka] where: R 1 , R 4 , R 5 , and R 11 is as defined herein; Z 2 is absent or -O-, -S-, NR 25 - and -C(R 22 )2-, as well as optionally substituted Z 12 -alkyl, Ring A is absent or selected from 5- or 6-membered optionally substituted aryl and 5- or 6-membered optionally substituted heteroaryl; Z 3 is Z 12 , optionally substituted alkyl, optionally substituted Z 12 -alkyl, optionally substituted Z 12 -heteroaryl, optionally substituted Z 12 - a linking moiety selected from aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z 12 -CHO-, -O-, -S-, -NR 26 - and -C(R 22 )2- is selected from R 25 and R 26 are each H, optionally substituted (C1-C6) alkyl (e.g., C (1~3) alkyl), and optionally substituted acyl; Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0277] In some embodiments of formula (Ie'), the ASGPR binding moiety (X) of the compounds of the present disclosure is of formula (Ie''): [ka] It can be described as:

[0278] In some embodiments of formula (Ie'), the ASGPR binding moiety (X) of the compounds of the present disclosure is of formula (Ie): [ka] where: R 1 , R 4 , R 5 , and R11 is as defined herein; Z 2 is absent or -O-, -S-, NR 25 - and -C(R 22 )2-, as well as optionally substituted Z 12 -alkyl, Ring A is absent or selected from 5- or 6-membered optionally substituted aryl and 5- or 6-membered optionally substituted heteroaryl; Z 3 is Z 12 , optionally substituted alkyl, optionally substituted Z 12 -alkyl, optionally substituted Z 12 -heteroaryl, optionally substituted Z 12 - a linking moiety selected from aryl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea; Z 12 -CHO-, -O-, -S-, -NR 26 - and -C(R 22 )2- is selected from R 25 and R 26 are each H, optionally substituted (C1-C6) alkyl (e.g., C (1~3) alkyl), and optionally substituted acyl; Each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0279] In some embodiments, Z 2 is absent. In some embodiments, Z 2 is C(R 22 )2, where R 22 is H or optionally substituted (C1-C3) alkyl. In some embodiments, Z 2 is -CH-. In some embodiments, Z2 is NR 25 where R 25 is selected from H, optionally substituted (C1-C3) alkyl, and optionally substituted acyl. In some embodiments, Z 2 is —N(COCH)—. In some embodiments, Z 2 is -NH-. In some embodiments, Z 2 is -S-. In some embodiments, Z 2 is O.

[0280] In some embodiments, the compound of formula (Ie) has the formula (If)-(Ii): [ka] wherein ring A, R 1 , R 4 , R 5 , R 11 , Z 3 and R 25 is as defined herein.

[0281] In some embodiments of any one of Formulas (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 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.

[0282] In some embodiments of any one of Formulas (Ie)-(Ii), the A ring is absent.

[0283] In some embodiments of any one of Formulas (Ie)-(Ii), the A ring is phenyl or substituted phenyl.

[0284] 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 a triazole. In certain embodiments of (If), the A ring is absent.

[0285] In some embodiments of Formula (Ig), the A ring is a 5- or 6-membered heteroaryl and R 25 is 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 R 25 is H or optionally substituted acyl. In certain embodiments, R 25 is —COCH. In certain embodiments, R 25 is H.

[0286] 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 a triazole. In certain embodiments of (Ih), the A ring is absent.

[0287] 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 a triazole. In certain embodiments of (Ii), the A ring is absent.

[0288] In certain embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure is represented by formula (Ij)-(Im): [ka] wherein: R 1 , R 4 , R 5 , R 11 , Z 3 and R 25 is as defined herein. Y 1 ~Y 3 are each independently N or CR 27 and R 24 and R 27 are H, optionally substituted C (1~6) -alkyl, optionally substituted fluoroalkyl, and halogen.

[0289] In some embodiments of any one of Formulas (Ie)-(Im), Z 3 is selected from —O—, —CHO—, —OCH—, optionally substituted —OCH-heteroaryl, optionally substituted —OCH-aryl, optionally substituted —CHO-heteroaryl, and optionally substituted —CHO-aryl.

[0290] In some embodiments, Z 3 teeth, [ka] is selected from.

[0291] In some embodiments of any one of Formulas (Ie)-(Im), Z 3 is -C(R 22 )2-, optionally substituted alkyl, optionally substituted amide, optionally substituted sulfonamide, optionally substituted urea, and optionally substituted thiourea. In some embodiments, Z 3is -CH-. In some embodiments, Z 3 is -CHCH-. In some embodiments, Z 3 is -CH2CH2CH2-. In some embodiments, Z 3 is -NHSO2-(C 1~3 -alkyl). In some embodiments, Z 3 is -N(Ac)-(C 1~3 -alkyl).

[0292] In some embodiments of any one of Formulas (Ie)-(Im), Z 3 -S- and -NR 26 wherein R is selected from 26 is selected from H and optionally substituted (C1-C3) alkyl.

[0293] In some embodiments of Formula (Ik), Y 1 ~Y 3 At least one of Y is N. In certain embodiments, Y 1 ~Y 3 At least two of Y are N. In certain embodiments, Y 1 and Y 3 is N and Y 2 is CR 25 In certain embodiments, Y 1 and Y 2 is N, Y 3 is CR 25 In certain embodiments, Y 1 and Y 2 is CR 25 , Y 3 is N. In certain embodiments, R 25 , is H. In certain embodiments, R 24 is C (1-3) Alkyl, or C (1-3) In certain embodiments, the fluoroalkyl is CF.

[0294] In certain embodiments of any one of Formulas (Ie)-(Im), R1 is OH.

[0295] In some embodiments of any one of Formulas (Ie)-(Im), R 4 and R 5 are each H. In certain embodiments, R 4 ~R 5 At least one of R is a pro-moiety. 4 and R 5 are cyclically linked to form a promoiety (eg, as described herein).

[0296] In certain embodiments, the compound of formula (Ie) is selected from one of the following structures: [ka]

[0297] In certain embodiments, the compound of formula (Ie) is selected from one of the following structures: [ka]

[0298] In certain embodiments, the compound of formula (Ie) is [ka] is.

[0299] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (In′): [ka] where: R 1 , R 4 , R 5 , and Z 1 is as defined herein; Y 1 and Y2 are -O-, -S-, and NR, respectively. 28 - and -C(R 22 )2 are independently selected from R 28 is H, optionally substituted (C1-C6) alkyl, and -C(O)R 22 is selected from Each R 22 are 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'), Y 1 is attached to the sugar ring via an α-configuration. In some embodiments of formula (In′), Y 1 is connected to the sugar ring via a β configuration.

[0300] In some embodiments, the ASGPR binding moiety (X) of the compounds of the present disclosure has the formula (In) [ka] where: R 1 , R 4 , R 5 , and Z 1 is as defined herein; Y 1 and Y 2 are -O-, -S-, and NR, respectively. 28 - and -C(R 22 )2 are independently selected from R 28 is H, optionally substituted (C1-C6) alkyl, and -C(O)R 22 is selected from Each R 22 are independently selected from H, halogen, and optionally substituted (C1-C6) alkyl; and Ring B is a 5- or 6-membered optionally substituted cyclic group.

[0301] In some embodiments of formulas (In)-(In′), Y 1 is O. In certain embodiments, Y 1 is S. In certain embodiments, Y 1 is -NR 28 In certain embodiments, Y 1 is -C(R 22 )2, and each R 22 is H.

[0302] In some embodiments of formulas (In)-(In′), Y 2 is -NR 28 -, wherein R 28 is H. In certain embodiments, Y 2 is -NR 28 -, wherein R 28 is -C(O)R 22 In certain embodiments, R 22 is methyl.

[0303] In some embodiments of Formula (In) to (In'), Ring B is a 5-membered or 6-membered heterocycle. In certain embodiments, Ring B is a 5-membered heterocycle. In certain embodiments, Ring B is a 6-membered heterocycle.

[0304] In some embodiments of formulas (In)-(In′), Z 1 is Z 11 wherein Z 11 -O-, -S-, NR 21 - and -C(R 22 )2. In certain embodiments, Z 1 is —O—. In certain embodiments, Z 1 is -S-. In certain embodiments, Z 1 is NR 21 In certain embodiments, Z 1 is -C(R 22 )2, wherein each R 22 is H.

[0305] In some embodiments of formulas (In)-(In′), Z 1 is an arbitrarily substituted Z 11 -heteroaryl or optionally substituted Z 11 In some embodiments, Z 1 is CH2-heteroaryl or CH2-aryl. In some embodiments of Formulas (In)-(In'), Z 1 is an optionally substituted amide. In some embodiments of formulas (In)-(In′), Z 1 is an optionally substituted sulfonamide. In some embodiments of Formulas (In)-(In′), Z 1 is an optionally substituted urea or an optionally substituted thiourea.

[0306] In some embodiments, the compound of Formula (In)-(In′) has one of the following structures: [ka]

[0307] In certain embodiments of any one of Formulas (Ia) through (In), n is 1 and L is a group consisting of Z, 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. 1 In certain embodiments, the linker L comprises a linear linker having a backbone of 20 or more consecutive atoms covalently linking X and Y (or Z) through a chain of 20 to 50 consecutive atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 21 to 50 consecutive atoms, a chain of 22 to 50 consecutive atoms, a chain of 23 to 50 consecutive atoms, a chain of 24 to 50 consecutive atoms, a chain of 25 to 50 consecutive atoms, a chain of 26 to 50 consecutive atoms, a chain of 27 to 50 consecutive atoms, a chain of 28 to 50 consecutive atoms, or a chain of 29 to 50 consecutive atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 30 to 60 contiguous atoms. 1In certain embodiments, the linker L separates X and Y (or Z) by a chain of 31 to 60 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 32 to 60 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 33 to 60 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 34 to 60 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 35-50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 36 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 41 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 46-50 contiguous atoms. 1 ) and separate.

[0308] In certain embodiments of any one of Formulas (Ia) through (In), n is 2 or greater and L is a linking moiety Z 1 is a branched linker that covalently attaches two or more X moieties to Y via

[0309] In certain embodiments of any one of Formulas (Ia) through (In), n is 2 or greater, each branch of L comprises a linear linker of 14 or more consecutive atoms, e.g., 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; and Z 1Each X moiety is covalently linked to a branch point of the linker, L, via a linker. In certain embodiments, each branch of L comprises a linear linker of 14 to 50 consecutive atoms, e.g., 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, e.g., 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 covalently links each X moiety (each Z 1 In certain embodiments, L comprises more than 14 consecutive atoms covalently linking each Z 1 The group comprises 15 consecutive atoms separating the group from the branch point of L. In certain embodiments, L is a group that is 1 The group comprises 16 consecutive atoms separating the group from the branch point of L. In certain embodiments, L is a group that is 1 The group comprises 17 consecutive atoms separating the group from the branch point of L. In certain embodiments, L is a group that is 1 The group comprises 18 consecutive atoms separating the group from the branch point of L. In certain embodiments, L is a group that is 1 The group comprises 19 consecutive atoms separating the group from the branch point of L. In certain embodiments, L is a group that is 1 The group comprises 20 consecutive atoms separating the group from the branch point of L. In certain other cases, L may be a group having a branch point at each Z 1 The group comprises a linear linker of 20 or more consecutive atoms separating it from the branch point L.

[0310] In certain embodiments of any one of Formulas (Ia) through (In), n is 2 and L is each Z of X. 1 Branched linkers having 14 or more consecutive atoms separating the branch points of the groups and L are included.

[0311] In certain embodiments of any one of Formulas (Ia) through (In), n is 3 and L is each Z of X. 1 Branched linkers having 14 or more consecutive atoms separating the branch points of the groups and L are included.

[0312] In certain embodiments of any one of Formulas (Ia)-(In), the linker L is of Formula (II) (e.g., as described herein).

[0313] In certain embodiments of any one of Formulas (Ia), (Ib), or (Id)-(In), R 1 is OH. In certain other cases, R 1 is —OC(O)R. In certain embodiments, R 1 is —C(O)NHR, where R is an optionally substituted alkyl. In certain embodiments, R terminates in an alkenyl or alkynyl group. In certain other cases, R 1 is an optionally substituted triazole. In certain embodiments, the triazole has the structure [ka] It is of the type.

[0314] In certain embodiments of Formulas (Ia)-(Ic), R 2 is —NHCOCH. In certain other embodiments, R 2 is -NHCOCF. In certain other embodiments, R 2 is —NHCOCH2CF3. In certain embodiments, R 2 is —OH. In certain other cases, R 2 is an optionally substituted triazole. In certain embodiments, the triazole has the structure [ka] It is of the type.

[0315] In certain embodiments, R 1 or R 2When is a substituted triazole, the triazole is a 1,2,3-triazole and the substituent is at the 4- or 5-position. In certain embodiments, the substituent on the triazole moiety is optionally substituted (C 1~6 ) alkyl, optionally substituted (C 1~6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkaryl, and optionally substituted alkylheteroaryl. It is understood that any convenient substituent can be included in the triazole moiety, see, for example, the triazole moieties disclosed in Mamidayala et al., J. Am. Chem. Soc. 2012, 134, 1978-1981.

[0316] In certain embodiments of any one of Formulas (Ia)-(In), R 4 ~R 5 At least one of R is a promoiety. In certain embodiments, the promoiety is an ester. In certain embodiments, an ester of formula -OCOCH, -OCOCH(CH), or -OCOC(CH). In certain embodiments, R 4 ~R 5 At least one of R is of formula -COCH, -COCH(CH), or -COC(CH). 4 ~R 5 At least one of R is of formula -CHOCOC(CH). 4 is a professional ingredient, R 5 is H. In certain other cases, R 5 is H, R 4 is a pro-moiety. In certain embodiments, R 4 and R 5 and R are both pro-moieties. 4 and R 5 are linked in a ring to form a promoiety. In certain embodiments, R 4 and R 5 are linked in a ring to form a ring of formula (Io) or (Ip) [ka] wherein R 1 ~R 3 and Y 4 is as defined herein.

[0317] In certain embodiments of any one of Formulas (Ia)-(In), R 4 and R 5 are both H.

[0318] In certain embodiments of Formula (I), n is 2 or 3 and X is selected from one of the following structures: [ka] In the formula, R 5 and R 23 are independently H or (C 1~3 ) alkyl.

[0319] In certain embodiments of Formula (I), n is 1, 2, or 3, and X is selected from one of the following structures: [ka]

[0320] In the formula, R 5 and R 4 are independently H or a pro-moiety, or R 5 and R 4 are linked in a ring to form a pro moiety, n1 and n2 are each independently an integer of 1 to 6, and Y 4 is a suitable counterion. In some embodiments, Y 4 is sodium.

[0321] In certain embodiments of Formula (I), n is 1, 2, or 3, and X is selected from one of the following structures: [ka]

[0322] In certain embodiments of Formula (I), n is 1, 2, or 3, and X is selected from one of the following structures: [ka]

[0323] In certain embodiments of Formula (I), n is 1, 2, or 3, and X is selected from one of the following structures: [ka]

[0324] In certain embodiments of Formula (I), n is 1, 2, or 3 and X has the structure: [ka] is.

[0325] In certain embodiments of Formula (I), n is 1, 2, or 3 and X has the structure: [ka] is.

[0326] In certain embodiments of Formula (I), n is 1 and X is [ka] is.

[0327] In certain embodiments of any one of Formulas (Ia) through (Ip), -Z 1 -L 1 -moiety (e.g., of a linker of any of formula (II), (IIa), or (IIb) described herein). In some embodiments, the subject compounds are [ka] Selected from -Z 1 -L 1 - group, wherein each R 21 is independently selected from H, and optionally substituted (C-C) alkyl, and each R 22 are 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.

[0328] In certain embodiments, Z 1 -L 1 -The base is [ka] and o is 1 or 2.

[0329] In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and p is 1 or 2.

[0330] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0331] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0332] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0333] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein s and t each independently represent an integer of 1 to 3.

[0334] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein u is 1 to 3.

[0335] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, v and w each independently represent an integer of 1 to 3.

[0336] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, x is 0 to 3.

[0337] In certain embodiments, Z 1 -L 1 -The base is [ka] where y is 1 to 3.

[0338] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H and z is 1 to 4.

[0339] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H, and z1 is 1 to 4.

[0340] In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and q is 1 to 3.

[0341] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0342] In some embodiments, the subject compound is [ka] Selected from -Z 1 Contains the -L- group.

[0343] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0344] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0345] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0346] In certain embodiments, Z 1 -L 1 -The base is [ka] is.

[0347] In certain embodiments, -Z 1 -L 1- includes optionally substituted -NH-heteroaryl-. In certain embodiments, heteroaryl is triazole. In certain embodiments, heteroaryl is pyridine. In certain embodiments, heteroaryl is pyrimidine. In certain cases, heteroaryl is thiadiazole.

[0348] In certain embodiments, -Z 1 -L 1 -teeth, [ka] wherein each R 24 are H, optionally substituted C, (1~6) - independently selected from alkyl, optionally substituted fluoroalkyl, and halogen; 25 is independently selected from H, optionally substituted (C1-C6) alkyl, and optionally substituted acyl. In certain embodiments, R 25 is H. In certain embodiments, R 24 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF.

[0349] Exemplary ASGPR Ligands Exemplary moieties that bind to ASGPR and synthons that can be utilized to prepare compounds of the present disclosure that contain an ASGPR ligand of interest are shown in Tables 1-5.

[0350] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1. [Table 1-2]

[0351] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1A. [Table 1A]

[0352] In certain embodiments, the compound of formula (Ib) is a compound shown in Table 1B. [Table 1B]

[0353] In certain embodiments, the compound of formula (Ic) is a compound shown in Table 2a. [Table 2a]

[0354] In certain embodiments, the compound of formula (Id) is a compound shown in Table 3a. [Table 3a]

[0355] In certain embodiments, the compound of formula (Id) is a compound shown in Table 4. [Table 4-2] [Table 4-3]

[0356] In certain embodiments, the compound of formula (Id') is a compound shown in Table 5. [Table 5-2]

[0357] Further exemplary moieties that bind to ASGPR, and synthons that can be used to prepare compounds of the present disclosure that contain an ASGPR ligand of interest, are shown in the table below. The building blocks described herein can, in some embodiments, be used to prepare compounds disclosed herein. As will be understood by those skilled in the art, reactive functional groups present on the building blocks described herein can react with complementary functional groups on a linker moiety to attach the ASGPR-binding compound X to Y.

[0358] For example, compounds of the present disclosure can be prepared using the building blocks described herein, as illustrated in Scheme 1. In Scheme 1, compounds of formula (I) [ka] The compound Formula (II') [ka] where: 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; L 1 ~L 6 are each independently, Z 1 and Y, where X and Y are as defined herein.

[0359] Scheme I is for illustrative purposes and is not intended to limit the scope of the disclosure in any way. However, as will be appreciated by those skilled in the art, compounds of the present disclosure have a variety of L moieties, which may be selected from the group consisting of X, -L ... 1 -Part) to Z 1 to provide an exemplary ASGPR-binding compound X component. M1 and RM2 are each independently a reactive functional group for coupling reactions (e.g., alkyne, -N, -C(O)OH, -NH, etc.), and Y' is a chemoselective ligation group that can be conjugated to Y or the amino acid residue(s) of Y.

[0360] Scheme 1 [ka] Methods and exemplary reagents and starting materials for each step (ie, compounds of Formulas 1-1, 1-2, 1-3) are described throughout or can be derived from the art.

[0361] Exemplary building blocks (eg, compounds of formula 1-1, 1-2, or 1-3 in Scheme 1) are shown in the table below.

