M6PR cell surface receptor binding compounds and conjugates

Abstract

The present disclosure provides certain compounds that include a ligand moiety that specifically binds to the cell surface mannose-6-phosphate receptor (M6PR). The M6PR-binding compounds can trigger the receptor to internalize the bound compound into the cell. The ligand moiety of the present disclosure can be linked to various moieties of interest without affecting the specific binding to M6PR and the function of M6PR. Compounds are also provided that are conjugates of the ligand moiety linked to a biomolecule, such as an antibody, that can utilize a cellular pathway to remove a specific target protein from the cell surface or the extracellular environment. For example, the conjugates described herein can sequester a target molecule of interest in the lysosomes of a cell and / or degrade the molecule in the lysosomes of a cell. Methods of using the conjugates to sequester and / or target a protein for lysosomal degradation are also provided.

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Application No. 63 / 221,915, filed July 14, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] 2. Introduction Many therapeutic agents act by binding to functionally important sites in target proteins, thereby modulating the activity of those proteins, or by recruiting immune effectors, such as many monoclonal antibody drugs, to act on target proteins. However, there exists an untapped treasure trove of medically important human proteins that are considered "undruggable" because these proteins are not readily amenable to currently available therapeutic targeting approaches. Therefore, there is a need for therapeutic agents that can target a wider range of proteins.

[0003] Mannose-6-phosphate is a monosaccharide ligand that plays an important role in the intracellular retention and secretion of lysosomal hydrolases to which it is bound. Incorporation of this sugar residue into newly synthesized enzymes transports the enzymes from the Golgi apparatus to lysosomes, where they become activated. The cell membrane-bound cell surface mannose-6-phosphate receptor (M6PR) plays a role in many biological processes, including the secretion and internalization of such lysosomal enzymes. Endocytosis via the M6PR allows compounds bearing the mannose-6-phosphate (M6P) ligand to be internalized into the cell and transported to lysosomes.

[0004] Alternative ligands that bind to cell surface M6PR and subsequently cause transport across the cell membrane are of great interest. Summary of the Invention

[0005] 3. Summary of the Invention The present disclosure provides certain compounds comprising a ligand moiety that specifically binds to the cell surface mannose-6-phosphate receptor (M6PR). Compounds that bind to the cell surface M6PR can trigger the receptor to internalize the bound compound into 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 M6PR and its function. Also provided are compounds that are conjugates of the ligand moiety linked 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 the extracellular environment. For example, the conjugates described herein may sequester and / or degrade a target molecule of interest in the lysosomes of a cell. Also provided herein are compositions comprising such conjugates, as well as methods of using the conjugates to sequester and / or target a polypeptide of interest for lysosomal degradation, and methods of using the conjugates to treat a disorder or disease.

[0006] 4. Brief description of the drawings These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and accompanying drawings, in which: [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows an exemplary native mass spectrometry (MS) analysis of a representative conjugate, matuzumab-(compound A) conjugate, versus deglycosylated matuzumab.

[0008] [Figure 2] FIG. 1 shows an exemplary native mass spectrometry (MS) analysis of a representative conjugate, matuzumab-(compound 520(I-7)) conjugate, versus deglycosylated matuzumab.

[0009] [Figure 3]FIG. 1 shows the time course of activity of cetuximab-(Compound A) and cetuximab-(Compound 520 (I-7)) conjugates on surface EGFR levels in parental Hela cells and M6PR knockout (KO) cells as measured by surface staining.

[0010] [Figure 4] FIG. 1 shows the time course of activity of matuzumab-(compound A) and matuzumab-(compound 520 (I-7)) conjugates on surface EGFR levels in parental Hela cells and M6PR KO cells as measured by surface staining.

[0011] [Figure 5] FIG. 1 shows in-cell Western blotting images showing the dose response of cetuximab-(compound A), cetuximab-(compound 520(I-7)), matuzumab-(compound A), and matuzumab-(compound 520(I-7)) conjugates on total EGFR levels in Hela parental cells and M6PR KO cells.

[0012] [Figure 6] FIG. 1 shows the time course of activity of cetuximab-(Compound A), cetuximab-(Compound 520(I-7)), matuzumab-(Compound A), and matuzumab-(Compound 520(I-7)) conjugates on relative normalized EGFR levels in parental Hela cells and M6PR KO cells.