[0362] Exemplary building blocks that can be used to prepare compounds of the present disclosure containing a desired ASGPR ligand (X) (eg, compounds of formula 1-1, 1-2, or 1-3 in Scheme 1) are shown in Table 6. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19]

[0363] In some embodiments of the ASGPR ligand (X) component that can be used to prepare compounds of the present disclosure, R 3 is H, so that the ASGPR ligand (X) contains a CH2 at position 1 and R 2 is the connecting part Z 1 Exemplary building blocks that can be used to prepare compounds of the present disclosure containing the desired ASGPR ligand (X) are shown in Table 7. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14]

[0364] In some embodiments, the ASGPR ligand (X) building block that can be used to prepare the disclosed compounds is a bicyclic structure. Exemplary building blocks that can be used to prepare the disclosed compounds containing the desired ASGPR ligand (X) are shown in Table 8. [Table 8-1] [Table 8-2]

[0365] Other building blocks that can be used and / or modified to assemble the ASGPR ligands of the present disclosure are shown in Tables 8A-8B. [Table 8A-1] [Table 8A-2] [Table 8B-1] [Table 8B-2] [Table 8B-3] [Table 8B-4]

[0366] Prodrug Embodiments of the present disclosure include any prodrug of the ASGPR-binding moieties described herein that are incorporated into the compounds and conjugates of the present disclosure.

[0367] The term "prodrug" refers to a substance that is converted into a drug in vivo by some physiological or chemical process (e.g., a prodrug is converted into the desired drug form when adjusted to physiological pH).

[0368] Any prodrug form of the ASGPR binding moieties described herein may be useful because they may provide certain therapeutic benefits, for example, as a result of increasing the half-life of the resulting compound or conjugate in the body or reducing the required active dose.

[0369] Prodrugs may be useful in some situations because they may be easier to administer than the parent drug. For example, they may be oral bioavailable whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug.

[0370] Prodrug derivatives of ASGPR binding moieties generally contain a promoiety substituent at an appropriate labile site on the compound, the promoiety being a group that is removed by enzymatic or chemical reaction when the prodrug is converted to a drug in the body.

[0371] In some embodiments, the promoiety is a group attached to a hydroxyl group of a compound or drug via an ester linkage.

[0372] In some embodiments, prodrug derivatives of one or more hydroxyl groups of the sugar ring can be incorporated into the compound. For example, an ester promoiety can be incorporated into one or more of the 3- and / or 4-hydroxyl groups of the sugar (e.g., as described herein). In some embodiments, the 3- and 4-hydroxyl groups of the sugar are cyclically linked to form a promoiety (e.g., as described herein).

[0373] Linker Valency The ASGPR ligand moiety (X) can be used in a monovalent or multivalent configuration with respect to the attachment of "n" X groups to the ASGPR displayed on the linker scaffold. A monovalent configuration includes a single ASGPR ligand moiety (X) per linker of the bifunctional molecule, with it being understood that more than one linker can be attached to Y. A multivalent configuration includes two or more such ASGPR ligand moieties per linker (e.g., a bivalent or trivalent, or higher valency, linker). The present disclosure provides specific linker scaffolds and linker valencies illustrating preferred ASGPR ligand moieties in the bifunctional molecules of the present disclosure.

[0374] In some embodiments, the linked ASGPR ligand moieties (X) of the bifunctional molecule are monovalent (e.g., in Formula (I), n is 1), and the linker covalently attaches a single ASGPR ligand moiety (X) to a biomolecule (Y) via a linking moiety at position 1, 6, or 2 of the sugar ring analog. 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) that covalently attaches the ASGPR ligand X to Y via a linking moiety at any one of positions 1, 2, or 6 of X. In certain embodiments, the linker L comprises a backbone of 20 to 100 consecutive atoms (e.g., 25 to 80, 25 to 60, or 25 to 50 consecutive atoms) that attaches the ASGPR ligand (X) to Y.

[0375] In some embodiments, the bifunctional molecule is multivalent with respect to X, where in Formula (I), n is 2 or greater, such that the conjugate comprises two or more ASGPR ligand binding moieties (X) per multivalent linker connecting Y. In such cases, the multivalent linker (L) is a branched or dendrimer linker. In certain embodiments, the bifunctional molecule has one or more bivalent linkers (e.g., in Formula (I), n is 2). In certain embodiments, the bifunctional molecule has one or more trivalent linkers (e.g., in Formula (I), n is 3).

[0376] In certain embodiments, each branch of the branched linker comprises a linear linker portion that covalently attaches each X moiety (via a linker moiety described herein) to a branch point of the branched linker or dendrimer linker. In certain embodiments, each branch of the linker comprises a linear linker portion having a backbone of 8 or more contiguous atoms, e.g., 10 or more, 12 or more, 14 or more, 16 or more, 18 or more, or 20 or more contiguous atoms, between the X ligand moiety and the branch point of the linker. In certain embodiments, each branch of the linker comprises a linear linker portion having a backbone of 8 to 50 contiguous atoms, e.g., 10 to 50, 12 to 50, 14 to 50, or 14 to 40, 14 to 30, or 14 to 20 contiguous atoms.

[0377] Linker The terms "linker," "linking moiety," and "linking group" are used interchangeably and refer to a linking moiety that covalently bonds two or more moieties, compounds, or other biomolecules, such as a ligand and a protein of interest. In certain embodiments, the linker is divalent and connects two moieties. In certain embodiments, the linker is a trivalent or higher polyvalent branched linking group. In certain embodiments, a linker connecting two or more moieties has a linear or branched backbone with a length of 500 atoms or less (e.g., 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 20 atoms or less), for example, measured between the two or more moieties. The linking moiety can be a covalent bond connecting two groups, or a linear or branched chain between 1 and 500 atoms in length, e.g., a chain 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, and the linker can be linear, branched, cyclic, or single-atom. In certain embodiments, 1, 2, 3, 4, 5, or more, 10, or even more carbon atoms in the linker backbone can be optionally substituted with heteroatoms, such as sulfur, nitrogen, or oxygen heteroatoms. In certain cases, the linker includes an ethylene glycol or longer polyethylene glycol (PEG) linking group, such as when every other atom in that segment of the linker backbone is substituted with oxygen. The bonds between the backbone atoms of the linker can be saturated or unsaturated, and typically there are no more than one, two, or three unsaturated bonds in the linker backbone. Linkers can include one or more substituents, such as, for example, alkyl groups, aryl groups, alkenyl groups, etc. Linkers include, but are not limited to, one or more of oligo(ethylene glycol) (also known as PEG), ether, thioether, disulfide, amide, carbonate, carbamate, urea, sulfonamide, thiourea, tertiary amine, linear or branched alkyl (e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), etc.).The linker backbone comprises a cyclic group, such as an aryl, heterocycle, cycloalkyl group or hetero group, and more than one atom of the cyclic group, such as 2, 3 or 4 atoms, is included in the backbone.

[0378] In some embodiments, the "linker" or linking moiety is derived from a molecule having a reactive terminus suitable for conjugation to, for example, a protein of interest. In certain circumstances, the reactive terminus of the linker precursor comprises a chemoselective ligation group capable of conjugation to an amino acid residue(s) of a polypeptide. In certain circumstances, the chemoselective ligation group is conjugated to an accessible cysteine ​​thiol group or lysine side chain amine group of a polypeptide. A variety of conjugation chemistries can be utilized in the conjugates of the present 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 active ester, such as a perfluorophenyl ester or tetrafluorophenyl ester, or N-hydroxysuccinimidyl ester (NHS), or sulfo-NHS, or an amine-reactive group as defined herein.

[0379] In certain embodiments of the formulas described herein, the linker L comprises one or more straight-chain or branched-chain carbon moieties and / or polyether (e.g., ethylene glycol) moieties (e.g., repeating units of —CHCHO—), as well as combinations thereof. In certain embodiments, these linkers optionally have an amide bond, a urea or thiourea linkage, a carbamate linkage, an ester linkage, an amino linkage, an ether linkage, a thioether linkage, a sulfhydryl linkage, a heteroaryl linkage, or other heterofunctional linkage. In certain embodiments, the linker backbone comprises one or more carbon atoms, nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. In certain embodiments, the linker comprises one or more ether bonds, thioether bonds, amine bonds, amide bonds, carbon-carbon bonds, carbon-nitrogen bonds, carbon-oxygen bonds, carbon-sulfur bonds, 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 cases, the linker includes one or more heteroaryl ring structures, for example, a triazole, such as a 1,2,3-triazole.

[0380] 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.

[0381] In certain embodiments, the linker L is connected to X (or Z) by a chain of 10 to 100 contiguous atoms. 1 ) and Y. In certain embodiments, the linker L separates X (or Z 1) and Y are separated by a chain of 10 to 60 consecutive atoms, a chain of 12 to 60 consecutive atoms, a chain of 16 to 50 consecutive atoms, a chain of 20 to 50 consecutive atoms, a chain of 30 to 50 consecutive atoms, or a chain of 40 to 50 consecutive atoms.

[0382] The linker is Z of the ASGPR ligand portion (X). 1 It is understood that the linker may be considered to be directly connected to the Z group (e.g., as described herein). In some embodiments of Formula II (or any formula described herein for the ASGPR ligand moiety (X)), the linker is 1 Alternatively, the -Z 1 -L 1 The - group (e.g., as described herein) can be considered part of the linking moiety connecting L to Y. The present disclosure is meant to include all such arrangements of ASGPR ligand moieties (X) and linkers (L).

[0383] In some embodiments of Formula (I), L is a group represented by Formula (XI): [ka] wherein: L 1 and L 3 are each independently a linear linking moiety, and L 2 is a branched linking moiety, and in the formula, L 1 ~L 3 together provide a linear or branched linker between X and Y, a, b, and c are independently 0 or 1; * is Z 1 X's L via 1 represents the attachment point to ** represents the conjugation point between the linker L and Y; During the ceremony, When n is 1, b is 0 and at least one of a and c is 1; When n is 2 or 3, a, b, and c are each 1.

[0384] 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 has the formula (Xia): [ka] It is of the type.

[0385] 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 has the formula [ka] It is of the type.

[0386] In certain embodiments, the linear linker of formula (Xia) comprises a Z backbone, 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. 1 In certain embodiments of formula (Xia), the linear linker has a backbone of 10 or more consecutive atoms covalently linking X to Y via a chain of 20 to 50 consecutive atoms. 1 ) and Y. In certain embodiments of Formula (Xa), the linear linker L separates X (or Z) from Y by a chain of 30 to 60 contiguous atoms. 1 ) and Y.

[0387] 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 has the formula (Xib): [ka] It is of the type.

[0388] 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 has the formula (Xic): [ka] It is of the type.

[0389] In some embodiments of the linker of any one of formulas (XI) or (Xia) through (Xic), each L 1 is represented by formula (XII) [ka] wherein: L 10 is the linking part, * is Z 1 X's L via 1 represents the attachment point to L 11 ~L 19 is independently absent or a linking moiety, In the formula, each L 1 L 10 ~L 19 -C 1~6 -Alkylene-, -C 1~12 -Alkylene-, -C 1~20 -Alkylene-, -NHCO-C 1~6 -Alkylene-, -CONH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHCONH-C 1~6 -Alkylene-, -NHCSNH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHCO-, -C 1~6 -Alkylene-CONH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHCONH-, -C 1~6 -Alkylene-NHCSNH-, -O(CH2) p -, -(OCH2CH2) p -, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -NHCONH-, -NHCSNH-, -CO-, -SO2-, -O-, -S-, arylene, heteroarylene, heteroalkylene, cycloalkylene, -NH-, -NC 1~6 -N(CH3)-, and -N(CH3)-, wherein each L 1 L 10 ~L19 are each independently substituted with one or more halo (e.g., 1 to 3, or 1 to 5), and p is independently 1 to 50, e.g., 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.

[0390] In some embodiments of the linker of any one of formulas (XI) or (Xia) through (Xic), each L 1 is represented by formula (XII) [ka] wherein: L 10 is the linking part, * is Z 1 X's L via 1 represents the attachment point to L 11 ~L 19 is independently absent or a linking moiety, In the formula, each L 1 L 10 ~L 19 -C 1~6 -Alkylene-, -CF2-, -C 1~12 -Alkylene-, -C 1~20 -Alkylene-, -NHCO-C 1~6 -Alkylene-, -CONH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHCONH-C 1~6 -Alkylene-, -NHCSNH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHCO-, -C 1~6 -Alkylene-CONH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHCONH-, -C 1~6 -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(C 1~6 -alkyl)-, and -N(CH3)-, where each p is independently 1 to 50, e.g., 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.

[0391] In certain embodiments of Formula (XII), the linking moiety L 1 comprises a linear backbone of 6 to 40 consecutive atoms, e.g., 10 to 40, 10 to 30, 16 to 30, or 20 to 30 consecutive atoms. In certain embodiments of Formula (XII), the linking moiety L 1 is 6 to 20 consecutive atoms, e.g., 6 to 16 consecutive atoms, e.g., 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutive atoms, 1 It comprises a linear skeleton of

[0392] In certain embodiments, the linking moiety of formula (XII) comprises one or repeating ethylene glycol moieties (e.g., -CH2CHO- or -OCH2CH2-). In certain embodiments, the linking moiety of formula (XII) comprises 1 to 10 ethylene glycol moieties, e.g., 1, 2, 3, 4, 5, or 6 ethylene glycol moieties.

[0393] In certain embodiments, the linking moiety of formula (XII) comprises one or more triazole (e.g., 1,2,3-triazole) containing linking moieties. The triazoles can be derived from azide-alkyne click chemistry and therefore have two possible directions depending on the synthetic method: [ka]

[0394] In certain embodiments, the triazole-containing linking moiety is: [ka] where w1 and u1 are independently a value from 0 to 12, such as 0, 1, 2, 3, 4, 5, or 6.

[0395] In some embodiments of the linker of formula (XI), b is 1 and L 2 is represented by formula (XIIIa) or (XIIIb) [ka] wherein: L 20 is an amino acid residue (e.g., residues such as Gly, Ala, beta-Ala, Lys, Orn, Asp, Glu, Ser, Cys, or derivatives thereof), -NH-CH[(CH2) q ]2O- or -NH-C[(CH2) q ]3O-, [ka] -C 1~6 -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 - a branched linking moiety comprising one or more linking moieties independently selected from In the formula, each p is independently 1 to 50, and q is 1 to 6.

[0396] In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L 2 (L2A)~(L2D) [ka] wherein: Z 2 and Z 3are each independently selected from absent, -NHCO-, -CONH-, -CO-, -O-, -NH-, and -Nme-; x is 1 to 12 (e.g., 1 to 6, or 1 to 3), y is 0 to 12 (for example, 1 to 6, or 1 to 3).

[0397] In some embodiments of any one of L2A to L2D, Z 2 In some embodiments of any one of L2A-L2D, Z 2 In some embodiments of any one of L2A to L2D, Z 2 In some embodiments of any one of L2A to L2D, Z 2 is —O—. In some embodiments of any one of L2A-L2D, Z 2 In some embodiments of any one of L2A-L2D, Z 2 In some embodiments of any one of L2A to L2D, Z 2 does not exist.

[0398] In some embodiments of any one of L2A to L2D, Z 3 In some embodiments of any one of L2A-L2D, Z 3 In some embodiments of any one of L2A to L2D, Z 3 In some embodiments of any one of L2A to L2D, Z 3 is —O—. In some embodiments of any one of L2A-L2D, Z 3 In some embodiments of any one of L2A-L2D, Z 3 In some embodiments of any one of L2A to L2D, Z 3 does not exist.

[0399] In some embodiments of L2A, Z2 is -O-, y is 0, and the linking moiety is of the structure L2Ai [ka] It is of the type.

[0400] In some embodiments of L2B, Z 2 is -O- or -CO-, and the linking moiety is structure L2Bi or L2Bii [ka] It is of the type.

[0401] In some embodiments of L2C, Z 2 is -O-, -CO-, -NHCO-, or -NH-, and the linking moiety is of structure L2Ci, L2Cii, L2Ciii, or L2Civ [ka] It is of the type.

[0402] In some embodiments of L2D, Z 2 does not exist, and the linking part has the structure L2Di [ka] It is of the type.

[0403] In some embodiments of any one of Formulas 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.

[0404] In some embodiments of any one of Formulas 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.

[0405] In some embodiments of Formula (XI), b is 1 and the linking moiety L 2 teeth, [ka] is selected from.

[0406] In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L 2 is represented by formula (XIV) [ka] wherein: r is 1 or 2, If n is 2, then r is 1; If n is 3, then r is 2.

[0407] In some embodiments of the linker of formula (XI), b is 1 and the linking moiety L 2 is the formula (Xva) or (XVb) [ka] wherein: r is 1 or 2, If n is 2, then r is 1; If n is 3, then r is 2.

[0408] In some embodiments, L 2 is of formula (XIIIa) or (XIIIb), and L 2 comprises two or more amino acid residues (e.g., three or more, or four or more amino acid residues, linear or dendrimer).2 comprises four or more amino acid residues that are branched linking moieties selected from Lys, Orn, Asp, Glu, Ser, and Cys (e.g., where the side chain, amino, and carboxylic acid are each linked to adjacent moieties).

[0409] In some embodiments of the linker of any one of Formula (XI) or (Xa)-(Xc), each L 3 is represented by formula (XVI) [ka] wherein: L 30 ~L 39 is independently absent or a linking moiety, Z is a residue moiety resulting from the covalent bond between the chemoselective ligation group of the linker and the compatible group of Y; In the formula, L 30 ~L 39 are -C respectively. 1~20 -Alkylene-, -NHCO-C 1~6 -Alkylene-, -CONH-C 1~6 -Alkylene-, -NHC 1~6 -Alkylene-, -NHCONH-C 1~6 -Alkylene-, -NHCSNH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHCO-, -C 1~6 -Alkylene-CONH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHCONH-, -C 1~6 -Alkylene-NHCSNH-, -O(CH2) p -, -(OCH2CH2) p and independently selected from -, -NHCO-, -CONH-, -NHSO2-, -SON2NH-, -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.

[0410] In certain embodiments, the linking moiety of formula (XVI) comprises a linear backbone of 6 to 40 consecutive atoms, for example, 10 to 40, 10 to 30, or 20 to 30 consecutive atoms.

[0411] In certain embodiments, the linking moiety of Formula (XVI) comprises repeating ethylene glycol moieties (e.g., -CHCHO- or -OCHCH-). In certain embodiments, the linking moiety of Formula (XVI) comprises 2 to 20 ethylene glycol moieties, e.g., 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 circumstances, the linking moiety of Formula (XVI) comprises two or more ethylene glycol moieties, e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or even more ethylene glycol moieties.

[0412] In certain embodiments, the linking moiety of formula (XVI) comprises one or more triazole linking moieties. In some cases, the linker comprises one or more 1,2,3-triazole linking moieties. In certain embodiments, the one or more 1,2,3-triazolyl moieties are selected from one of the following structures: [ka] In the formula, w1, u1, and q1 are independently 1 to 25 (e.g., 1 to 12, 1 to 6, etc.).

[0413] In certain embodiments, the linking moiety L 3 is (C 10 ~C 20 -Alkylene (e.g., C 12 -alkylene), or -(OCH2CH2) p -, where p is 1 to 25, for example, 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25, or 20 to 24.

[0414] In some embodiments, the linker L is represented by Formula XVII [ka] 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 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (e.g., 1, 2, or 3); Z is the residue moiety resulting from the covalent bond between a chemoselective ligation group (eg, as described herein) of the linker precursor and a compatible group of Y.

[0415] In some embodiments of Formula XVII, Z is a residue moiety resulting from the covalent bond (e.g., via a thioether bond) between a thiol-reactive chemoselective ligation group and one or more cysteine ​​residue(s) of Y. In some embodiments, the thiol-reactive chemoselective ligation group comprises a maleimide, a maleimide bromide, a haloacetamide, a vinyl sulfone, or a thiolactone. In some embodiments, the thiol-reactive group is selected from one of the following structures: [ka] During the ceremony, u is 1 to 11 (e.g., 1 to 5), v is 1 to 11 (e.g., 1 to 5), X is H or Br.

[0416] In some embodiments, the thiol reactive group is [ka] wherein X is H or Br.

[0417] In some embodiments, Z is [ka] where *** represents the point of attachment to Y.

[0418] In some embodiments of Formula XVII, Z is a residue moiety resulting from the covalent attachment (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 comprises an active ester (e.g., N-hydroxysuccinimidyl (NHS) ester, sulfo-NHS ester, pentafluorophenyl (PFP) ester, tetrafluorophenyl (TFP) ester, etc.).