[0013] [Figure 7]Figure 1 shows M6PR binding affinity curves for various exemplary conjugates of fluorescently labeled matuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]). A shows the affinity for M6PR of unlabeled control (A), compound 520 (I-7), compound 602 (I-8), compound 603 (I-9), compound 605 (I-11), and compound 716 (I-12). Binding to M6PR was measured by ELISA. The conjugates of compound 520 (I-7) (m, i.e., DAR=8) and compound 605 (I-11) (m, i.e., DAR=4) showed the highest and lowest binding affinity, respectively. d4 is DAR4, and d8 is DAR8. RFU is relative fluorescence unit.

[0014] [Figure 8A]

[0023] Figure 1 shows serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibody in mice. Intracellular levels of conjugates of compound 520 (I-7) (d8 DAR=8) and (d4 DAR=4) in mouse serum were measured using ELISA at 0.5, 1, 2, 6, and 24 hours after administration. UNLB is the antibody control. [Figure 8B]

[0023] Figure 1 shows serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibody in mice. Intracellular levels of conjugates of compound 604 (I-10) and compound 605 (I-11) in mouse serum were measured using ELISA at 0.5, 1, 2, 6, and 24 hours after administration. UNLB is the antibody control. [Figure 8C]

[0023] Figure 1 shows serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibody in mice. Intracellular levels of conjugates of compound 603 (I-9) and compound 716 (I-12) in mouse serum were measured using ELISA at 0.5, 1, 2, 6, and 24 hours after administration. UNLB is the antibody control.

[0015] [Figure 9]Figure 1 shows the cellular uptake of an exemplary anti-IgG2a conjugate and bound target protein over time in Jurkat cells. The conjugate was detected by a fluorescent Alexa488-conjugated target IgG2a antibody, and intracellular fluorescence levels (MFI) were measured using FACS after 1 and 24 hours.

[0016] [Figure 10] FIG. 1 shows the relative cellular uptake of 10 nM exemplary anti-IgG2a conjugates and bound target protein (Alexa488-conjugated target IgG2a antibody) as a percentage of the uptake of the reference compound 520 (I-7) (d8 is DAR=8) conjugate after 24 hours in Jurkat cells.

[0017] [Figure 11] 1 is a graph of the results of an M6PR binding assay for various antibody conjugates of exemplary compounds with various DAR loading numbers.

[0018] [Figure 12] FIG. 1 is a graph of cellular fluorescence (MFI) versus antibody conjugate concentration ([Ab]) showing that exemplary M6PR-binding antibody conjugates exhibited strong uptake of target protein into Jurkat cells after 1 hour of incubation.

[0019] [Figure 13] FIG. 1 is a graph of cellular fluorescence (MFI) versus antibody conjugate concentration ([Ab]) showing that various antibody conjugates of exemplary M6PR or ASGPR binding compounds showed comparable potent uptake into HepG2 cells after 1 hour of incubation.

[0020] [Figure 14]FIG. 1 is a graph showing CI-M6PR-dependent cellular uptake of an exemplary antibody conjugate bound to an Alexa488-labeled IgE target in wild-type (WT) K562 cells versus CI-M6PR knockout (KO) cells.

[0021] [Figure 15] 1 is a graph of the cellular uptake in Jurkat cells of various conjugates of omalizumab (anti-IgE) with exemplary M6PR-binding compounds, the conjugates binding to Alexa488-labeled target IgE.

[0022] [Figure 16] FIG. 16 is a graph showing a comparison of the cellular uptake activity of certain exemplary conjugates from the graph in FIG. 15.

[0023] [Figure 17] FIG. 16 is a graph showing a comparison of the cellular uptake activity of certain exemplary conjugates from the graph in FIG. 15.

[0024] [Figure 18] 1 is a graph of the cellular uptake in Jurkat cells of various conjugates of omalizumab (anti-IgE) with exemplary M6PR ligand-linkers, which conjugates are bound to Alexa488-labeled target IgE.

[0025] [Figure 19] 19 is a graph showing a comparison of the cellular uptake activity of certain exemplary conjugates from the graph in FIG. 18.

[0026] [Figure 20] 19 is a graph showing a comparison of the cellular uptake activity of certain exemplary conjugates from the graph in FIG. 18.