[0419] In some embodiments, the linker L is (XVIIIa) to (XVIIIc): [ka] 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 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (for example, 1, 2, or 3).

[0420] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), a is 2 to 6, for example, 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.

[0421] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), b is 1 to 4, e.g., 1 to 3. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3.

[0422] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), c is 1 to 4, e.g., 1 to 3. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3.

[0423] In some embodiments of any one of Formulas (XVII) or (XVIIIa) through (XVIIIc), r is 1. In some embodiments, r is 2.

[0424] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), d is 1 to 4, e.g., 1 to 3. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3.

[0425] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), e is 1 to 5, e.g., 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.

[0426] In some embodiments of any one of Formulas (XVII) or (XVIIIa)-(XVIIIc), f is 1 to 4, e.g., 1 to 3. In some embodiments, f is 1. In some embodiments, f is 2. In some embodiments, f is 3.

[0427] In some embodiments of any one of Formulas (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.

[0428] In some embodiments of any one of Formulas (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.

[0429] In some embodiments of any one of formulas (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.

[0430] In some embodiments of any one of Formulas (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.

[0431] In some embodiments of any one of formulas (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.

[0432] In some embodiments of any one of formulas (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.

[0433] In some embodiments of any one of formulas (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.

[0434] In some embodiments of any one of Formulas (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.

[0435] In some embodiments of any one of Formulas (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.

[0436] In some embodiments of any four of Formulas (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.

[0437] In some embodiments of any one of formulas (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.

[0438] In some embodiments, the linker L is L A [ka] wherein Z 4 is 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 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (for example, 1, 2, or 3).

[0439] L A In some embodiments, Z 4 is —NHC(O)NH—. In certain embodiments, Z 4 is —NHC(O)—. In certain embodiments, Z 4 is —C(O)NH—. In certain embodiments, Z 4 is —O—. In certain embodiments, Z 4is -NH-.

[0440] L A In some embodiments, a is 1 to 4, b is 1 to 4, c is 1 to 3, d is 1 to 3, e is 1 to 6, and f is 1 to 3. In some embodiments, a is 4, b is 1, c is 2, d is 2, e is 5, and f is 2.

[0441] In some embodiments, Z 4 is -NHC(O)NH-, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 1, d is 1 to 3, e is 1 to 6, and f is 1 to 3. In some embodiments, Z 4 is -NHC(O)-, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 1, d is 1 to 3, e is 1 to 6, and f is 1 to 3.

[0442] In some embodiments, the linker L is L B [ka] 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 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (for example, 1, 2, or 3).

[0443] L BIn some embodiments, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 1, d is 1 to 3, e is 1 to 6, and f is 1 to 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.

[0444] L B In some embodiments, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 2, d is 1 to 3, e is 1 to 6, and f is 1 to 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.

[0445] In some embodiments, the linker L is L C [ka] 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, 1, 2, or 3, etc.); c is 1 to 6 (e.g., 1 to 3, 1, 2, or 3, etc.); r is 1 or 2, d is 1 to 6 (e.g., 1 to 3, 1, 2, or 3, etc.); e is 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (e.g., 1 to 3, 1, 2, or 3, etc.).

[0446] L C In some embodiments, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 1, d is 1 to 3, e is 1 to 6, and f is 1 to 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.

[0447] L c In some embodiments, a is 1 to 4, b is 1 to 4, c is 1 to 3, r is 2, d is 1 to 3, e is 1 to 6, and f is 1 to 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.

[0448] In certain embodiments of the ASGPR binding moiety (X) described herein, -Z 1 -L 1 - moiety (e.g., one of the linkers described herein). In some embodiments, the subject compounds are [ka] -Z comprising a linking moiety selected from 1 -L 1 - includes parts, In the formula, each R 21 is independently selected from H, and optionally substituted (C-C) alkyl, and each R 22 are 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.

[0449] In certain embodiments, Z 1 -L 1 -The base is [ka] and o is 1 or 2.

[0450] In certain embodiments, Z 1 -L 1-The base is [ka]

[0451] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0452] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0453] In certain embodiments, Z 1 -L 1 -The base is [ka] where r is 1 to 3.

[0454] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein s and t each independently represent an integer of 1 to 3.

[0455] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein u is 1 to 3.

[0456] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, v and w each independently represent an integer of 1 to 3.

[0457] In certain embodiments, Z 1 -L 1 -The base is [ka] In the formula, x is 0 to 3.

[0458] In certain embodiments, Z 1 -L 1 -The base is [ka] where y is 1 to 3.

[0459] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H and z is 1 to 4.

[0460] In certain embodiments, Z 1 -L 1 -The base is [ka] where R 21 is H, and z1 is 1 to 4.

[0461] In certain embodiments, Z 1 -L 1 -The base is [ka] and each R 22 is H and q is 1 to 3.

[0462] In certain embodiments, Z 1 -L 1 -The base is [ka] wherein q is 1 to 3.

[0463] In some embodiments, the subject compound is [ka] -Z comprising a linking moiety selected from 1 -L- group, where R 21 is independently selected from H, and optionally substituted (C-C) alkyl (e.g., methyl), and each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl (e.g., methyl). In certain embodiments, R 21 is H. In certain embodiments, each R 22 is H.

[0464] In certain embodiments, -Z 1 -L 1 -The base is [ka] wherein q is 1 to 3. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0465] In certain embodiments, -Z 1 -L 1 -The base is [ka] is.

[0466] In certain embodiments, -Z 1 -L 1 - includes optionally substituted -NH-heteroarylene-. In certain embodiments, a heteroarylene is triazole. In certain embodiments, a heteroarylene is pyridine. In certain embodiments, a heteroarylene is pyrimidine. In certain embodiments, a heteroarylene is thiadiazole.

[0467] In certain embodiments, -Z 1 -L 1 -teeth, [ka] wherein R 24 and R 25 are H, optionally substituted C, (1~6) - independently selected from alkyl, optionally substituted fluoroalkyl, and halogen; 21 is independently selected from H, optionally substituted (C1-C6) alkyl, and optionally substituted alkanoyl. In certain embodiments, R 21 is H. In certain embodiments, R 24 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF. In certain embodiments, R 25 is C (1~3) -Alkyl, or C (1~3) -fluoroalkyl. In certain embodiments, fluoroalkyl is CF.

[0468] In some embodiments, the linker comprises a polypeptide scaffold, in which some or all of the side groups of the amino acid residues of such polypeptide scaffold have been modified to attach to X-linked moieties (e.g., as described herein). It is understood that the X-linked moieties (e.g., as described herein) can be conjugated to amino acid residues such as Asp, Lys, Orn, Glu, and Ser of the linker-containing polypeptide via any convenient conjugation chemistry. In some embodiments, the linker comprises a polylysine polypeptide. In some embodiments, the linker comprises a polyornithine polypeptide. In some embodiments, the linker comprises a polyserine polypeptide. In some embodiments, the linker comprises a polyaspartic acid polypeptide. The polypeptide backbone of such a linker can be a randomly polymerized polymer having an average length, or a polymer of a defined length, for example, prepared in a controlled, stepwise manner. In certain embodiments, the polypeptide linker has a length of 10 to 100 amino acid residues, e.g., 20 to 90, or 20 to 50 amino acid residues. In some embodiments, the N- or C-terminus of the polypeptide linker is modified to include a linking moiety to an additional X-linked moiety (e.g., as described herein). In some embodiments, the N- or C-terminus 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) comprising a polypeptide that specifically binds to an autoantibody.

[0469] In some embodiments, a "linker" or linking moiety is derived from a molecule having two reactive ends, one for conjugation to a moiety of interest (Y), such as a biomolecule (e.g., an antibody), and one for conjugation to a moiety that binds to an ASGPR cell surface receptor (designated X). When Y is a polypeptide, the polypeptide-conjugation reactive end of the linker is a site that can be conjugated to a polypeptide via a cysteine ​​thiol or lysine amine group on the polypeptide, as the case may be, and thus can be a thiol-reactive group, such as maleimide or dibromomaleimide, or as defined herein, or an amine-reactive group, such as an active ester (e.g., a perfluorophenyl ester or a tetrafluorophenyl ester), or as defined herein.

[0470] In certain embodiments of the formulas described herein, the linker L comprises one or more straight-chain or branched-chain carbon moieties and / or polyether (e.g., ethylene glycol) moieties (e.g., repeating units of —CHCHO—), and combinations thereof. In certain embodiments, these linkers optionally have an amide bond, a urea or thiourea linkage, a carbamate linkage, an ester linkage, an amino linkage, an ether linkage, a thioether linkage, a sulfhydryl linkage, a heteroaryl linkage, or other heterofunctional linkage. In certain embodiments, the linker comprises one or more carbon atoms, nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. In certain embodiments, the linker comprises one or more ether bonds, thioether bonds, amine bonds, amide bonds, carbon-carbon bonds, carbon-nitrogen bonds, carbon-oxygen bonds, carbon-sulfur bonds, 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 cases, the linker includes one or more heteroaryl ring structures, for example, a triazole, such as a 1,2,3-triazole.

[0471] In certain embodiments, the length of L is about 10 Å to about 20 Å. In certain embodiments, the length of L is about 15 Å to about 20 Å. In certain embodiments, the length of L is about 15 Å. In certain embodiments, the length of L is about 16 Å. In certain embodiments, the length of L is about 17 Å.

[0472] In certain embodiments, L is a linker of about 5 Å to about 500 Å. In certain embodiments, L is about 10 Å to about 400 Å. In certain embodiments, L is about 10 Å to about 300 Å. In certain embodiments, L is about 10 Å to about 200 Å. In certain embodiments, L is about 10 Å to about 100 Å. In certain embodiments, L is about 10 Å to about 20 Å, about 20 Å to about 30 Å, about 30 Å to about 40 Å, about 40 Å to about 50 Å, about 50 Å to about 60 Å, about 60 Å to about 70 Å, about 70 Å to about 80 Å, about 80 Å to about 90 Å, or about 90 Å to about 100 Å. In certain embodiments, L is a linker of about 5 Å to about 500 Å and 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 of about 10 Å to about 500 Å and 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 of about 10 Å to about 400 Å and 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 of about 10 Å to about 200 Å and 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.

[0473] In certain embodiments, the linker L connects X and Y (or Z) by a chain of 4 to 500 contiguous atoms. 1In certain embodiments, the linker L separates X and Y (or Z) by a chain of 4 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 6 to 50 consecutive atoms, a chain of 11 to 50 consecutive atoms, a chain of 16 to 50 consecutive atoms, a chain of 21 to 50 consecutive atoms, a chain of 26 to 50 consecutive atoms, a chain of 31 to 50 consecutive atoms, a chain of 36 to 50 consecutive atoms, a chain of 41 to 50 consecutive atoms, or a chain of 46 to 50 consecutive atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 6 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 11 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 16 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 21 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 26 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 31 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 36 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 41 to 50 contiguous atoms. 1 In certain embodiments, the linker L separates X and Y (or Z) by a chain of 46-50 contiguous atoms. 1 ) and separate.

[0474] In certain embodiments, the linker L connects X and Y (or Z) by a chain of 4 or 5 consecutive atoms, a chain of 6-10 consecutive atoms, a chain of 11-15 consecutive atoms, a chain of 16-20 consecutive atoms, a chain of 21-25 consecutive atoms, a chain of 26-30 consecutive atoms, a chain of 31-35 consecutive atoms, a chain of 36-40 consecutive atoms, a chain of 41-45 consecutive atoms, or a chain of 46-50 consecutive atoms. 1 ) and separate.

[0475] In certain embodiments, the linker L is a linker between X and Y (or Z 1 ) and comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted alkylene linked to X, or a heteroatom linked to X. In certain embodiments, the linker L is a chain of 5 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted alkylene linked to X, or a heteroatom linked to X. In certain embodiments, the linker L is a chain of 7 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted alkylene linked to X, or a heteroatom linked to X. In certain embodiments, the linker L is a chain of 10 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted alkylene linked to X, or a heteroatom linked to X.

[0476] In certain embodiments, the linker L is a linker between X and Y (or Z 1 ) and comprises an alkylene, heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, the linker L is a chain of 5 to 500 contiguous atoms separating X and Y (or Z).1 ) and comprises an alkylene, heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, the linker L is a chain of 7 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an alkylene, heteroatom, or optionally substituted heteroarylene linked to X. In certain embodiments, the linker L is a chain of 10 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an alkylene, heteroatom, or optionally substituted heteroarylene linked to X.

[0477] In certain embodiments, the linker L is a linker between X and Y (or Z 1 ) and comprises an optionally substituted triazole linked to X. In certain embodiments, the linker L is a chain of 5 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an optionally substituted triazole linked to X. In certain embodiments, the linker L is a chain of 7 to 500 contiguous atoms separating X and Y (or Z). 1 ) and comprises an optionally substituted triazole linked to X. In certain embodiments, the linker L is a chain of 10 to 500 contiguous atoms separating X and Y (or Z). 1 ) and an optionally substituted triazole linked to X.

[0478] In some embodiments, the linker L is a chain of 16 to 400 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted alkylene linked to X, or a heteroatom linked to X.

[0479] The linker is Z of the ASGPR binding moiety (X). 1It is understood that the linker may be considered to be directly connected to a group (e.g., as described herein). In some embodiments of any one of Formulas (Ia)-(Ip), the linker is Z 1 Alternatively, -Z 1 -L 1 The - group (e.g., as described herein) can be considered part of the linking moiety connecting L to Y. The present disclosure is meant to include all such arrangements of ASGPR binding moieties (X) and linkers (L).

[0480] In some embodiments of Formula (I)-(Ia), L is a group represented by Formula (II): [ka] is a linker of the formula: L 1 and L 3 are independently linkers, and L 2 is a branched linking moiety, and in the formula, L 1 ~L 3 together provide a linear or branched linker between X and Y, a, b, and c are independently 0 or 1; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y, During the ceremony, If n is 1, a is 1 and b is 0, If n>1, a is 1 and b is 1.

[0481] In some certain embodiments of the linker of formula (II), L 1 ~L 3 are -C respectively. 1~20 -Alkylene-, -NHCO-C 1~6 -Alkylene-, -CONH-C 1~6 -Alkylene-, -NHC 1~6 -Alkylene-, -NHCONH-C 1~6 -Alkylene-, -NHCSNH-C 1~6-Alkylene-, -C 1~6 -Alkylene-NHCO-, -C 1~6 -Alkylene-CONH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHCONH-, -C 1~6 -Alkylene-NHCSNH-, -O(CH2) p , -(OCH2CH2) p and independently comprise one or more linking moieties independently selected from -, -NHCO-, -CONH-, -NHSO2-, -SONH-, -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., a pyrrolidine-2,5-dione, piperazine, or piperidine ring described herein), amino acid residue (natural or unnatural amino acid residue), -NH-, and -Nme-, wherein each p is independently 1 to 50.

[0482] In certain embodiments of the linker of formula (II), L 1 ~L 3 contains repeating ethylene glycol moieties (e.g., -CH2CHO- or -OCH2CH2-). In certain embodiments, the linker of Formula (II) contains 1 to 25 ethylene glycol moieties, e.g., 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 situations, the linker of Formula (II) contains 3 or more ethylene glycol moieties, e.g., 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, or even more ethylene glycol moieties.

[0483] In certain embodiments of the linker of formula (II), L 1 ~L 3 In some embodiments, the linker comprises one or more 1,2,3-triazole linking moieties. In certain embodiments, the one or more 1,2,3-triazole linking moieties are selected from one of the following structures: [ka] In the formula, w1, u1, and q1 are independently 1 to 25 (e.g., 1 to 12, 1 to 6, etc.).

[0484] In certain embodiments of a linker of formula (II), n is 1, such that b is 0, and the linker has formula (IIa): [ka] wherein: L 1 and L 3 are independently linkers (e.g., as described herein), and L 1 ~L 3 together provide a linear linker between X and Y, a is 1, c is 0 or 1, ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y.

[0485] In certain embodiments of the linker of Formula (IIa), the linear linker has a Z backbone, 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. 1 In certain embodiments of Formula (IIa), the linear linker has a backbone of 20 or more consecutive atoms covalently linking X and Y (or Z) by a chain of 20 to 50 consecutive atoms. 1 In certain embodiments, the linear linker L separates X and Y (or Z) by a chain of 21 to 50 consecutive atoms, a chain of 22 to 50 consecutive atoms, a chain of 23 to 50 consecutive atoms, a chain of 24 to 50 consecutive atoms, a chain of 25 to 50 consecutive atoms, a chain of 26 to 50 consecutive atoms, a chain of 27 to 50 consecutive atoms, a chain of 28 to 50 consecutive atoms, or a chain of 29 to 50 consecutive atoms. 1In certain embodiments of Formula (IIa), the linear linker separates X and Y (or Z) by a chain of 30 to 60 contiguous atoms. 1 In certain embodiments, a linear linker separates X and Y (or Z) by a chain of 31 to 60 contiguous atoms. 1 In certain embodiments, a linear linker separates X and Y (or Z) by a chain of 32 to 60 contiguous atoms. 1 In certain embodiments, a linear linker separates X and Y (or Z) by a chain of 33 to 60 contiguous atoms. 1 In certain embodiments, a linear linker separates X and Y (or Z) by a chain of 34 to 60 contiguous atoms. 1 In certain embodiments, the linear linker L separates X and Y (or Z) by a chain of 35-50 contiguous atoms. 1 In certain embodiments, the linear linker L separates X and Y (or Z) by a chain of 36 to 50 contiguous atoms. 1 In certain embodiments, the linear linker L separates X and Y (or Z) by a chain of 41 to 50 contiguous atoms. 1 In certain embodiments, the linear linker L separates X and Y (or Z) by a chain of 46-50 contiguous atoms. 1 ) and separate.

[0486] In certain other embodiments of Formula (II), n is 2 or greater and L 1 ~L 3 together provide a branched linker between X and Y.

[0487] In certain embodiments of Formula (II), n is 2 or greater and L 2 teeth, [ka] wherein x and y are each independently 1 to 10.

[0488] In certain embodiments of Formula (II), L 1 ~L 2 comprises a backbone of 14 or more consecutive atoms between X and the branch atom, for example, 14 to 50, 14 to 40, 14 to 35, or 14 to 30 consecutive atoms between X and the branch atom.

[0489] In certain embodiments of Formula (II) or (IIa), L 3 comprises 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 12 to 70, 12 to 60, 12 to 50, or 10 to 60 consecutive straight or branched chain atoms.

[0490] In certain embodiments of Formula (II) or (IIa), L 3 is (C 10 ~C 20 -Alkylene (e.g., C 12 -alkylene), or -(OCH2CH2) p -, wherein p is 1 to 25, for example, 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25, or 20 to 24.

[0491] In certain embodiments, L is a group of formula (Iib): [ka] wherein: L 1 ~L 5 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 0, 1, or 2; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y, During the ceremony, If n is 1, a is 1 and c is 0, If n>1, a is 1 and c is 1.

[0492] In some embodiments, L is a group of formula (IIb'): [ka] wherein: L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y.

[0493] In certain embodiments, L is a group of formula (IIb'): [ka] wherein: L 1 ~L 6 are each independently a linking moiety, and together they form Z 1 and Y, forming a linear or branched linker therebetween; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** is Z 1 X's L via 1 represents the attachment point to *** represents the attachment point to Y.

[0494] In certain embodiments, L 1 ~L 5 Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -Alkylene-NHC(S)NH-, -O(CH2) p -, -(OCH2CH2) p and independently comprise one or more linking moieties independently selected from -, -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, an amino acid residue, -NH-, and -NMe-, wherein L 1 ~L 5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 -C 1~20 -Alkylene-, -NR 16 C(O)-C 1~6 -Alkylene-, -C(O)NR 16 -C 1~6 -Alkylene-, -NR 16 -C 1~6 -Alkylene-, -NR 16 C(O)NR 16 -C 1~6 -Alkylene-, -NR 16 C(S)NR 16 -C 1~6 -Alkylene-, -C 1~6 -Alkylene-NR 16 C(O)-, -C 1~6 -Alkylene-C(O)NR 16 -, -C 1~6 -Alkylene-NR 16 -, -C 1~6 -Alkylene-NR 16 C(O)NR 16 -, -C 1~6 -Alkylene-NR 16 C(S)NR16 -, -O(CH2) p -, -(OCH2CH2) p -, -NR 16 C(O)-, -C(O)NR 16 -, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or -NR 16 - is a linking group comprising one or more linking moieties independently selected from Each R 16 is independently —H, (C1-C6) alkyl, or monocyclic heteroaryl.