[0027] [Figure 21] 19 is a graph showing a comparison of the cellular uptake activity of certain exemplary conjugates from the graph in FIG. 18.

[0028] [Figure 22] 1 is a graph of M6PR binding affinity data for various exemplary cetuximab (anti-EGFR) conjugates of the present disclosure.

[0029] [Figure 23] 1 is a graph showing the cellular uptake activity of certain exemplary target-binding conjugates of the present disclosure.

[0030] [Figure 24] 1 is a synthetic scheme for an M6PR binding moiety suitable for attachment to a linker and / or moiety of interest.

[0031] [Figure 25] 1 is a synthetic scheme for an M6PR binding moiety suitable for attachment to a linker and / or moiety of interest. DETAILED DESCRIPTION OF THE INVENTION

[0032] 5. MODE FOR CARRYING OUT THE INVENTION As summarized above, the present disclosure provides certain compounds comprising a specific ligand moiety, X, that specifically binds to the cell-surface mannose-6-phosphate receptor (M6PR), also referred to as an M6PR-binding moiety or M6PR-ligand moiety. The M6PR-binding moieties of the present disclosure can be linked to various moieties of interest without affecting their specific binding to and function of the cell-surface M6PR. The inventors have demonstrated that the compounds of the present disclosure can exploit the function of cell-surface M6PR in biological systems, for example, for internalization and / or sequestration of target molecules into lysosomes of cells, and in some cases, subsequent lysosomal degradation. The compounds of the present disclosure find use in a variety of applications. In some embodiments, the M6PR-binding moiety X delivers a moiety of interest into cells. In some embodiments, the compounds are bifunctional compounds comprising an M6PR-binding moiety X linked to a target-binding moiety for internalization and / or lysosomal degradation of the bound target molecule.

[0033] Thus, the present disclosure provides compounds of formula (XI) comprising one or more M6PR binding moieties linked to a moiety of interest, Y: [ka] (In the formula, X is an M6PR binding moiety (e.g., as described herein); n is 1 to 500 (e.g., X is linked via a monovalent or polyvalent linker as described herein); m is 1 to 500 (e.g., 1 to 100, or 1 to 10), L is a linker, Y is a moiety of interest (e.g., as described herein) or a salt thereof.

[0034] The compounds and conjugates, and methods of the present disclosure are described in further detail below. Certain M6PR-binding compounds are described. In some embodiments, the compounds are biomolecular conjugates comprising one or more linked M6PR-binding moieties. Linkers (L) and moieties of interest (Y) used in the M6PR-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.

[0035] 5.1.M6PR joint part As summarized above, the M6PR-binding moieties (also referred to as M6PR ligand moieties) of the present disclosure can be linked to various moieties of interest without affecting their specific binding to and function on the cell surface M6PR. The present inventors have demonstrated that when M6PR-binding moieties having the specific structures described below bind to cell surface M6PR with high affinity and are configured via a linker based on the bifunctional compounds of the present disclosure, it is possible to exploit the function of cell surface M6PR in biological systems, for example, for internalization and / or degradation of target molecules.

[0036] The terms "mannose-6-phosphate receptor" and "M6PR" refer to receptors of the mannose-6-phosphate receptor family. M6PR is a transmembrane glycoprotein receptor that targets enzymes to lysosomes in cells. MP6R endogenously transports proteins bearing N-glycans capped with mannose-6-phosphate (M6P) residues to lysosomes and cycles between endosomes, the cell surface, and the Golgi complex. See, e.g., Ghosh et al., Nat. Rev. Mol. Cell Biol. 2003;4:202-213. The M6PR family includes the cation-independent mannose-6-phosphate receptor (CI-M6PR). CI-M6PR is also known as insulin-like growth factor 2 receptor (IGF2R), and in humans is encoded by the IGF2R gene (see, e.g., NCBI Reference Sequence: NM_000876.3 and NCBI Gene ID: 3482). The CI-M6PR binds to insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P)-tagged proteins. The compounds of the present disclosure can specifically bind to cell surface M6PR, e.g., the internalized CI-M6PR cell surface receptor. In certain embodiments, the surface CI-M6PR is human CI-M6PR. It should be understood that the terms M6PR and CI-M6PR are used interchangeably when referring to the binding properties of the M6PR-binding moieties and compounds of the present disclosure.