[0495] In certain embodiments, L 1 ~L 5 Each of the -C 1~20 -Alkylene-, -NHC(O)-C 1~6 -Alkylene-, -C(O)NH-C 1~6 -Alkylene-, -NH-C 1~6 -Alkylene-, -NHC(O)NH-C 1~6 -Alkylene-, -NHC(S)NH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHC(O)-, -C 1~6 -Alkylene-C(O)NH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHC(O)NH-, -C 1~6 -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, an amino acid residue, -NH-, and -NMe-; 1 ~L 5 are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L 6 teeth, [ka] where R z teeth, [ka] is.

[0496] In certain embodiments of the linker of formula (IIb) or (IIb'), L 1 ~L 3 are -C respectively. 1~20 -Alkylene-, -NHCO-C 1~6 -Alkylene-, -CONH-C 1~6 -Alkylene-, -NHC 1~6 -Alkylene-, -NHCONH-C 1~6 -Alkylene-, -NHCSNH-C 1~6 -Alkylene-, -C 1~6 -Alkylene-NHCO-, -C 1~6 -Alkylene-CONH-, -C 1~6 -Alkylene-NH-, -C 1~6 -Alkylene-NHCONH-, -C 1~6 -Alkylene-NHCSNH-, -O(CH2) p , -(OCH2CH2) p and independently comprise one or more linking moieties independently selected from -, -NHCO-, -CONH-, -NHSO2-, -SONH-, -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., a pyrrolidine-2,5-dione, piperazine, or piperidine ring described herein), amino acid residue (natural or unnatural amino acid residue), -NH-, and -Nme-, wherein each p is independently 1 to 50.

[0497] In certain embodiments of Formula (Iib) or (IIb'), -(L 1 ) a- includes an optionally substituted alkyl or ethylene glycol linking moiety. In certain embodiments, L 1 is an optionally substituted -C 1~6 In certain embodiments, L 1 contains an ethylene glycol linking moiety.

[0498] In certain embodiments of Formula (Iib), L 1 teeth, -C 1~6 -Alkylene-, -(CH2CH2O) t -, --C 1~6 -Alkylene-NR 4 CO-, -C 1~6 -alkyleneCONH-, or OCH2, where t is 1 to 20; 4 is independently selected from H and optionally substituted (C1-C6) alkyl. In certain embodiments, L 1 -C 1~6 -Alkylene-, e.g., --C 1~3 In certain embodiments, L 1 is -(CH2CH2O) t -, and t is 1 to 20, e.g., 1 to 15, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In certain embodiments, L 1 is --C 1~6 -Alkylene-NR 4 In certain embodiments, L 1 -C 1~6 -alkyleneCONH-. In certain embodiments, L 1 is OCH2.

[0499] In some embodiments of formula (Iib) or (IIb'), one or more L 1 are independently -CH2O-, -(CH2CH2O) t -, -NR 4 CO-, -C 1~6 -alkylene-, [ka] where R 13 is H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R 21 )2, -OCOR 21 , -COOR 21 , -CONHR 21 , and -NHCOR 21 is selected from Each r is independently 0 to 20, and L 1 Any of the moieties are optionally further substituted.

[0500] In certain embodiments of Formula (Iib) or (IIb'), L 2 teeth, -NR 4’ CO-C 1~6 -Alkylene-, -CONR 4’ -C 1-6 alkylene, [ka] -OCH2-, and -(OCH2CH2) q -, wherein q is 1 to 10, u is 0 to 10, w is 1 to 10, and R 4’ is independently selected from H, and optionally substituted (C1-C6) alkyl. In certain embodiments, L 2 is -NR 4’ CO-C 1~6 In certain embodiments, L 2 -CONR 4’ -C 1~6 - alkylene.

[0501] In certain embodiments, L 2 teeth, [ka] wherein w is 1 and u is 0 or 1.

[0502] In certain embodiments, L2 teeth, [ka] wherein w is 1 and u is 0 or 1.

[0503] In certain embodiments, L 2 teeth, [ka] wherein w is 1, u is 0 or 1, and q is 1.

[0504] In certain embodiments, L 2 teeth, [ka] where u is 0 or 1.

[0505] In certain embodiments, L 2 teeth, [ka] is.

[0506] In certain embodiments, L 2 is —OCH. In certain other embodiments, L 2 is (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, for example, 2 to 6, 4 to 6, 2 to 4.

[0507] In certain embodiments of Formula (Iib), L 4 does not exist or -C 1~6 -Alkylene-, -(CH2CH2O) t -, --C 1~6 -Alkylene-NHCO-, -C1~6 -alkyleneCONH-, or OCH2. In certain embodiments, L 4 does not exist.

[0508] In certain embodiments, L 4 -C 1~6 In certain embodiments, L 4 is -(CH2CH2O) t -, where t is 1 to 20, e.g., 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, L 1 is --C 1~6 -alkylene-NHCO-. In certain embodiments, L 4 -C 1~6 -alkyleneCONH-. In certain embodiments, L 4 is OCH2.

[0509] In some embodiments of the subject compounds, n is 1 and L in formula (Iib) 3 does not exist.

[0510] In certain embodiments of the subject compounds, n is 2 or greater, and L in formula (Iib) 3 is a branched linking moiety.

[0511] Thus, in some embodiments of formula (Iib) or (IIb'), L 3 is a branched linking moiety, e.g., a bivalent or trivalent linking moiety. For example, L 3 The linking moiety has the following general formula: [ka] It may be one of the following.

[0512] In some embodiments of Formula (Iib) or (IIb'), the branched linking moiety has a higher valence and can be described by one of the following general formulas: [ka] etc. In the formula, any two L 3 The groups can be directly linked or connected via any linear linking moiety (eg, as described herein).

[0513] In some embodiments of formula (Iib) or (IIb'), the branched linking moiety comprises one, two, or more L, each of which is a trivalent moiety. 3 Linking moieties, which when linked together provide multiple branching points for covalent attachment of ligands, can be represented by the general formula: [ka] In the formula, t is 0 to 500, for example, 0 to 100, 0 to 20, or 0 to 10.

[0514] In some embodiments, a branched linking moiety (e.g., L 3 ) include one or more of amino acid residues (e.g., Asp, Lys, Orn, Glu), N-substituted amides (-N(-)C(O)-), tertiary aminos, polyols (e.g., O-substituted glycerol), and the like.

[0515] In some embodiments of formula (Iib) or (IIb'), one or more L 4 teeth, [ka] wherein each x and y is independently 1 to 10, 1 to 6, 1 to 3, etc., e.g., 1 or 2. In certain embodiments, each x is 1, 2, or 3, e.g., 2.

[0516] In some embodiments of Formula (Iib) or (IIb'), L 5 is -CH2O-, -(CH2CH2O) t -, -NR 4CO-, -C 1~6 -alkylene-, [ka] is selected from: R 13 is H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R 21 )2, -OCOR 21 , -COOR 21 , -CONHR 21 , and -NHCOR 21 is selected from Each r is independently 0 to 20, and L 5 Any of the moieties are optionally further substituted.

[0517] In certain embodiments, L 5 is —CH2O—. In certain embodiments, L 5 is -(CH2CH2O) t -, where t is 1 to 20, for example, 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In certain embodiments, L 5 is -NR 4 CO—, where R 4 is H or optionally substituted (C1-C6) alkyl. In certain embodiments, L 5 -C 1~6 -alkylene-.

[0518] In certain embodiments, L 5 teeth, [ka] In the formula, r is 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0519] In certain embodiments, L 5 teeth, [ka] wherein each r is independently 0 to 20, e.g., 0 to 15, 0 to 10, 0 to 8, or 0 to 5; R 13 is H or optionally substituted (C1-C6) alkyl.

[0520] In certain embodiments, L 5 teeth, [ka] wherein r is 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5; 13 is H or optionally substituted (C1-C6) alkyl.

[0521] In certain embodiments, L 5 teeth, [ka] wherein r is 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5; 13 is H or optionally substituted (C1-C6) alkyl.

[0522] In certain embodiments, L 5 teeth, [ka] wherein r is 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5; 13 is H or optionally substituted (C1-C6) alkyl.

[0523] In certain embodiments, L 5 teeth, [ka] wherein each r is independently 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0524] In certain embodiments, L 5 teeth, [ka] wherein each r is independently 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0525] In certain embodiments, L 5 teeth, [ka] wherein each r is independently 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0526] In certain embodiments, L 5 teeth, [ka] wherein each r is independently 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0527] In certain embodiments, L 5 teeth, [ka] In the formula, r is 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5.

[0528] In some embodiments of Formula (Iib) or (IIb'), L 5comprises one or more of amino acid residues (e.g., Asp, Lys, Orn, Glu), amino acid analogs, N-substituted amides (-N(-)C(O)-), tertiary amino acids, polyols (e.g., O-substituted glycerol), and the like. Amino acid analogs include, but are not limited to, unnatural amino acids, as well as other modifications known in the art. Amino acids include 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.

[0529] In some embodiments of Formula (Iib) or (IIb'), L 1 ~L 5 is the following unit [ka] wherein R a is (C1-C6) alkyl or substituted (C1-C6) alkyl, for example, (C1-C6) alkyl substituted with an amine, a tertiary amine, an optionally substituted alkoxy, an optionally substituted carboxyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R a It is understood that can be linked to the M6PR binding moiety.

[0530] In some embodiments, the linker comprises a polypeptide scaffold in which some or all of the side groups of the amino acid residues have been modified to attach an ASGPR-binding moiety (e.g., as described herein). It is understood that the ASGPR-binding moiety (e.g., as described herein) can be conjugated to amino acid residues such as Asp, Lys, Orn, Glu, and Ser of the linker-containing polypeptide via 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 polyaspartic acid polypeptide. The polypeptide may be a randomly polymerized polymer having an average length, or a polymer of a defined length, for example, prepared in a controlled, stepwise manner. In certain embodiments, the polypeptide linker segment has a length of 10 to 100 amino acid residues, e.g., 20 to 90, or 20 to 50 amino acid residues. In some embodiments, the N- or C-terminus of the polypeptide linker segment is modified to include a linking unit to an additional M6PR binding moiety (e.g., as described herein), hi some embodiments, the N- or C-terminus of the polypeptide linker segment is modified with one or more linking units suitable for attachment to a Y, moiety of interest (e.g., as described herein).

[0531] 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.

[0532] 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.

[0533] 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 more consecutive atoms.

[0534] In certain embodiments, the ASGPR-binding compound of the present disclosure, having a specific configuration with a linker of desired valency and length, can simultaneously specifically bind to both ASGPR and the target with high affinity, and exhibit high target uptake activity. Thus, the conjugate of the present disclosure can sequester the target protein in the lysosome of the cell and degrade the target protein. For example, the ASGPR-binding moiety (e.g., Z 1 Conjugates of trivalent ASGPR-binding compounds having 14 or more atoms between the ASGPR-binding compound (e.g., Z 1These conjugates can exhibit superior cellular uptake compared to conjugates of trivalent ASGPR-binding compounds having a shorter linker (e.g., less than 14 atoms) between the ASGPR ligand and the branch point. For example, in certain embodiments, conjugates having a 1-triazole moiety and a short linkage (e.g., 6 atoms) from the ASGPR ligand to the branch point of the ligand (I-157, linker length to the branch point is 6 atoms) exhibited lower uptake activity in HepG2 cells than conjugates having a 1-triazole moiety and a longer linkage (e.g., 14 atoms) from the ASGPR ligand to the branch point (I-143, length is 14 atoms) (see, e.g., Figure 2A). Based on this finding, multivalent ASGPR-binding compounds having a specific range of linker lengths between the ASGPR-binding moiety and the linker branch point that provide desirable binding and cellular uptake of the bound target are described herein.

[0535] Furthermore, trivalent ASGPR-binding compound conjugates (e.g., compounds of Formula (I) where n=3) can exhibit superior intracellular uptake activity compared to bivalent or monovalent ASGPR-binding compound conjugates (e.g., compounds of Formula (I) where n=2 or 1). In certain embodiments, the conjugate (I-124, n=3) exhibited superior uptake activity in HepG2 cells compared to the bivalent conjugate (I-144, n=2) (see, e.g., Figure 2B).

[0536] Furthermore, conjugates of multivalent ASGPR-binding compounds having 12 or more atoms between the branch point of the linker and the Y moiety of interest can exhibit superior cellular uptake compared to conjugates of multivalent ASGPR-binding compounds having shorter linkers (e.g., fewer than 12 atoms) between the branch 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 branch point of the linker and Y exhibit comparable uptake activity. For example, conjugates having longer linkers between the ASGPR linker and Y (e.g., the conjugate of compound I-137 having 81 atoms between the branch point and Y, and the conjugate of compound I-129 having 33 atoms between the branch point and Y) were observed to exhibit comparable activity to reference conjugates (e.g., the conjugate of compound I-124 having 12 atoms between the branch point and Y) (see, e.g., Figure 2B).

[0537] Thus, in certain embodiments, the linker of formula (II), or (IIb'), or (Iib) is a branched linker, wherein each branch of the linker comprises a linear linker of 14 or more consecutive atoms, and each X moiety is selected from the group consisting of Z 1 and covalently bonded to a branch point of the linker via a linker. In certain embodiments, each branch of the linker comprises a linear linker of 15 or more consecutive atoms to the branch point. In certain embodiments, each branch of the linker comprises a linear linker of 16 or more consecutive atoms to the branch point. In certain embodiments, each branch of the linker comprises a linear linker of 17 or more consecutive atoms to the branch point. In certain embodiments, each branch of the linker comprises a linear linker of 18 or more consecutive atoms to the branch point. In certain embodiments, each branch of the linker comprises a linear linker of 19 or more consecutive atoms to the branch point.

[0538] In certain embodiments of Formula (II), or (IIb'), or (Iib), the linker connects each X moiety to Z 1and a linear linker covalently linking the branch point to Y. In certain embodiments, the linear linker covalently linking the branch point to Y is 12 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 15 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 20 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 25 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 30 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 40 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y is 50 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y, is 60 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y, is 70 or more consecutive atoms. In certain embodiments, the linear linker covalently linking the branch point to Y, is 80 or more consecutive atoms.

[0539] Exemplary Linkers and Linking Moieties Exemplary linkers and linking moieties (eg, those that link an ASGPR ligand (X) to a moiety of interest (Y)) that can be used to prepare compounds of the present disclosure are shown in Tables 9-11.

[0540] In certain embodiments, the linker is a linear linker or linking moiety as shown in Table 9. [Table 9-1] [Table 9-2] [Table 9-3]

[0541] Table 10 includes various linker component synthetic precursors (eg, linear and branched linker precursors) that can be utilized to prepare the subject compounds. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9]

[0542] In certain embodiments, the linker is a branched linker or linking moiety as shown in Table 11. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6]

[0543] Chemoselective Ligation Groups 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 functional group or group that can be conjugated with a compatible group on a second moiety. For example, the chemoselective ligation group (or a precursor thereof) can be one of a pair of groups associated with conjugation chemistries such as azide-alkyne click chemistry, copper-free click chemistry, Staudinger ligation, tetrazine ligation, hydrazine-iso-Picteth-Spengler (HIPS) ligation, cysteine-reactive ligation chemistry (e.g., thiol-maleimide, thiol-haloacetamide, or alkyne hydrothiolation), amine-activated ester coupling, tyrosine-specific conjugation chemistry (e.g., eY-CLICK), methionine-specific conjugation chemistry (e.g., oxaziridine-based or ReACT chemistry), reductive amination, dialkylsquarate chemistry, and the like.

[0544] Chemoselective ligation groups available for linking two moieties include amino (e.g., the N-terminal amino group of a polypeptide or a lysine side chain group), azide, aryl azide, alkynyl (e.g., ethynyl or cyclooctyne or derivatives), active ester (e.g., N-hydroxysuccinimide (NHS) ester, sulfo-NHS ester or PFP ester or thioester), haloacetamide (e.g., iodoacetamide or bromoacetamide), chloroacetyl, bromoacetyl, methylaryl bromide, chloromethylaryl azide, ... Examples of suitable heteroaryls include, but are not limited to, aryls, methylbromide heteroaryls, chloromethylheteroaryls, hydrazides, maleimides, vinyl sulfones, 2-sulfonylpyridines, cyanoalkynes, thiols (e.g., cysteine ​​residues), disulfides or protected thiols, isocyanates, isothiocyanates, aldehydes, ketones, alkoxyamines, hydrazides, aminooxys, phosphines, HPS hydrazinyl-indolyl groups or aza-HPS hydrazinyl-pyrrolo-pyridinyl groups, tetrazines, cyclooctene, squarates, and the like.

[0545] In some situations, a chemoselective ligation group can spontaneously conjugate to a compatible chemical group when the two groups are contacted under appropriate conditions (e.g., copper-free click chemistry conditions). In some situations, a chemoselective ligation group can conjugate to a compatible chemical group when the two groups are contacted in the presence of a catalyst or other reagent (e.g., copper-catalyzed click chemistry conditions).

[0546] In some embodiments, the chemoselective ligation group is a photoactive ligation group. For example, upon irradiation with ultraviolet light, the diazirine group forms a reactive carbene that can insert into the C-H, N-H, and O-H bonds of a second moiety.

[0547] In some situations, Y is a reactive functional group or a precursor of a functional group capable of conjugating with a compatible group on a second moiety, for example, a carboxylic acid is a precursor of an active ester chemoselective ligation group.

[0548] In certain embodiments of Formula (I), Y is a reactive moiety that can form a covalent bond with a polypeptide (e.g., with an amino acid side chain of the polypeptide that has a compatible reactive group). The reactive moiety can be referred to as a chemoselective ligation group.

[0549] 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 generate a residue moiety Z resulting from the covalent attachment of a thiol-reactive chemoselective ligation group to one or more cysteine ​​residue(s) of a protein, e.g., an Ab.

[0550] In certain embodiments of Formula (I), Y is a Cys-reactive chemoselective ligation group (e.g., a maleimide derivative described in Table 12). In certain embodiments, the Cys-reactive chemoselective ligation group comprises a maleimide group. In some embodiments, the chemoselective ligation group comprises a maleimide group from Table 12, e.g., mal-1 through mal-7.

[0551] 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 generate a residue moiety Z obtained by covalently attaching the amine-reactive chemoselective ligation group to one or more lysine residue(s) of a protein, e.g., an Ab.

[0552] In certain embodiments of Formula (I), Y is a Lys-reactive chemoselective ligation group (e.g., an active ester described in Table 12). In some embodiments, the Lys-reactive chemoselective ligation group is a PFP ester.

[0553] Exemplary chemoselective ligation groups, and their synthetic precursors, that can be adapted for use in the compounds of the present disclosure are shown in Table 12. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5]

[0554] In Table 12, [ka] can represent the linking moiety to Y or the point of attachment to the linked X moiety.

[0555] Table 12a shows exemplary residue moieties, where "***" indicates the attachment point of Y. [Table 12a]

[0556] Exemplary Compounds with Chemoselective Ligation Groups The present disclosure provides: (1) one or more specific ASGPR ligands (X) (e.g., as described herein, e.g., ligands X1-X20 in Tables 1-4) or specific ASGPR ligands (X) (e.g., as described herein); (2) a linker comprising one or more linking moieties (e.g., any one or more of the linking moieties described herein, e.g., in Tables 8-10), and (3) Compounds of formula (I) include those that can include a chemoselective ligation group (Y), such as any one of the groups described herein (e.g., Table 12).

[0557] In some embodiments, the chemoselective ligation group can be tailored to provide a linkage that provides additional benefits, such as, but not limited to, conjugate stability.

[0558] In some embodiments, the chemoselective ligation group is [ka] Includes:

[0559] Table 13 shows various monovalent ligand-linker compounds for use in the conjugates of the present disclosure. [Table 13-1] [Table 13-2]

[0560] Table 14 shows various multivalent ligand-linker compounds for use in the conjugates of the present disclosure. [Table 14-1] [Table 14-2]

[0561] In some embodiments, the compound of formula (I) is an ASGPR-binding compound described in International Application No. WO / 2023288033, filed July 14, 2022, the entire disclosure of which is incorporated herein by reference.

[0562] The following table shows some exemplary ASGPR-binding compounds of the present disclosure that include a chemoselective ligation group or a precursor thereof. It is understood that the present disclosure includes Y (e.g., as described herein) conjugates of each exemplary compound in Tables 13-23. For example, conjugates are included in which the chemoselective ligation group is conjugated to a different Y, such as a biomolecule or small molecule ligand for a target protein.

[0563] The chemoselective ligation group of such compounds can be utilized to connect to another Y moiety of interest (e.g., as described below). It will be appreciated 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 conjugates, such as biomolecular conjugates that specifically bind to target proteins. [Table 15-1] [Table 15-2] [Table 15-3] [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] Table 16-7 Table 16-8 Table 16-9 Table 16-10 Table 16-11 Table 16-12 Table 16-13 Table 16-14 Table 16-15 Table 16-16 Table 16-17 Table 16-18 Table 16-19 Table 16-20 Table 16-21 Table 16-22 Table 16-23 [Table 16-24] [Table 16-25] [Table 16-26] [Table 16-27] [Table 17-1] [Table 17-2] [Table 18-1] [Table 18-2]

[0564] The present disclosure is intended to encompass any one stereoisomer of the compounds described herein. In some circumstances, the compounds include enantiomers of DN-acetylgalactosamine (GalNAc), or analogs or derivatives of GalNAc.

[0565] Other exemplary compounds Table 19 shows exemplary ASGPR-binding compounds of the present disclosure that include a binding moiety or precursor thereof. [Table 19-1] [Table 19-2]

[0566] Table 20 shows exemplary trivalent ASGPR binding intermediate compounds of the present disclosure that include the X group of formula (Ie). [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8] [Table 20-9] [Table 20-10] [Table 20-11]

[0567] Table 21 shows exemplary monovalent ASGPR-binding intermediate compounds of the present disclosure that include a promoiety and an X group of formula (Ib). [Table 21]

[0568] Table 22 shows exemplary ASGPR-binding intermediate compounds of the present disclosure that include an X group of formula (In). [Table 22]

[0569] Table 23 shows exemplary ASGPR binding intermediate compounds. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] [Table 23-8] [Table 23-9] [Table 23-10] [Table 23-11] [Table 23-12] [Table 23-13] [Table 23-14] [Table 23-15] [Table 23-16] [Table 23-17] [Table 23-18] [Table 23-19] [Table 23-20] [Table 23-21] [Table 23-22] [Table 23-23] [Table 23-24] [Table 23-25] [Table 23-26] [Table 23-27] [Table 23-28]

[0570] The present disclosure is intended to encompass any one stereoisomer of the compounds described herein. In some circumstances, the compounds include enantiomers of DN-acetylgalactosamine (GalNAc), or analogs or derivatives of GalNAc.

[0571] Conjugates with desired moieties The compounds of the present disclosure can be referred to as conjugates, for example, when the moiety of interest (Y) is a molecule (e.g., as described herein). Such conjugates can be prepared by conjugating the chemoselective ligation group of any one of the compounds described herein with a compatible reactive group on molecule Y. The compatible group on molecule Y can be introduced by modification prior to conjugation or can be a group present within the molecule. Alternatively, such conjugates can be prepared de novo, for example, by modifying the molecule of interest Y as a starting material and introducing, for example, a linker to which ligand X can be attached.

[0572] In some embodiments, the moiety of interest to which the ASGPR-binding moiety is attached is a biomolecule. In some embodiments, the moiety of interest is a biomolecule. In some embodiments, the biomolecule is selected from a peptide, a protein, a polynucleotide, a polysaccharide, a glycan, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment. In some embodiments, the moiety of interest Y is selected from a small molecule, a small molecule drug, a chemotherapeutic agent, a cytotoxic agent, a diagnostic agent, a dye, a fluorophore, etc.

[0573] In a preferred embodiment, the target moiety is a molecule that specifically binds to a target of interest, i.e., a target binding moiety.In such an embodiment, the conjugate of the present disclosure provides for the target to be taken up into cells and / or degraded after the target is non-covalently bound to the conjugate.In certain embodiments, the conjugate of the present disclosure has a specific arrangement of ASGPR binding moieties with desired affinity and a linker with desired valency and length, and can specifically bind to both ASGPR and the target simultaneously with high affinity.Therefore, the conjugate of the present disclosure can sequester the target protein in lysosomes of cells and degrade the target protein.

[0574] In some embodiments, the moiety of interest is not a molecule that binds to an extracellular target, but rather a molecule that is itself desired to be delivered intracellularly, hi some embodiments, the moiety of interest is selected from an enzyme (e.g., a lysosomal enzyme), a nanoparticle, a viral composition (e.g., a viral particle), a therapeutic protein, a therapeutic antibody, and a cytotoxic agent.

[0575] In some embodiments, the moiety of interest is a lysosomal enzyme delivered to cells for use in enzyme replacement therapy, such as acid alpha-glucosidase (GAA). Lysosomal enzymes of interest that can be adapted for use in the conjugates of the present disclosure include 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, β-galactosidase, β-glucuronidase, β-mannosidase, cathepsin D, cathepsin K, ceramidase, cystinosin, ganglioside activator GM2, galactosidase, and the like. These include, but are not limited to, cerebrosidase, 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-sulfatase, N-aspartyl-β-glucosaminidase, palmitoyl-thioesterase-1, acid phosphatase, protective protein / cathepsin A (PPCA), sialin, and tripeptidyl peptidase 1.

[0576] Aspects of the present disclosure include compounds of formula (I) where the moiety of interest Y is selected from a small molecule, a dye, a fluorophore, a monosaccharide, a disaccharide, a trisaccharide, and a biomolecule. In some embodiments, Y is a small molecule that specifically binds to a target molecule, such as a target protein.

[0577] In some embodiments of the compounds of the present disclosure, Y is a biomolecule. In some embodiments, the biomolecule is selected from a protein, a polynucleotide, a polysaccharide, a peptide, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment. In some embodiments, Y is a biomolecule that specifically binds to a target molecule, such as a target protein.

[0578] In certain embodiments, compounds of the present disclosure may also be referred to as conjugates, for example, when the moiety of interest (Y) is a molecule, such as a biomolecule, in which case 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 on 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 a residue (e.g., Z) that is the product of chemoselective ligation chemistry.

[0579] Aspects of the present disclosure include compounds of formula (I) in which the moiety of interest Y is a moiety that specifically binds to a target molecule, such as a target protein. The target protein may be a membrane-bound protein or an extracellular protein. In some embodiments of the compounds of the present disclosure, Y is a biomolecule that specifically binds to the target protein. The present disclosure provides conjugates of certain ASGPR-binding compounds and conjugates. In some embodiments, the conjugates include a region of interest Y that specifically binds to a target protein and can be used in methods of cellular uptake or internalization of the target protein via binding to a cell surface receptor and eventual degradation of the target protein.

[0580] 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., a peptide-binding motif, a protein domain, an artificial polypeptide, or a 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.

[0581] In some embodiments, one Y biomolecule is conjugated via a linker, L, to a single moiety (X) that specifically binds to a cell surface receptor (e.g., ASGPR). In some embodiments, one Y biomolecule is conjugated to one (Xn-L) group; 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., divalent, trivalent, etc.). In some embodiments of Formula (I), when Y is a biomolecule, it is understood that Y can be conjugated to more than one (Xn-L) group, and each (Xn-L) group itself may be monovalent or multivalent (e.g., divalent, trivalent, etc.). In such embodiments, the ratio of linked (Xn-L)-groups to biomolecules is said to be 2 or greater.

[0582] In some embodiments, Y is a moiety that specifically binds to a target protein and the compound has formula (III'): [ka] is a conjugate of n is 1 to 20; m is the average load from 1 to 80; each X is a moiety that binds to a cell surface ASGPR; each L is a linker; each Z is a residue moiety resulting from the covalent bond between a chemoselective ligation group and a compatible group of Y; Y is a moiety of interest that binds to the target protein.

[0583] In some embodiments of Formula (III'), Y is an antibody or antibody fragment.

[0584] In some embodiments, Y is an antibody or antibody fragment that specifically binds to a target protein, and the compound has formula (III): [ka] A conjugate of formula n is 1 to 20; m is the average load from 1 to 80; each X is a moiety that binds to a cell surface ASGPR; each L is a linker; each Z is a residue moiety resulting from the covalent bond between the chemoselective ligation group and a compatible group on the Ab; An Ab is an antibody or antibody fragment that specifically binds to a target protein.

[0585] 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 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.

[0586] In certain embodiments of the conjugate of Formula (III), Z is a residual moiety resulting from the covalent attachment of a chemoselective ligation moiety of Table 12 (eg, Table 12a).

[0587] 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 in Table 1. In certain embodiments, each X is independently selected from one of the following compounds: [ka]

[0588] In certain embodiments of Formula (III) or (III'), each X is independently selected from one of the following compounds: [ka] In the formula, R 5 and R 4 are independently H or a pro-moiety, or R 5 and R 4 are linked in a ring to form a pro moiety, n1 and n2 are each independently an integer of 1 to 6, and Y 4 is a suitable counterion. In some embodiments, Y 4 is sodium.

[0589] In certain embodiments of Formula (III) or (III'), n is 1 and X is [ka] is.

[0590] In certain other embodiments of Formula (III) or (III'), each X is independently of Formula (Ic) (e.g., as described herein). In certain embodiments, each X is independently selected from a compound in Table 2 or 2a.

[0591] 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 in Table 3 or 3a. In certain embodiments, each X is independently selected from a compound in Table 4. In certain embodiments, each X is a compound in Table 5.

[0592] In certain embodiments of Formula (III), each X is independently selected from one of the following compounds: [ka]

[0593] In certain embodiments of the conjugate of formula (III) or (III'), L is a linker of formula (II) (eg, as described herein).

[0594] 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 ligand and the linker is of 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.

[0595] In certain embodiments of the conjugate of formula (III) or (III'), Z is a residual moiety resulting from the covalent attachment of a chemoselective ligation moiety of Table 9.

[0596] In certain embodiments of the conjugate of formula (III) or (III'), Z is a residue moiety resulting from the covalent bond between the thiol-reactive chemoselective ligation group and one or more cysteine ​​residue(s) of the Ab. In certain embodiments, the thiol-reactive chemoselective ligation group is a maleimide derivative.

[0597] In certain other embodiments of the conjugate of formula (III), Z is a residue moiety resulting from the covalent bond between the amine-reactive chemoselective ligation group and 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.

[0598] In certain embodiments, conjugates having the linker structures described herein have weak binding affinity to cell surface receptors. Without being bound by any particular mechanism or theory, such weaker binding affinity may be compensated for to increase the half-life of the conjugate and may be useful for adjusting (e.g., modifying) the pharmacokinetic properties of the conjugates described herein. In certain embodiments, such weaker binding conjugates are still capable of sufficiently strong uptake.

[0599] Conjugates of a polypeptide, e.g., an antibody (Ab), and a compound (Xn-LY) can 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 can be prepared using any suitable method disclosed in the art (see, e.g., Bioconjugate Techniques (Hermanson ed., 2d ed. 2008)).

[0600] In certain embodiments of the conjugates described herein, L is attached to a lysine residue of the polypeptide via an amide bond. In certain embodiments of the conjugates described herein, L is attached to a cysteine ​​residue of the polypeptide via a thioether bond. In certain embodiments of the conjugates described herein, L is attached to a lysine residue of the Ab via an amide bond. In certain embodiments of the conjugates described herein, L is attached to a cysteine ​​residue of the Ab via a thioether bond. In certain embodiments of the conjugates described herein, L is attached to two cysteine ​​residues of the Ab via two thioether bonds, the two cysteine ​​residues being from open cysteine-cysteine ​​disulfide bonds of the Ab. In certain embodiments, the open cysteine-cysteine ​​disulfide bonds are interchain disulfide bonds.

[0601] In certain embodiments of the conjugates described herein, when L is attached to a lysine residue of a polypeptide (e.g., an antibody) via an amide bond, m is an integer from 1 to 80. In certain embodiments of the conjugates described herein, when L is attached to a cysteine ​​residue of P via a thioether bond, m is an integer from 1 to 8.

[0602] In certain embodiments, conjugation to a polypeptide or antibody Ab can be performed via site-specific conjugation. For example, site-specific conjugation can achieve uniform loading and minimize conjugate subpopulations that may alter antigen binding or pharmacokinetics. In certain embodiments, for example, conjugation can involve engineering cysteine ​​substitutions at positions on the polypeptide or antibody, such as on the heavy and / or light chains of the antibody, that provide reactive thiol groups, do not interfere with folding and assembly of the polypeptide or antibody, and do not 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, the entire contents of which are incorporated herein by reference). In another non-limiting approach, selenocysteine ​​is co-translationally inserted into a polypeptide or antibody sequence by recoding the stop codon UGA from the terminus to insert a selenocysteine, allowing site-specific covalent attachment at the nucleophilic selenol group of selenocysteine ​​in the presence of 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). Still other non-limiting techniques that allow for site-specific conjugation to polypeptides or antibodies include engineering unnatural amino acids, including, for example, p-acetylphenylalanine (p-acetyl-Phe), p-azidomethyl-N-phenylalanine (p-azidomethyl-Phe), and azidolysine (azido-Lys), at specific linkage sites, and may further include engineering unique functional tags, including, for example, 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 entire contents of each of which are incorporated by reference. See also US 2019 / 0060481 A1 and US 2016 / 0060354 A1, the entire contents of each of which are incorporated by reference. All of these methodologies are contemplated for use in connection with making the conjugates described herein.

[0603] The loading of a compound of Formula (I) onto a polypeptide (e.g., an antibody) described herein is represented by "m" in Formula (III) and is the average number of "Xn-L-" or "Xn-" units per conjugate molecule. As used herein, the term "DAR" refers to the average value of "m" or the loading of a conjugate. The number of "X" moieties (e.g., folate moieties) per "Xn-L-" or "Xn-" unit is represented by "n" in Formula (III). As used herein, the term "valency" refers to the number of "X" moieties ("n") per unit. It will be understood that the loading, i.e., DAR, is not necessarily the same as the number of "X" moieties per conjugate molecule. For example, if there is one "X" moiety per unit (n=1, valency is "1") and one "Xn-L-" unit (m=1) per conjugate, there will be 1x1=1 "X" moiety per conjugate. However, if there are two "X" moieties per unit (n=2, valency is "2") and four "Xn-L-" units per conjugate (m=4), then there will be 2 x 4 = 8 "X" moieties per conjugate. Thus, for the conjugates described herein, the total number of "X" moieties per conjugate molecule is n x m. As used herein, the term "total valency" refers to the total number of "X" moieties (n x m, total valency) per conjugate molecule.

[0604] The DAR(loading) can range from 1 to 80 units per conjugate. The conjugates provided herein can include a population of polypeptides, antibodies, or antigen-binding fragments conjugated with, for example, units ranging from 1 to 80. The average number of units per polypeptide or antibody in a preparation of conjugates resulting from a conjugation reaction can be characterized by conventional means, such as mass spectrometry. The quantitative distribution of DAR(loading) in terms of m can also be determined. In some cases, isolation, purification, and characterization of homogeneous conjugates with a particular value of m can be achieved by means such as electrophoresis.

[0605] In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 80. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 70. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 60. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 50. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 40. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 35. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 30. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 25. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 20. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 18. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 15. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 12. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 10. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 9. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 8. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 7. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 6. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 5. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 4. In certain embodiments, the DAR for the conjugates provided herein ranges from 1 to 3.In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 12. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 10. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 9. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 8. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 7. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 6. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 5. In certain embodiments, the DAR for the conjugates provided herein ranges from 2 to 4. In certain embodiments, the DAR for the conjugates provided herein ranges from 3 to 12. In certain embodiments, the DAR for the conjugates provided herein ranges from 3 to 10. In certain embodiments, the DAR for the conjugates provided herein ranges from 3 to 9. In certain embodiments, the DAR range for the conjugates provided herein is 3 to 8. In certain embodiments, the DAR range for the conjugates provided herein is 3 to 7. In certain embodiments, the DAR range for the conjugates provided herein is 3 to 6. In certain embodiments, the DAR range for the conjugates provided herein is 3 to 5. In certain embodiments, the DAR range for the conjugates provided herein is 3 to 4.

[0606] In certain embodiments, the DAR of the conjugates 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.

[0607] In certain embodiments, the DAR for the conjugates 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 the conjugates 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.

[0608] In some embodiments, the DAR range for the conjugates provided herein is 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 range for the conjugates provided herein is 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 the conjugates provided herein is about 1. In some embodiments, the DAR for the conjugates provided herein is about 2. In some embodiments, the DAR for the conjugates provided herein is about 3. In some embodiments, the DAR for the conjugates provided herein is about 4. In some embodiments, the DAR for the conjugates provided herein is about 3.8. In some embodiments, the DAR for the conjugates provided herein is about 5. In some embodiments, the DAR for the conjugates 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 the conjugates provided herein is about 18. In some embodiments, the DAR for the conjugates provided herein is about 19. In some embodiments, the DAR for the conjugates provided herein is about 20.

[0609] 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.

[0610] In certain embodiments, fewer than the theoretical maximum number of units are conjugated to a polypeptide, e.g., an antibody, during the conjugation reaction. The polypeptide may contain, for example, lysine residues that do not react with a compound or linker reagent. Generally, for example, antibodies do not contain many free reactive cysteine ​​thiol groups that can be linked to a drug unit; in fact, most cysteine ​​thiol residues in antibodies exist as disulfide bonds. In certain embodiments, antibodies can be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) under partial or complete reducing conditions to generate reactive cysteine ​​thiol groups. In certain embodiments, the antibody is subjected to denaturing conditions to expose reactive nucleophilic groups, such as lysine or cysteine. In some embodiments, the compound is conjugated via a lysine residue on the antibody. In some embodiments, a linker unit or drug unit is conjugated via a cysteine ​​residue on the antibody.

[0611] In certain embodiments, the amino acid attached to the unit is in the heavy chain of the antibody. In certain embodiments, the amino acid attached to the unit is in the light chain of the antibody. In certain embodiments, the amino acid attached to the unit is in the hinge region of the antibody. In certain embodiments, the amino acid attached to the unit is in the Fc region of the antibody. In certain embodiments, the amino acid attached to the unit is in a constant region of the antibody (e.g., CH1, CH2, or CH3 of the heavy chain, or CH1 of the light chain). In still other embodiments, the amino acid attached to the unit or Drug Unit is in a VH framework region of the antibody. In still other embodiments, the amino acid attached to the unit is in a VL framework region of the antibody.

[0612] The DAR (loading) of the conjugate can be controlled in various ways, such as (i) limiting the molar excess of compound or coupling reagent relative to the polypeptide, (ii) limiting the coupling reaction time or temperature, (iii) partial or limiting reducing conditions for cysteine ​​thiol modification, or (iv) recombinantly modifying the amino acid sequence of the polypeptide to alter the number and position of cysteine ​​residues to control the number and / or position of linker-drug attachments (e.g., in the case of thiomab prepared as disclosed in WO2006 / 034488, which is incorporated herein by reference in its entirety).

[0613] It should be understood that preparation of the conjugates described herein may result in a mixture of multiple conjugates having a distribution of one or more units attached to a polypeptide, e.g., an antibody. Individual conjugate molecules in the mixture can be identified by mass spectrometry and separated by HPLC, e.g., hydrophobic interaction chromatography, including methods known in the art. In certain embodiments, homogeneous conjugates with a single DAR (loading) value can be separated from the conjugation mixture by electrophoresis or chromatography.