[0037] Compounds comprising such an M6PR binding moiety (X) (e.g., as described herein) may bind to other receptors, and may bind with lower affinity, e.g., as measured by immunoassays or other assays known in the art. In certain embodiments, X, or a compound described herein comprising such X, specifically binds to cell surface CI-M6PR with an affinity that is at least 2 logs, 2.5 logs, 3 logs, 4 logs, or more, greater than the affinity with which X or the compound binds to another cell surface receptor. In certain embodiments, X or a compound described herein comprising X specifically binds to cell surface CI-M6PR with an affinity (K) of 20 mM or less. d) specifically binds to CI-M6PR. In certain embodiments, such binding affinity (K 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. In this context, the terms "bind," "bind to," "specifically bind," or "specifically bind to" are used interchangeably.

[0038] The M6PR-binding compounds of the present disclosure include a moiety (X) (e.g., as described herein) that is a D-mannopyranose analog that specifically binds to the cell surface receptor M6PR. The M6PR-binding compounds can be monovalent or multivalent (e.g., bivalent or trivalent or higher), where a monovalent compound includes a single M6PR ligand moiety and a monovalent compound includes two or more such moieties.

[0039] 5.1.1.α-linked pyranose ring The M6PR binding portion of the compounds of the present disclosure has formula (II): [ka] (In the formula, W is a hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 2 are O, S, NR 21 , and C(R 22 )2, where each R 21 are 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. The pyranose ring may be linked together as represented by

[0040] In some embodiments of Formula (II), Z 2 is represented by the following formula (IIa): [ka] The linking moiety is attached to the pyranose sugar ring with the α configuration at the anomeric or 1-position, as shown in

[0041] 5.1.2. β-linked pyranose ring The present inventors have demonstrated that an M6PR-binding compound having an M6PR-binding moiety with the anomeric α-configuration of formula (IIa) can exhibit good receptor binding and internalization activity, but in some cases, constructing the central pyranose sugar ring of the M6PR-binding moiety in the β-configuration at the anomeric position can confer even stronger M6PR binding and internalization activity. In some embodiments, such an M6PR-binding moiety can increase the stability of the pyranose ring.

[0042] Thus, in some embodiments of formula (II), Z 2 is represented by the following formula (IIb): [ka] It is a linking moiety that is attached to a sugar ring that has a β configuration at the anomeric or 1-position, as shown in

[0043] 5.2.M6PR binding compounds Although the moiety of formula (II) can exhibit binding activity to M6PR, the inventors have discovered that certain types of cyclic groups are present in specific configurations adjacent to the pyranose ring of formula (II) and in the binding moiety Z 2 These results demonstrate that linking via the nucleotide sequence can result in an M6PR-binding moiety with the desired binding activity.

[0044] Thus, in some embodiments of Formula (II), the M6PR binding moiety (X) has the formula (III): [ka] (In the formula, W is a hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 2 are O, S, NR 21 , and C(R 22 )2, where each R 21 are 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; A is independently an optionally substituted cyclic group; each Z 3 are independently linked parts) or a prodrug thereof, or a salt thereof.

[0045] In some embodiments of Formulas (II)-(III), W is a non-hydrolyzable hydrophilic head group.

[0046] In some embodiments of Formulas (II)-(III), Z 2 is optionally substituted ethylene. In some embodiments of Formulas (II)-(III), Z 2 is optionally substituted ethenylene.

[0047] In some embodiments of Formulas (II)-(III), Z 2 is O. In some embodiments of Formulas (II)-(III), Z 2 is S. In some embodiments of Formulas (II)-(III), Z 2 Ha-NR 21 In some embodiments of Formulas (II)-(III), Z 2 -C(R 22 )2-, where each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl. In some embodiments of Formulas (II)-(III), Z 2is -CH2-.

[0048] In some embodiments of Formulas (II)-(III), A is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, or an optionally substituted cycloalkyl. In some embodiments of Formulas (II)-(III), A is independently an optionally substituted aryl or heteroaryl linking moiety (e.g., an optionally substituted monocyclic or bicyclic aryl or heteroaryl).

[0049] Exemplary Z groups of formulas (II) to (III) 3 Linking moieties are described herein.