[0614] In certain embodiments of the conjugate of Formula (III), m is 1 to 20, e.g., 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 weight of about 4.

[0615] It should be understood that preparation of the conjugates described herein may result in a mixture of multiple conjugates having a distribution of one or more units attached to a polypeptide, e.g., an antibody. Individual conjugate molecules in the mixture can be identified by mass spectrometry and separated by HPLC, e.g., hydrophobic interaction chromatography, including methods known in the art. In certain embodiments, homogeneous conjugates with a single DAR (loading) value can be separated from the conjugation mixture by electrophoresis or chromatography.

[0616] target binding moiety A target binding moiety can be any moiety that has an affinity for a target of less than 1 μM, e.g., 300 nM or less, 100 nM or less, 30 nM or less, 10 nM or less, 3 nM or less, or 1 nM or less, as measured, for example, in an in vitro binding assay.

[0617] 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 a peptide, a protein, a polynucleotide, a polysaccharide, a glycan, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment.

[0618] In some embodiments, the target-binding moiety is a polypeptide (e.g., a peptide or protein-binding motif, a protein domain, a modified polypeptide, or a glycoprotein) that specifically binds to a target molecule, such as a target protein. In some embodiments, the target-binding moiety of a bifunctional compound comprises 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 comprises a receptor ligand that binds to a target cell surface receptor, or a receptor-binding portion or fragment of a receptor ligand. The target-binding polypeptide may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of naturally occurring amino acids, unnatural amino acids, and / or amino acid variants or analogs known in the art. Useful modifications include, for example, N-terminal acetylation, amidation, methylation, etc.

[0619] 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.

[0620] In some embodiments, the target binding moiety is a glycan. In some embodiments, the target binding moiety is a glycan epitope of an autoantibody.

[0621] antibody 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.

[0622] The ASGPR-binding moiety can be site-specifically covalently bound to an antibody or antibody fragment via any linking moiety. The ASGPR-binding moiety can be covalently bound to an 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. The ASGPR-binding moiety can be covalently bound to an antibody or antibody fragment via one or more lysine residues on the antibody or antibody fragment and an amine-reactive chemoselective ligation group.

[0623] In some embodiments, the bifunctional conjugate of the present disclosure comprises an antibody (Ab). In some embodiments, the Ab is a monoclonal antibody. In some embodiments, the Ab is a human antibody. In some embodiments, the Ab is a humanized antibody. In some embodiments, the Ab is a chimeric antibody. In some embodiments, the Ab is a full-length antibody comprising two heavy chains and two light chains. In some embodiments, the Ab is an IgG antibody, e.g., an IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, the 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.

[0624] In some embodiments, the antibody or antibody fragment specifically binds to a cancer antigen.

[0625] In some embodiments, the antibody or antibody fragment specifically binds to a hepatocyte antigen.

[0626] In some embodiments, the antibody or antibody fragment specifically binds to an antigen displayed on a macrophage.

[0627] In some embodiments, the antibody or antibody fragment specifically binds to the full complement or a fragment thereof, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within the full complement or a fragment thereof.

[0628] 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.

[0629] In some embodiments, the antibody or antibody fragment specifically binds to an epidermal growth factor (EGF) protein, e.g., human EGF, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the EGF protein.

[0630] In some embodiments, the antibody or antibody fragment specifically binds to an epidermal growth factor receptor (EGFR) protein, e.g., human EGFR. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the EGFR protein. In some embodiments, the antibody or antibody fragment comprises CDRs present in cetuximab. In some embodiments, the antibody or antibody fragment comprises a variable light chain and a variable heavy chain present in cetuximab. In some embodiments, the antibody is cetuximab. In some embodiments, the antibody or antibody fragment comprises CDRs present in matuzumab. In some embodiments, the antibody or antibody fragment comprises a variable light chain and a variable heavy chain present in matuzumab. In some embodiments, the antibody is matuzumab.

[0631] In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor (VEGF) protein, e.g., a human VEGF protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the VEGF protein.

[0632] In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor receptor (VEGFR) protein, such as a human VEGFR protein. In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor receptor 2 (VEGFR2) protein, such as a human VEGFR2 protein. In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor receptor 3 (VEGFR3) protein, such as a human VEGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within a VEGFR protein, a VEGFR2 protein, or a VEGFR3 protein.

[0633] In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor (FGF), such as human FGF, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the FGF protein.

[0634] In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor (FGFR), e.g., human FGFR. In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor 2 (FGFR2) protein, e.g., human FGFR2 protein, e.g., FGFR2b protein. In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor 3 (FGFR3) protein, e.g., human FGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within an FGFR protein, FGFR2 protein, or FGFR3 protein.

[0635] In some embodiments, the antibody specifically binds to the receptor tyrosine kinase cMET protein. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within the receptor tyrosine kinase cMET protein.

[0636] In some embodiments, the antibody specifically binds to a CD47 protein, e.g., a human CD47 protein, hi some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within the CD47 protein.

[0637] 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 the immune checkpoint inhibitor. In some embodiments, the antibody specifically binds to a programmed cell death protein, such as human PD-1. In some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within the PD-1 protein.

[0638] In some embodiments, the antibody specifically binds to a programmed death-ligand 1 (PD-L1) protein, e.g., human PD-L1, hi some embodiments, the antibody specifically binds to one or more immunodominant epitope(s) within the PD-L1 protein.

[0639] In some embodiments, the antibody binds to TIM3, hi some embodiments, the antibody binds to one or more immunodominant epitope(s) within TIM3.

[0640] 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 the 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 one or more immunodominant epitope(s) within a 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., TNF-α), 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., TNF-α), IL1a, IL1b, IL4, IL5, IL6, IL12 / IL23, IL13, IL17, or p40.

[0641] In some embodiments, the antibody binds to a major histocompatibility protein (e.g., an 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., an MHC class I or class II molecule). In some embodiments, the antibody binds to β2 microglobulin. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within β2 microglobulin.

[0642] Modified Virus Compositions In certain embodiments, Y is a viral particle, a viral capsid, a viral envelope, or a viral protein. In some embodiments, the viral composition is a viral particle comprising a transgene. In some embodiments, the viral protein is a viral capsid protein or a viral envelope protein.

[0643] In certain aspects, provided herein are modified viral compositions comprising a viral composition, e.g., a viral particle, a viral capsid, or a viral protein (e.g., a viral capsid protein or an envelope protein), attached (e.g., directly or indirectly via an intervening linker sequence) to an ASGPR-binding moiety that binds to a cell surface receptor. In certain embodiments, the modified viral composition comprises a viral particle comprising a polynucleotide that optionally includes a transgene (e.g., a transgene useful for therapeutic applications).

[0644] The modified viral compositions, e.g., viral conjugates, provided herein can include any viral composition described herein, e.g., any viral particle, capsid, or viral protein, e.g., a capsid protein or envelope protein, or fragment thereof, described herein.

[0645] In certain embodiments, the viral compositions described herein may comprise viral particles. As used herein, the terms "virus particle," "viral particle," "virus vector," or "viral vector" are used interchangeably. A "virus particle" refers to a viral capsid and a polynucleotide (DNA or RNA), including a viral genome, a portion of a viral genome, or a polynucleotide derived from a viral genome (e.g., one or more ITRs), where the polynucleotide optionally includes a transgene. In certain circumstances, a viral particle further comprises an envelope (generally comprising a lipid portion and an envelope protein) surrounding or partially surrounding the capsid.

[0646] Viral particles may also be referred to as "recombinant viral particles" or "recombinant viral particles," and as used herein, these terms refer to viral particles that have been genetically modified, for example, by deletion or other mutation of endogenous viral genes and / or the addition or insertion of a heterologous nucleic acid construct into the polynucleotide of the viral particle. Thus, a recombinant viral particle generally refers to a viral particle that includes a capsid coat or shell (and any outer envelope) packaged therein a polynucleotide sequence that includes sequences of viral and non-viral origin (i.e., a polynucleotide heterologous to the virus). This polynucleotide sequence is typically the sequence of interest for genetic modification of a cell.

[0647] In certain aspects, the viral compositions described herein, when referred to herein in the context of viruses, may include "viral capsids," "empty viral particles," "empty virus particles," or "capsids" or "empty particles," which terms as used herein refer to a three-dimensional shell or coat comprising viral capsid proteins, optionally surrounded or partially surrounded by an outer envelope. In certain embodiments, the viral composition is a viral particle or fragment thereof, a viral capsid or fragment thereof, a viral protein, e.g., a viral capsid protein or fragment thereof, or an envelope protein or fragment thereof.

[0648] In some embodiments, the viruses used in the modified virus compositions provided herein are adenoviruses (AV), adeno-associated viruses (AAV), retroviruses (e.g., lentiviruses (LV), rhabdoviruses, murine leukemia viruses), herpes simplex viruses, coronaviruses, reoviruses, etc. In some embodiments, the viral vectors, viral particles, or viral proteins used in the present disclosure are derived from non-enveloped viruses, such as adeno-associated viruses (AAV).

[0649] In some embodiments, lentiviral vectors can be used for CAR-T gene delivery, vaccines, or research tools to introduce genes into mature T cells to generate immunity against cancer, for example, through delivery of chimeric antigen receptors (CARs) or cloned T cell receptors.

[0650] Naturally occurring AAV forms viral particles that include a three-dimensional capsid coat or shell ("capsid") composed of capsid proteins (VP1, VP2, VP3) and the AAV viral genome contained within the capsid.

[0651] The modified AAV compositions described herein, e.g., AAV conjugates or fusions, can include any AAV composition described herein, e.g., any AAV particle, capsid, or capsid protein described herein, or fragments thereof. The term "AAV capsid protein" or "AAV cap protein" refers to a protein encoded by an AAV capsid (cap) gene (e.g., VP1, VP2, VP3) or a variant or fragment thereof. This term includes capsid proteins expressed by or derived from AAV (e.g., recombinant AAV, such as chimeric AAV). For example, the term includes, but is not limited to, capsid proteins derived from any AAV serotype or variants thereof, 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.

[0652] Bridging molecules that bind viral compositions In some embodiments, Y is a bridging moiety that specifically binds to a viral composition, such as 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 bond.

[0653] Any suitable moiety that binds to 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 the present disclosure.

[0654] In certain embodiments, the bridging moiety is a polypeptide that specifically binds to a viral composition. In some embodiments, the bridging moiety is a polypeptide that binds to a viral composition, such as a viral particle, a viral capsid, a viral envelope, or a viral protein (e.g., a viral capsid protein or a viral envelope protein). In certain aspects, when the viral protein is part of a viral particle, the bridging composition is bound to the viral capsid protein or the viral envelope protein.

[0655] In certain embodiments, the bridging moiety is an antibody or antibody fragment (e.g., an antigen-binding fragment of an antibody) that specifically binds to the viral composition. In certain embodiments, a bridging moiety that binds to a viral protein may also bind to a viral particle, for example, by binding to a viral protein incorporated into the viral particle. Similarly, in certain embodiments, a bridging moiety that binds to a viral particle may bind to a viral protein even if the viral protein is not incorporated into the viral particle. The viral particle may be an AAV viral particle. The viral protein may be an AAV capsid protein.

[0656] In some embodiments, a cross-linking moiety of the present disclosure specifically binds to an AAV composition, e.g., an AAV particle, an AAV capsid, or an AAV viral protein (e.g., an AAV capsid protein, e.g., a VP1, VP2, or VP3 protein).

[0657] Antibodies or antigen-binding fragments that may be utilized in connection with the modified virus compositions provided herein, e.g., in connection with the cross-linking compositions and cross-linking moieties presented herein, include, but are not limited to, monoclonal antibodies, antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity), single-chain antibodies, and fragments thereof (e.g., domain antibodies).

[0658] small molecule In some embodiments, the target-binding moiety of the bifunctional compound of the present 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 the target protein. The small molecule target-binding moiety can be covalently linked to one or more ASGPR-binding moieties via a linker. The linker can be covalently linked to the small molecule via substitution at any suitable site on the small molecule, thereby substantially retaining binding to the target protein.

[0659] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of the target protein (e.g., as described herein). Any convenient small molecule known to bind to the target of interest can be adapted for use in the subject compounds and conjugates.

[0660] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of VEGF.

[0661] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of PD-L1.

[0662] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of an EGFR protein, a VEGFR protein, an FGFR2 protein, or an FGFR3 protein.

[0663] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of a TNF protein (e.g., TNF-α). TNF-alpha (TNFα) is a soluble cytokine produced by monocytes and macrophages as part of immune and inflammatory processes and is involved in various cellular responses, including differentiation, proliferation, inflammation, and cell death. TNFα is a type II membrane protein that is 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 modulation of intracellular NF-κB, JNK, and p38-MAPK signaling pathways.

[0664] 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 the present disclosure can include potent TNFα inhibitors, for example, inhibitors with submicromolar inhibitory activity. In some embodiments, the TNFα inhibitor is an allosteric inhibitor. In some embodiments, the TNFα binding moiety is an allosteric desymmetrizing TNFα inhibitor. An allosteric desymmetrizing TNFα inhibitor refers to a compound that binds to an allosteric site within TNFα and stabilizes the trimer unit in an asymmetric structure, thereby allowing the TNFα trimer to recruit only two of the three copies of the TNF receptor (TNFR, e.g., TNFR1), leading to the inability of the TNFα-TNFR signaling complex.

[0665] See, for example, Xiao et al. in Journal of Medicinal Chemistry 2020 63 (23), 15050-15071, and McMillan et al. in Nature Communications (2021) 12:582, who publish analyses of X-ray co-crystal structures of exemplary inhibitors bound to TNFα. Allosteric desymmetrized TNFα inhibitors can act via specific mechanisms of action to provide potent inhibitory activity. For example, (a) the binding site of TNFα inhibitors is a cavity created within the TNFα trimer by the displacement of monomer A, (b) the inhibitor stabilizes the TNFα trimer in an inactive conformation by forming critical π-π and hydrogen-bonding interactions, (c) allosteric desymmetrizing TNFα inhibitors bind to the TNFα trimer, causing major disruption of one TNFR binding site and minor disruption of a second site, while leaving the third site unchanged, and (d) allosteric desymmetrizing TNFα inhibitors regulate TNF-R activity through an allosteric mechanism rather than directly competing with TNFRs. Thus, binding of allosteric desymmetrizing TNFα inhibitors to a symmetric TNFα trimer can result in the formation of an asymmetric trimer, potentially preventing the recruitment of three TNF receptor molecules required for signal transduction.

[0666] target As summarized above, the bifunctional compounds of the present disclosure can include a moiety of interest (Y) that specifically binds to a target molecule. The target molecule can be a cell surface molecule or an extracellular molecule.

[0667] In some embodiments of the compounds and methods of the present disclosure, the target molecule is a cell surface molecule. "Cell surface molecule" refers to a target molecule associated with a cell membrane, for example, the molecule has a domain that is inserted into or spans the cell membrane, such as a cell membrane anchoring domain or a transmembrane domain. The cell surface molecule can be any cell surface molecule for which targeted degradation via the endosomal / lysosomal pathway is desired. In some embodiments, the cell surface molecule is a cell surface receptor.

[0668] 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, receptors of the epidermal growth factor receptor (EGFR) family (e.g., HER2 (human epidermal growth factor receptor 2)), receptors of the fibroblast growth factor receptor (FGFR) family, receptors of the vascular endothelial growth factor receptor (VEGFR) family, receptors of the platelet-derived growth factor receptor (PDGFR) family, receptors of the rearranged during transfection (RET) receptor family, receptors of the Eph receptor family, receptors of the discoidin domain receptor (DDR) family, and mucin proteins (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 T cell receptors, B cell receptors, natural killer (NK) cell receptors, macrophage receptors, monocyte receptors, neutrophil receptors, dendritic cell receptors, mast cell receptors, basophil receptors, and eosinophil receptors.

[0669] In some embodiments, the moiety of interest (Y) specifically binds to a cell surface molecule, and its effect is mediated through a bulk biophysical or collective effect rather than through a specific molecular interaction (and therefore less susceptible to inhibition). Non-limiting examples of such cell surface molecules are mucins. Examples of mucins include, but are not limited to, MUC1, MUC16, MUC2, MUC5AC, MUC4, CD43, CD45, GPIb, and the like.

[0670] In some embodiments, when a moiety of interest specifically binds to a cell surface molecule, the cell surface molecule is present on a cancer cell. "Cancer cell" refers to a cell that exhibits a neoplastic cell phenotype that can be characterized by one or more of aberrant cell growth, aberrant cell proliferation, loss of density-dependent growth inhibition, anchorage-independent growth potential, the ability to promote tumor growth and / or development in immunocompromised non-human animal models, and / or suitable indicators of cellular transformation. As used herein, "cancer cell" is used interchangeably with "tumor cell," "malignant cell," or "cancerous cell" and encompasses cancer cells such as solid tumors, semi-solid tumors, hematopoietic malignancies (e.g., leukemia cells, lymphoma cells, myeloma cells, etc.), primary tumors, and metastatic tumors. In some embodiments, the cell surface molecule present on a cancer cell is a tumor-associated antigen or a tumor-specific antigen. In certain aspects, when a moiety of interest (Y) specifically binds to 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 T cells, B cells, natural killer (NK) cells, macrophages, monocytes, neutrophils, dendritic cells, mast cells, basophils, and eosinophils. In certain aspects, the cell surface molecule present on an immune cell is an inhibitory immunoreceptor. As used herein, an "inhibitory immunoreceptor" is a receptor present on an immune cell that negatively regulates an immune response. Examples of inhibitory immunoreceptors that may be inhibited according to the methods of the present disclosure include inhibitory immunoreceptors 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 immunoreceptors that can be inhibited by the methods of the present disclosure include sialic acid-binding lg-like (siglec) receptors (eg, siglec 7, siglec 9).Further examples of inhibitory immunoreceptors that can 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 immunoreceptors are described, for example, in Steevels et al. (2011) Eur. J. Immunol. 41(3):575-587. In some embodiments, the cell surface molecule present on an immune cell is a ligand of the inhibitory immunoreceptor. In certain aspects, the cell surface molecule present on an immune cell is an immune checkpoint molecule. Non-limiting examples of immune checkpoint molecules to which the moiety of interest (Y) can specifically bind include PD-1, PD-L1, CTLA4, TIM3, LAG3, TIGIT, and members of the B7 family.

[0671] In some embodiments of the compounds and methods of the present disclosure, the target molecule is an extracellular molecule. "Extracellular molecule" refers to a soluble molecule that is located outside the cell membrane of any cell in the vicinity of a soluble molecule. The extracellular molecule can be any extracellular molecule for which targeted degradation via the endosomal / lysosomal pathway is desired.

[0672] 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 toxin, ESAT-6), an infectious particle (e.g., whole virus, whole bacteria, etc.), a coagulation factor (e.g., factor IX), a target of an FDA-approved antibody that binds to the extracellular molecule (e.g., TNFα), a chemokine or cytokine (e.g., a mediator of sepsis or chronic inflammation such as IL-1), a protein hormone (e.g., insulin, ACTH, etc.), a protein mediator of mood disorders, a protein mediator of energy homeostasis (e.g., leptin, ghrelin, etc.), a protein allergen present in the bloodstream or an antibody against such an allergen (e.g., in the case of peanut allergy), a protein toxin (e.g., snake venom hyaluronidase, etc.), an autoantibody, etc.

[0673] In some embodiments, the target molecule is an extracellular molecule that is an antibody, e.g., an antibody specifically bound to a cell surface molecule or a different extracellular molecule. In some embodiments, the antibody is an autoantibody. In some embodiments, the target is human immunoglobulin A (IgA). In some embodiments, IgA is a specific antibody that plays an important role in mucosal immune function. In the blood, IgA interacts with an Fc receptor called CD89, which is expressed on immune effector cells, initiating an inflammatory response. Abnormal IgA expression is thought to be associated with many autoimmune and immune-mediated diseases. In some embodiments, the target is human immunoglobulin G (IgG). The Fc region of IgG contains a conserved N-glycosylation site at asparagine 297 in the constant region of the heavy chain. Various N-glycans can be attached to this site. N-glycan IgG composition has been associated with several autoimmune, infectious, and metabolic diseases. Furthermore, overexpression of IgG4 has been associated with IgG4-associated diseases. In some embodiments, the target is human immunoglobulin E (IgE). IgE is a type of immunoglobulin that plays a key role in type I hypersensitivity, which can lead to a variety of allergic diseases and conditions.

[0674] 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), etc.), cytokines (e.g., interleukins, interferons, tumor necrosis factor (TNF), transforming growth factor β (TGF-β), including any specific subtypes of such cytokines), hormones, etc. In certain aspects, the moiety of interest (Y) specifically binds apolipoprotein E4 (ApoE4).

[0675] Pharmaceutical Composition In another embodiment, provided herein is a pharmaceutical composition comprising one or more conjugates disclosed herein and a pharmaceutically acceptable carrier.

[0676] In certain embodiments, the pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more conjugates provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier.

[0677] Pharmaceutical carriers suitable for administration of the conjugates provided herein include any carriers known to those skilled in the art to be suitable for the particular method of administration.

[0678] The conjugates described herein can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients.

[0679] In certain embodiments, the conjugates are formulated into one or more suitable pharmaceutical formulations, such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or transdermal patch formulations and dry powder inhalants.

[0680] In the compositions provided herein, the conjugates described herein can be mixed with a suitable pharmaceutical carrier. The concentration of the conjugate in the composition can be, for example, effective to deliver an amount that, upon administration, treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof.

[0681] In certain embodiments, the pharmaceutical compositions provided herein are formulated for single-dose administration. To formulate the composition, the weight fraction of the conjugate is dissolved, suspended, dispersed, or otherwise mixed in the selected carrier at an effective concentration to alleviate, prevent, or improve one or more symptoms of the condition being treated.

[0682] The concentration of the conjugate in the pharmaceutical compositions provided herein depends, for example, on the physicochemical properties of the conjugate, the administration schedule, the dosage, as well as other factors known to those of skill in the art.

[0683] The pharmaceutical compositions described herein are provided for administration to a subject, e.g., a human or an animal (e.g., a mammal), in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing an appropriate amount of the compound or a pharmaceutically acceptable derivative thereof. Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage forms, such as oral or nasal solutions or suspensions and oil-in-water emulsions containing an appropriate amount of the conjugate or a pharmaceutically acceptable derivative thereof. In certain embodiments, the conjugate is formulated and administered in unit dosage forms or multi-doses. As used herein, unit dosage form refers to a physically discrete unit suitable for human or animal (e.g., mammalian) subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of the conjugate sufficient to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules, syringes, and individually packaged capsules. The unit dosage form can be administered in divided doses or multiple times. A multiple-dosage form is a dosage form in which a plurality of identical unit-dosage forms are packaged in one container and administered in separate unit-dosage forms.Examples of multiple-dosage forms include vials, capsule bottles, or bottles.Therefore, in certain embodiments, a multiple-dosage form is a multiple of the unit-dosage form that is not separated in packaging.

[0684] In certain embodiments, the conjugate herein is in the form of a liquid pharmaceutical formulation. The liquid pharmaceutical formulation can be prepared, for example, by dissolving, dispersing, or mixing the conjugate and optional pharmaceutical auxiliary agents in a carrier such as water, saline, aqueous dextrose, glycerol, glycol, etc. to form a solution or suspension. In certain embodiments, the pharmaceutical composition provided herein to be administered can also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, pH buffering agents, etc.

[0685] Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy (2012) 22nd ed., Pharmaceutical Press, Philadelphia, Pa. Dosage forms or compositions can be prepared containing antibodies in the range of 0.005% to 100%, with the remainder consisting of non-toxic carriers.

[0686] In certain embodiments, parenteral administration is characterized by subcutaneous, intramuscular, or intravenous injection, although parenteral administration is also contemplated herein. Injectables can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, glucose, glycerol, or ethanol. Other administration routes may include enteral administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous injection, intraspinal administration, and intraperitoneal administration.

[0687] Preparations for parenteral administration include sterile solutions for injection, sterile dry soluble products (including subcutaneous tablets) such as lyophilized powders to be combined with a solvent immediately before use, sterile suspensions for injection, sterile dry insoluble products to be combined with a vehicle immediately before use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[0688] For intravenous administration, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0689] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable substances.

[0690] Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0691] In certain embodiments, intravenous or intraarterial infusion of a sterile aqueous solution containing a conjugate described herein is an effective method of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing a conjugate described herein, injected as needed to produce the desired pharmacological effect.

[0692] In certain embodiments, the pharmaceutical formulation is a lyophilized powder that can be reconstituted for administration as a solution, emulsion, or other mixture, or can be formulated as a solid or gel upon reconstitution.

[0693] The lyophilized powder is prepared by dissolving the conjugate described herein in a suitable solvent. In some embodiments, the lyophilized powder is sterilized. The suitable solvent may contain excipients or other pharmacological ingredients that improve the stability of the powder or a reconstitution solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The suitable solvent may also contain a buffer solution such as citrate, sodium phosphate, potassium phosphate, or other buffers known to those of skill in the art (in certain embodiments, at approximately neutral pH). Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides an exemplary formulation. In certain embodiments, the resulting solution is divided into vials for lyophilization. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0694] This lyophilized powder is reconstituted with water for injection to provide a formulation for parenteral administration. To reconstitute, the lyophilized powder is added to sterile water or other suitable carrier.

[0695] In certain embodiments, the conjugates provided herein can be formulated for topical administration or topical application, for example, in the form of gel, cream, and lotion, for topical application to the skin and mucous membranes, such as the eye, and for application to the eye, or for intravesical or intrathecal application.Topical administration is considered for transdermal delivery, administration to the eye or mucous membrane, or for inhalation therapy.Nasal drops of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0696] Uses and Methods In one aspect, provided herein is a method for removing a polypeptide of interest (target protein) from the surface of a cell using a conjugate described herein. In one aspect, provided herein is a method for removing a polypeptide of interest (target protein) from the extracellular environment using a conjugate described herein. For example, in one embodiment, provided herein is a method for removing a polypeptide of interest (target protein) from the surface of a cell by sequestering the target protein in the lysosomes of the cell using a conjugate described herein. In another embodiment, provided herein is a method for removing a polypeptide of interest (target protein) from the extracellular space (extracellular environment) of a cell by sequestering the target protein in the lysosomes of the cell using a conjugate described herein. In another embodiment, provided herein is a method for removing a polypeptide of interest (target protein) from the surface of a cell by sequestering the target protein in the lysosomes of the cell and degrading the target protein. In another embodiment, provided herein is a method for removing a polypeptide of interest (target protein) from the extracellular space (extracellular environment) of a cell by sequestering the target protein in the lysosomes of the cell using a conjugate described herein.

[0697] Removal of a target protein can refer to the reduction or depletion of the target protein from the cell surface or extracellular space or extracellular environment, i.e., the reduction or depletion of the amount of the target protein on the cell surface or in the extracellular environment.

[0698] In one aspect, provided herein is a method for sequestering a polypeptide of interest (target protein) in the lysosomes of a cell using a conjugate described herein. In one aspect, provided herein is a method for sequestering a polypeptide of interest (target protein) in the lysosomes of a cell using a conjugate described herein and degrading the polypeptide of interest.

[0699] In one aspect, provided herein are methods for degrading a polypeptide of interest (target protein) using the conjugates described herein.

[0700] In one aspect, provided herein is a method for depleting a polypeptide of interest (target protein) described herein by degradation via the lysosomal pathway of a cell.

[0701] In another aspect, provided herein is a method for depleting a polypeptide of interest (target protein) described herein by administering to a subject in need of treatment an effective amount of a conjugate or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein. In certain embodiments, the subject is a mammal (e.g., a human).

[0702] In some 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.

[0703] In another aspect, provided herein is a method of treating a disease or disorder by administering to a subject, e.g., a human, in need thereof an effective amount of a conjugate or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0704] 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 patient (e.g., a human), such as by mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery, and / or other physical delivery methods described herein or known in the art. In certain embodiments, administration is performed by intravenous infusion.

[0705] The term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent (e.g., a conjugate or pharmaceutical composition provided herein) sufficient to treat, diagnose, prevent, delay onset, reduce the severity and / or duration, and / or ameliorate a particular condition, disorder, or disease, and / or symptoms associated therewith. These terms also include the amount necessary to reduce, delay, or ameliorate the progression or progression of a given disease, reduce, delay, or ameliorate the recurrence, onset, or manifestation of a given disease, and / or improve or enhance the prophylactic or therapeutic effect(s) of another therapy or serve as a bridge to another therapy. In some embodiments, "effective amount," as used herein, refers to the amount of a conjugate described herein to achieve a particular result.

[0706] In certain embodiments, when the disorder or disease is cancer, an "effective amount" or "therapeutically effective amount" refers to the amount of a conjugate or pharmaceutical composition provided herein that, when administered to a human suffering from cancer, is sufficient to provide a therapeutic effect for the cancer. "Treating" or "treatment" of cancer includes one or more of the following: (1) Suppressing / inhibiting cancer growth, e.g., inhibiting cancer progression; (2) reducing / preventing cancer metastasis, e.g., reducing / preventing metastasis; (3) alleviating cancer symptoms, e.g., causing cancer regression; (4) reducing / preventing cancer recurrence; and (5) Relieving cancer symptoms.

[0707] 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., monkeys and humans), e.g., a human. In certain embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder described herein. In certain embodiments, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder described herein. In certain embodiments, the subject is a human.

[0708] The terms "therapies" and "therapy" can refer to any protocol(s), method(s), composition(s), formulation(s), and / or agent(s) that can be used to prevent, treat, manage, or ameliorate a disease or disorder or a symptom thereof (e.g., a disease or disorder provided herein, or one or more symptoms or conditions associated therewith). In certain embodiments, the terms "therapies" and "therapy" refer to drug therapy, adjuvant therapy, radiation therapy, surgery, biological therapy, supportive therapy, and / or other therapies useful in the 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 or pharmaceutical composition thereof described herein.

[0709] In certain embodiments, the disease or disorder is treated by depleting the target protein by degradation via the lysosomal pathway.

[0710] In certain embodiments, the disease or disorder is treated by depletion of a particular protein, such as a soluble protein (e.g., a secreted protein), a cell surface protein (e.g., a cell surface receptor protein (e.g., a tyrosine kinase receptor), a soluble cytokine receptor, and an immune checkpoint receptor (e.g., EGFR, VEGFR, FGFR, and PD-L1), a lectin, a complement, a lipoprotein, a transport protein, an MHC class I and class II molecule, a cytokine, a chemokine, and / or a receptor, or a fragment or subunit of any of the foregoing.

[0711] In certain embodiments, the disease or disorder is cancer.

[0712] In certain embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, endometrial cancer, hepatocellular carcinoma, renal cancer, melanoma, myeloid tumors, non-small cell lung cancer (NSCLC), Ewing's sarcoma, and Hodgkin's lymphoma.

[0713] In certain embodiments, the cancer is a solid tumor.

[0714] In certain embodiments, the disease or disorder is an inflammatory disease or an autoimmune disease.

[0715] In certain embodiments, the disease or disorder is an inflammatory disease.

[0716] 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.

[0717] definition It is to be understood that the present disclosure is not limited to particular embodiments described, which 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.

[0718] Unless otherwise defined, 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.

[0719] It should be noted that as used in this specification and 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 not only a single substituent but also two or more substituents, etc.

[0720] Certain terms are used in accordance with the definitions set forth below. It will be understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall under more than one term definition.

[0721] As used herein, the words "for example," "for instance," "such as," or "including" are intended to introduce examples that further clarify a more general subject matter. These examples are provided solely as an aid in understanding the disclosure and are not intended to be limiting in any way.

[0722] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should 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.

[0723] The terms "protein" and "polypeptide" are used interchangeably. Proteins may contain moieties other than amino acids (e.g., glycoproteins, etc.) and / or may be otherwise processed or modified. Those of skill in the art will understand that a "protein" can be an entire protein chain (with or without a signal sequence) produced by a cell, or a protein portion thereof. Those of skill in the art will understand that a protein can include one or more protein chains attached non-covalently or covalently, e.g., linked by one or more disulfide bonds, or associated by other means. In certain embodiments, polypeptides can exist as a single chain or as two or more associated chains, and can exist as multimers, e.g., dimers, trimers, etc. These terms also include amino acid polymers that are modified naturally or by intervention (e.g., by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or other manipulation or modification). The definition also includes 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, for example, terminal acetylation, amidation, methylation, etc. In some embodiments, proteins may contain natural amino acids, unnatural 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.

[0724] The terms "antibody" and "immunoglobulin" are terms of art and may be used interchangeably herein in their broadest sense to include a specific type of immunoglobulin molecule that contains one or more antigen-binding domains that specifically bind to an antigen or epitope.

[0725] In certain embodiments, an isolated antibody (e.g., a monoclonal antibody), or antigen-binding fragment thereof, described herein specifically binds to a protein of interest, e.g., EGFR, and is conjugated to one or more lysosomal targeting moieties, e.g., via a linker.

[0726] An "antigen" is a moiety or molecule that contains an epitope to which an antibody can specifically bind. Thus, an antigen is also specifically bound by an antibody. In certain embodiments, the antigen to which the antibodies described herein bind is a protein of interest, such as EGFR (e.g., human EGFR), or a fragment thereof, or, for example, the extracellular domain of EGFR (e.g., human EGFR).

[0727] "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 may be a linear epitope of contiguous amino acids or may include amino acids from two or more non-contiguous regions of the antigen.

[0728] The terms "bind," "binds," "specifically binds," or "specifically binds to," in the context of antibody binding, refer to an antibody that binds to an antigen (e.g., an epitope), as such binding is understood by one of skill in the art. For example, a molecule that specifically binds to an antigen may also bind to other polypeptides, which will generally result in lower affinity as determined, for example, by immunoassay, Biacore™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In certain embodiments, a molecule that specifically binds to an antigen has a K dAt least 2 log, 2.5 log, 3 log, or 4 log lower (higher affinity) affinity (K d ) binds to the antigen. In another specific embodiment, a molecule that specifically binds to an antigen does not cross-react with other proteins. In another specific embodiment, when EGFR is the protein of interest, a molecule that specifically binds to an antigen does not cross-react with other non-EGFR proteins.

[0729] Antibodies include full-length antibodies (e.g., complete immunoglobulins), antibody fragments, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain / antibody heavy chain pairs, and antibodies having two light chain / heavy chain pairs (e.g., identical pairs). Antibodies include, but are not limited to, antibodies, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, bivalent antibodies (including monospecific or bispecific bivalent antibodies), single chain antibodies or single chain Fvs (scFvs), camelized antibodies, affibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and epitope-binding fragments of any of the above.

[0730] An antibody can be any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, the antibodies described herein are IgG antibodies (e.g., human IgG), or classes (e.g., human IgG1, IgG2, IgG3, or IgG4) or subclasses thereof.

[0731] In certain embodiments, the antibody is a four-chain antibody unit comprising two heavy (H) / 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 certain embodiments, the H and L chains comprise constant regions, e.g., human constant regions. In even more specific embodiments, the L chain constant region of such an antibody is a kappa or lambda light chain constant region, e.g., a human kappa or lambda light chain constant region. In another specific embodiment, the H chain constant region of such an antibody comprises a gamma heavy chain constant region, e.g., a human gamma heavy chain constant region. In certain embodiments, such an antibody comprises an IgG constant region, e.g., a human IgG constant region.

[0732] The term "constant region" or "constant domain" is a well-known antibody terminology (sometimes referred to as "Fc") that refers to portions of antibodies, e.g., the carboxyl-terminal portions of the light and / or heavy chains, that are not directly involved in binding the antibody to an antigen, but which may exert various effector functions, such as interacting with Fc receptors. These terms refer to portions of immunoglobulin molecules that generally have more conserved amino acid sequences than immunoglobulin variable domains.

[0733] The term "heavy chain" as used in reference to an antibody can refer to any of the different types, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), mu (μ), etc., based on the amino acid sequence of the constant domain, which give rise to antibodies of the IgA, IgD, IgE, IgG, and IgM classes, respectively, and also include subclasses of IgG, such as IgG1, IgG2, IgG3, and IgG4.

[0734] The term "light chain" as used in reference to an antibody can refer to any of different types, e.g., lambda (λ) or kappa (κ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. In certain embodiments, the light chain is a human light chain.

[0735] The term "monoclonal antibody" is a well-known term of art that refers to an antibody obtained from a homogeneous or substantially homogeneous population of antibodies. The term "monoclonal" is not limited to a particular method for making the antibody. Generally, a population of monoclonal antibodies can be produced by a cell, a cell population, or a cell line. In certain embodiments, a "monoclonal antibody" as used herein is an antibody produced by a single cell (e.g., a hybridoma or host cell producing a recombinant antibody), and the antibody specifically binds to an epitope as determined, for example, by ELISA or other antigen-binding or competitive binding assays known in the art or shown in the Examples described herein. In certain embodiments, a monoclonal antibody may be a chimeric or humanized antibody. In certain embodiments, a monoclonal antibody is a monovalent antibody or a multivalent (e.g., bivalent) antibody. In certain embodiments, a monoclonal antibody is a monospecific antibody or a multispecific antibody (e.g., a bispecific antibody).

[0736] The term "variable region" or "variable domain" refers to a portion of an antibody, generally a light or heavy chain, typically about the amino-terminal 110-120 amino acids of a mature heavy chain and about 90-100 amino acids of a mature light chain. The variable region contains complementarity-determining regions (CDRs) flanked by framework regions (FRs). Generally, the spatial orientation of the CDRs and FRs from N- to C-terminus is as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Without being bound by any particular mechanism or theory, Although not preferred, it is believed that the CDRs of the light and heavy chains are primarily responsible for antibody-antigen interactions and the specificity of the antibody for its epitope. In certain embodiments, the numbering of the amino acid positions of the antibodies described herein is according to the EU Index as set forth in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242. In certain embodiments, the variable regions are human variable regions.

[0737] In certain embodiments, the CDRs of the antibody are numbered 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, USDapartment of Health and Human Services, NIH Publication No. 91-3242); or (ii) the Chothia numbering scheme (hereinafter referred to as "Chothia CDRs") (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., 1992, J. Mol. Biol., 227:799-817). 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 Duebel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001)); or (iii) the ImMunoGeneTics (IMGT) numbering system, as described, for example, in Lefranc, 1999, The Immunologist, 7:132-136 and Lefranc et al., 1999, Nucleic Acids Res., 27:209-212 (“IMGT CDRs”); or (iv) the ImMunoGeneTics (IMGT) numbering system, as described, for example, in MacCallum et al. al., 1996, J. Mol. Biol., 262:732-745 (referred to herein as "AbM CDRs").See also, for example, Martin, A., "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001); or (v) according to the Contact numbering system, referred to herein as "Contact CDRs" (the Contact definition is based on analysis of available complex crystal structures (bioinf.org.uk / abs) (see, for example, MacCallum et al., 1996, J. Mol. Biol., 262:732-745)).

[0738] As used herein, the terms "full-length antibody," "complete antibody," and "whole antibody" are used interchangeably to refer to an antibody in substantially its entire form, and not an antibody fragment as defined below. These terms specifically refer to antibodies having heavy chains that contain an Fc region.

[0739] An "antibody fragment" includes only a portion of an intact antibody, which portion retains at least one, two, three, and as many or all of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment contains the antigen-binding site of an intact antibody and thus retains the ability to bind to an antigen. In another embodiment, an antibody fragment, e.g., an antibody fragment comprising an 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, modulation of antibody half-life, conjugation function, and complement fixation. In another embodiment, an antibody fragment is a monovalent antibody with an in vivo half-life substantially similar to that of an intact antibody. For example, such an antibody fragment may contain an antigen-binding arm linked to an Fc sequence, which may confer in vivo stability to the fragment. Antibody fragments suitable for use in the compounds of the present disclosure include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0740] "Polynucleotide" or "nucleic acid," used interchangeably herein, refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or their analogs. Polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. Non-limiting examples of polynucleotides include genes, gene fragments, 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. Nucleic acid molecules can be linear or circular. 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. Polynucleotides can contain modified nucleotides, such as methylated nucleotides and their analogs. The nucleic acid molecule can be an aptamer.

[0741] The term "purification" refers to the separation of a substance (e.g., a compound, polynucleotide, protein, polypeptide, polypeptide composition) such that the substance of interest constitutes a majority of the sample. Typically, a substantially purified component of a sample comprises at least 50%, 80%-85%, 90-99%, such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, etc. of the sample. Techniques for purifying polynucleotides, polypeptides, and viral particles of interest are well known in the art and include, for example, ion exchange chromatography, affinity chromatography, and sedimentation by density.

[0742] The terms "treatment," "treating," and the like refer to achieving a desired pharmacological and / or physiological effect, such as a reduction in tumor burden. This effect can be preventative, meaning that a disease or its symptoms are completely or partially prevented, and / or therapeutic, meaning that a disease and / or harmful effects resulting from the disease are partially or completely cured. As used herein, "treatment" encompasses any treatment of a mammalian, particularly a human, disease, including (a) preventing the onset of a disease or disease symptoms in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease (e.g., diseases that may be associated with or caused by a primary disease, such as liver fibrosis, which may occur in the setting of chronic HCV infection); (b) inhibiting the disease, i.e., halting the progression of the disease; and (c) relieving the disease, i.e., causing regression of the disease (e.g., a reduction in tumor burden).

[0743] As used herein, the terms "individual," "host," "subject," and "patient" are used interchangeably and refer to animals, including, but not limited to, humans and non-human primates (including monkeys and humans), rodents (including rats and mice), cattle, horses, sheep, cats, dogs, etc. "Mammal" means a member or members of any mammalian species, including, by way of example, canines, felines, equines, bovines, ovines, rodents, etc., as well as primates (such as non-human primates) and humans. Non-human animal models, such as mammals, e.g., non-human primates, murines, lagomorphs, etc., can be used in experimental investigations.

[0744] A "therapeutically effective amount" or "effective 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 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 patient being treated.

[0745] Unless otherwise specified, when a compound may exist in 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 herein to include both optical isomers. For example, when a compound is described as having one of two tautomeric forms, it is intended herein to include both tautomers. Thus, the compounds provided herein may be enantiomerically pure or may be mixtures of stereoisomers or diastereomers. The compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or may be mixtures thereof. The chiral centers of the compounds described herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administering the compound in the (R) form is equivalent to administering the compound in the (S) form.

[0746] The present disclosure also encompasses all suitable isotopic variants of the compounds of the present disclosure, whether they are radioactive or not.Isotopic variants of the compounds of the present disclosure are understood to mean compounds in which at least one atom in the compounds of the present disclosure is replaced with another atom that has the same atomic number but has an atomic mass that is different from the atomic mass that is usually or mainly found in nature.Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, for example: 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131I. Certain isotopic variants of the compounds according to the present disclosure, particularly those incorporating one or more radioisotopes, may be useful, for example, in studying the mechanism of action or distribution of the active compound in the body. For this purpose, 3 H, 14 C, and / or 18 Compounds labeled with the F isotope are suitable. Furthermore, the incorporation of an isotope (e.g., deuterium) may increase the metabolic stability of the compound, resulting in certain therapeutic benefits, such as an increased half-life in the body or a reduced effective dose. In some embodiments, hydrogen atoms in the compounds described herein may be replaced with deuterium atoms. In certain embodiments, "deuterated," as applied to a chemical group, refers to a chemical group that is isotopically enriched with deuterium in amounts significantly greater than its natural abundance, unless otherwise specified. Isotopic variants of compounds according to the present disclosure can be prepared by a variety of methods, including, for example, those described below and in the Examples, using specific reagents and / or corresponding isotopic modifications of the starting compound.

[0747] Therefore, any embodiment described herein is meant to include salts, single stereoisomers, mixtures of stereoisomers, and / or isotopic forms of the compounds.

[0748] "Pharmaceutically acceptable excipient," "pharmaceutically acceptable diluent," "pharmaceutically acceptable carrier," and "pharmaceutically acceptable adjuvant" refer to excipients, diluents, carriers, and adjuvants that are generally safe, non-toxic, and not biologically or otherwise undesirable and include excipients, diluents, carriers, and adjuvants that are acceptable for veterinary and human pharmaceutical use...

Claims

1. Formula (I) 【Chemistry 473】 or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 500; m is 1 to 20; Y is the target moiety, L is a linker, X is a group represented by formula (II) 【Chemistry 474】 an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R １ Is, -Z １ -*, -H, -OH, optionally substituted (C １ ~C ６ ) alkyl, —OCH ３ , -OCH ２ CH═CH, optionally substituted —S—(C １ ~C ６ ) selected from alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, and optionally substituted —S-heteroaryl; R ２ Is, -Z １ -*, -NHCOCH ３ , -NHCOCF ３ , -NHCOCH ２ CF ３ , —OH, —NHR, and optionally substituted triazole; R ６ Is, -Z １ -*, -OH, -OR, optionally substituted (C １ ~C ６ ) alkyl, —OC(O)R, —C(O)NHR, —NR ｘｘ R ｙｙ , optionally substituted aryl, optionally substituted heteroaryl, —NHCOR, and —NRCOR; Each R is independently an optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ｘｘ and R ｙｙ are independently H, optionally substituted (C １ ~C ６ ) alkyl, or R ｘｘ and R ｙｙ can cyclize to form an optionally substituted heterocyclyl; In the formula, R １ , R ２ , and R ６ One of them is -Z １ -*, and "*" is Z １ and the linker (L), R ３ and R ４ are each independently H, or a pro-moiety, or R ３ and R ４ are linked in a ring to form a pro-moiety, R １１ is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z １ Is, -Z １１ -, -Z １１ -A １ -, -A ２ -, -NR ２１ CO-, -CONR ２１ -, -NR ２１ SO ２ -, -SO ２ NR ２１ -, -NR ２１ C(=O)NR ２１ - and -NR ２１ C(=S)NR ２１ - is a linking moiety selected from -Z １１ - is -O-, -S-, -N(R ２１ ) - or -C(R ２２ ) ２ and -A １ - and - A ２ - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R ２１ is H, optionally substituted (C １ ~C ６ ) independently selected from alkyl, —COR, and optionally substituted heteroaryl; Each R ２２ is H, halogen, and optionally substituted (C １ ~C ６ ) alkyl; A compound of formula (I), or a prodrug thereof, or a salt thereof, with the proviso that at least one of the following occurs: A) Z １ Is, -Z １１ -A １ - and - A ２ -A is a linking moiety selected from １ - and - A ２ - is an optionally substituted heterocyclylene, or -A ２ - is optionally substituted isoxazolyl; B) -L-Y is 【Chemistry 475】 Including, In the formula, R Ｙ teeth, 【Chemistry 476】 That is, C) R ６ is -OR, optionally substituted (C １ ~C ６ ) alkyl, —OC(O)-optionally substituted heteroaryl, —C(O)NH-optionally substituted heteroaryl, —NR ｘｘ R ｙｙ , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, or -NRCOR, where heteroaryl is other than triazole, and where each R is independently optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ｘｘ and R ｙｙ are independently H, optionally substituted (C １ ~C ６ ) alkyl, or R ｘｘ and R ｙｙ can cyclize to form an optionally substituted heterocyclyl; D) R １ is an optionally substituted C ２～６ alkyl, optionally substituted —S—(C １ ~C ６ ) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, or optionally substituted —S-heteroaryl; or E) at least one R ２１ is —COR or an optionally substituted heteroaryl.

2. X is a group represented by formula (a-II) 【Chemistry 477】 2. The compound of claim 1, wherein

3. Z １ Is, -Z １１ -A １ - and - A ２ A is a linking moiety selected from １ - and - A ２ The compound of claim 1 or 2, wherein - is an optionally substituted heterocyclylene.

4. Z １ teeth, 【Chemistry 478】 10. A compound according to any one of the preceding claims, wherein

5. -L-Y is 【Chemistry 479】 Including, In the formula, R Ｙ teeth, 【Chemical 480】 10. A compound according to any one of the preceding claims, wherein

6. R ６ is -OR, optionally substituted (C １ ~C ６ ) alkyl, —OC(O)-optionally substituted heteroaryl, —C(O)NH-optionally substituted heteroaryl, —NR ｘｘ R ｙｙ , optionally substituted aryl, or optionally substituted heteroaryl, provided that heteroaryl is other than triazole, wherein R is an optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ｘｘ and R ｙｙ are independently H, optionally substituted (C １ ~C ６ ) alkyl, or R ｘｘ and R ｙｙ is capable of cyclization to form an optionally substituted heterocyclyl.

7. R ６ is -O-(C １ ~C ６ 2. A compound according to any one of the preceding claims, wherein -O- is alkyl, optionally substituted heterocyclyl, or -O-aryl.

8. R １ is an optionally substituted C ２～６ alkyl, optionally substituted —S—(C １ ~C ６ 2. A compound according to any one of the preceding claims, wherein -S- is alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, or optionally substituted -S-heteroaryl.

9. R １ is an optionally substituted C ２～６ 10. A compound according to any one of the preceding claims, which is alkyl.

10. At least one R ２１ 10. A compound according to any one of the preceding claims, wherein is -COR or optionally substituted heteroaryl.

11. 10. The compound of any one of the preceding claims, wherein Y is an antibody or an antibody fragment.

12. Formula (I) 【Chemistry 481】 or a prodrug thereof, or a salt thereof, During the ceremony, n is 1 to 500; m is 1 to 20; L is a linker, X is a group represented by formula (II) 【Chemistry 482】 an asialoglycoprotein receptor (ASGPR) binding portion of the formula: R １ Is, -Z １ -*, -H, -OH, optionally substituted (C １ ~C ６ ) alkyl, —OCH ３ , -OCH ２ CH═CH, optionally substituted —S—(C １ ~C ６ ) selected from alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, and optionally substituted —S-heteroaryl; R ２ Is, -Z １ -*, -NHCOCH ３ , -NHCOCF ３ , -NHCOCH ２ CF ３ , —OH, and optionally substituted triazole; R ６ is -Z1-*, -OH, -OR, optionally substituted (C １ ~C ６ ) alkyl, —OC(O)R, —C(O)NHR, —NR ｘｘ R ｙｙ , optionally substituted aryl, and optionally substituted heteroaryl; R is an optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ｘｘ and R ｙｙ are independently H, optionally substituted (C １ ~C ６ ) alkyl, or R ｘｘ and R ｙｙ can cyclize to form an optionally substituted heterocyclyl; In the formula, R １ , R ２ , and R ６ One of them is -Z １ -*, and "*" is Z １ and the linker (L), R ３ and R ４ are each independently H, or a pro-moiety, or R ３ and R ４ are linked in a ring to form a pro-moiety, R １１ is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z １ Is, -Z １１ -, -Z １１ -A １ -, -A ２ -, -NR ２１ CO-, -CONR ２１ -, -NR ２１ SO ２ -, -SO ２ NR ２１ -, -NR ２１ C(=O)NR ２１ - and -NR ２１ C(=S)NR ２１ - is a linking moiety selected from -Z １１ - is -O-, -S-, -N(R ２１ ) - or -C(R ２２ ) ２ and -A １ - and - A ２ - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R ２１ is H, optionally substituted (C １ ~C ６ ) independently selected from alkyl, —COR, and optionally substituted heteroaryl; Each R ２２ is H, halogen, and optionally substituted (C １ ~C ６ ) alkyl; R ３ and R ４ are each independently H, or a pro-moiety, or R ３ and R ４ are linked in a ring to form a pro-moiety, R １１ is H or a bridging moiety connecting the 5-carbon to the 1-carbon of the ring, Z １ is -Z １１ -, -Z １１ -A １ -, -A ２ -, -NR ２１ CO-, -CONR ２１ -, -NR ２１ SO ２ -, -SO ２ NR ２１ -, -NR ２１ C(=O)NR ２１ - and -NR ２１ C(=S)NR ２１ - is a linking moiety selected from -Z １１ - is -O-, -S-, -N(R ２１ ) - or -C(R ２２ ) ２ and -A １ - and - A ２ - is an optionally substituted heterocyclylene, an optionally substituted arylene, or an optionally substituted heteroarylene; Each R ２１ is H, optionally substituted (C １ ~C ６ ) independently selected from alkyl, —COR, and optionally substituted heteroaryl; Each R ２２ is H, halogen, and optionally substituted (C １ ~C ６ ) alkyl; Y is a chemoselective ligation group, and at least one of the following occurs in a compound of formula (I), or a prodrug thereof, or a salt thereof: A) Z １ Is, -Z １１ -A １ - and - A ２ -A is a linking moiety selected from １ - and - A ２ - is an optionally substituted heterocyclylene, or -A ２ - is optionally substituted isoxazolyl; B) -L-Y is 【Chemistry 483】 Includes; C) R ６ is -OR, optionally substituted (C １ ~C ６ ) alkyl, —OC(O)-optionally substituted heteroaryl, —C(O)NH-optionally substituted heteroaryl, —NR ｘｘ R ｙｙ , optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, or -NRCOR, where heteroaryl is other than triazole, and where each R is independently optionally substituted (C １ ~C ６ ) alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R ｘｘ and R ｙｙ are independently H, optionally substituted (C １ ~C ６ ) alkyl, or R ｘｘ and R ｙｙ can cyclize to form an optionally substituted heterocyclyl; D) R １ is an optionally substituted C ２～６ alkyl, optionally substituted —S—(C １ ~C ６ ) alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —S-aryl, or optionally substituted —S-heteroaryl; or E) at least one R ２１ is —COR or an optionally substituted heteroaryl.

13. The compound of formula (II) has the formula (a-II) 【Chem.484】 The compound according to claim 12, represented by:

14. R １ Is, -Z １ -*, -H, or (C １ ~C ６ 14. The compound according to any one of claims 1 to 13, wherein:

15. R ２ Is, -Z １ -* or -NHCOCH ３ The compound according to any one of claims 1 to 13,

16. R ３ and R ４ 4. A compound according to any one of the preceding claims, wherein each is -H.

17. R ６ is -OH, -OC(O)R, -NR ｘｘ R ｙｙ or aryl, and R is (C １ ~C ６ ) alkyl, and R ｘｘ and R ｙｙ cyclizes to form an optionally substituted heterocyclyl.

18. -Z １ - * is -S-, -CH ２ -, 【Chemistry 485】 and "*" is Z １ and a linker (L).

19. R １ Is, -Z １ The compound according to claim 18, wherein -*.

20. R ２ Is, -Z １ The compound according to claim 18, wherein -*.

21. 10. A compound according to any one of the preceding claims, wherein L comprises 10 to 60 consecutive chain atoms.

22. L is a group represented by the formula (IIb'): 【Chemical 486】 wherein: n is 1, 2, or 3; L １ ~L ６ are each independently a linking moiety, and together they form Z １ and forming a linear or branched linker between Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** is Z １ X's L via １ represents the attachment point to 3. A compound according to any one of the preceding claims, wherein *** represents the point of attachment to Y.

23. L １ ~L ５ Each of the groups independently represents -C １～２０ -Alkylene-, -NHC(O)-C １～６ -Alkylene-, -C(O)NH-C １～６ -Alkylene-, -NH-C １～６ -Alkylene-, -NHC(O)NH-C １～６ -Alkylene-, -NHC(S)NH-C １～６ -Alkylene-, -C １～６ -Alkylene-NHC(O)-, -C １～６ -Alkylene-C(O)NH-, -C １～６ -Alkylene-NH-, -C １～６ -Alkylene-NHC(O)NH-, -C １～６ -Alkylene-NHC(S)NH-, -O(CH ２ ) ｐ -, -(OCH ２ CH ２ ) ｐ -, -NHC(O)-, -C(O)NH-, -NHS(O) ２ -, -S(O) ２ NH-, -C(O)-, -S(O) ２ and one or more linking moieties independently selected from -, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic cycloalkyl, an amino acid residue, -NH-, and -NMe-, wherein L １ ~L ５ are each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L ６ is -C １～２０ -Alkylene-, -NR １６ C(O)-C １～６ -Alkylene-, -C(O)NR １６ -C １～６ -Alkylene-, -NR １６ -C １～６ -Alkylene-, -NR １６ C(O)NR １６ -C １～６ -Alkylene-, -NR １６ C(S)NR １６ -C １～６ -Alkylene-, -C １～６ -Alkylene-NR １６ C(O)-, -C １～６ -Alkylene-C(O)NR １６ -, -C １～６ -Alkylene-NR １６ -, -C １～６ -Alkylene-NR １６ C(O)NR １６ -, -C １～６ -Alkylene-NR １６ C(S)NR １６ -, -O(CH ２ ) ｐ -, -(OCH ２ CH ２ ) ｐ -, -NR １６ C(O)-, -C(O)NR １６ -, -NHS(O) ２ -, -S(O) ２ NH-, -C(O)-, -S(O) ２ -, -O-, -S-, a monocyclic heteroaryl, a monocyclic aryl, a monocyclic heterocycle, an amino acid residue, or -NR １６ is a linking group comprising one or more linking moieties independently selected from: Each R １６ are independently -H, (C １ ~C ６ 23. The compound of claim 22, wherein: R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,

24. L １ ~L ５ Each of the groups independently represents -C １～２０ -Alkylene-, -NHC(O)-C １～６ -Alkylene-, -C(O)NH-C １～６ -Alkylene-, -NH-C １～６ -Alkylene-, -NHC(O)NH-C １～６ -Alkylene-, -NHC(S)NH-C １～６ -Alkylene-, -C １～６ -Alkylene-NHC(O)-, -C １～６ -Alkylene-C(O)NH-, -C １～６ -Alkylene-NH-, -C １～６ -Alkylene-NHC(O)NH-, -C １～６ -Alkylene-NHC(S)NH-, -O(CH ２ ) ｐ -, -(OCH ２ CH ２ ) ｐ -, -NHC(O)-, -C(O)NH-, -NHS(O) ２ -, -S(O) ２ NH-, -C(O)-, -S(O) ２ -, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic cycloalkyl, an amino acid residue, -NH-, and -NMe-, wherein L １ ~L ５ each independently optionally substituted with 1 to 5 halo; each p is independently 1 to 50; L ６ teeth, 【Chemistry 487】 and In the formula, R ｚ teeth, 【Chemical 488】 23. The compound of claim 22, wherein:

25. The compound according to any one of claims 22 to 24, wherein n is 1.

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

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

28. At least one L １ is —C optionally substituted with 1 to 5 halo １～２０ The compound according to any one of claims 22 to 27, wherein -alkylene-.

29. L １ is -CF ２ CH ２ The compound according to any one of claims 22 to 28, wherein

30. At least one L ２ is -(OCH ２ CH ２ ) ｐ The compound according to any one of claims 22 to 29, wherein

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

32. At least one L ３ is NHCONH-C １～６ The compound according to any one of claims 22 to 31, wherein -alkylene-.

33. At least one L ４ is -C １～６ The compound according to any one of claims 22 to 32, wherein the alkylene is -alkylene-NHCONH-.

34. At least one L ５ is -(OCH ２ CH ２ ) ｐ The compound according to any one of claims 22 to 33, wherein

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 and one or more pharmaceutically acceptable excipients.

36. 1. A method for internalizing a target molecule in a cell comprising a cell surface asialoglycoprotein receptor (ASGPR), the method comprising: A method comprising contacting a cell sample containing the cells 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 to the target protein and specifically binds to the ASGPR to promote uptake of the target protein into the cells.

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

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

39. A method for reducing the level 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 to the target protein and specifically binds to an ASGPR of a cell in the biological system to promote the uptake into cells and degradation of the target protein.

40. 40. The method of claim 39, wherein the biological system is a human subject.

41. 40. The method of claim 39, wherein the biological system is an in vitro cell 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.

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