[0050] Such M6PR-binding moieties of formula (III) can be bound to a moiety or molecule of interest to generate bifunctional compounds that effectively induce M6PR-mediated cellular internalization. The inventors have further demonstrated that when the moiety or molecule of interest is a target protein-binding moiety, the M6PR-binding compounds also induce M6PR-mediated internalization and / or degradation of the bound target protein.

[0051] Thus, in some embodiments of formula (XI), the M6PR binding compound has formula (XII): [ka] (In the formula, W is a hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 2 are O, S, NR 21 , and C(R 22 )2, where each R 21 are independently selected from H and optionally substituted (C-C) alkyl, and each R 22are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl; A is independently an optionally substituted cyclic group; each Z 3 are independently linking moieties, n is 1 to 500; L is a linker, Y is the part of the object, m is 1 to 100) or a prodrug thereof, or a salt thereof.

[0052] In some embodiments of formulas (XI)-(XII), m is 1 and the cell surface M6PR binding compound has formula (XIII): [ka] (In the formula, W is a hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 2 are O, S, NR 21 , and C(R 22 )2, where each R 21 are 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; A is independently an optionally substituted cyclic group; each Z 3 are independently linking moieties, n is 1 to 500; L is a linker, Y is a moiety of interest (e.g., as described herein) or a prodrug or salt thereof.

[0053] In some embodiments of Formula (XIII), Y is a chemoselective linking group. In some embodiments of Formula (XIII), n is 1. In some embodiments of Formula (XIII), Y is a chemoselective linking group linked to "n" M6PR binding moieties (Xn-) via a single linker -L-. In some embodiments of Formula (XIII), n is 2, 3, 4, or 5. In some embodiments of Formula (XIII), n is 5 to 10. In some embodiments of Formula (XIII), n is 10 to 100, e.g., 20 to 80, or 20 to 50. In some embodiments of Formula (XIII), when n is 5 or greater, L is a linker (e.g., as described herein) comprising a polypeptide.

[0054] In some embodiments of Formulas (XII)-(XIII), when n is 1 and A is phenyl, i) L comprises a backbone of at least 16 contiguous atoms (e.g., at least 18 contiguous atoms, or at least 20 contiguous atoms, and optionally up to about 200 contiguous atoms); ii) Y is a biomolecule; and / or ii) Z 3 is an amide, sulfonamide, urea, or thiourea linking moiety to the linker L.

[0055] In some embodiments of Formula (XII), Z 2 is a compound represented by formula (XIIa): [ka] is a linking moiety that is attached to a sugar ring having the alpha configuration at the anomeric or 1-position, as shown in formula (IIa), so as to give a compound of formula (IIa):

[0056] In some embodiments of Formula (XII), Z 2 is a compound represented by formula (XIIb): [ka] is a linking moiety that is attached to a sugar ring having a β-configuration at the anomeric or 1-position, as shown in formula (IIb), so as to give a compound of the formula:

[0057] In some embodiments of Formula (XI)-(XIIb), multiple M6PR binding moieties, for example of Formula (III), are linked via multiple linkers L to different linkage sites on a moiety of interest Y. In some embodiments, when Y is a biomolecule, the compounds of Formula (XI)-(XIIb) can be referred to as conjugates.

[0058] 5.2.1. Hydrophilic Head Group and Linking Moiety In some embodiments of Formulas (II)-(XIII), the M6PR binding moiety (X) comprises an analog of a D-mannopyranose ring having a hydrophilic head group, or a precursor or prodrug thereof, which is linked to a linking moiety (Z 1 ) attached to the 5-position of the sugar ring. The linking moiety may be 1 to 6 atoms in length, e.g., 1 to 5, 1 to 4, or 1 to 3 atoms in length, e.g., 1 or 2 atoms in length. It is understood that the length of the linking moiety may be selected in relation to the hydrophilic head group.

[0059] The hydrophilic head group (W) may be any suitable negatively charged group or salt thereof. In some embodiments, the hydrophilic head group is a neutral, polar hydrophilic group. Generally, the hydrophilic head group is capable of hydrogen bonding or electrostatic interactions with M6PR under aqueous or physiological conditions, similar to the interactions of the phosphate group of M6P. The hydrophilic head group may be a bioisostere (e.g., a structural or functional mimetic) of the 6-phosphate group of a naturally occurring mannose-6-phosphate ligand. In some embodiments, the hydrophilic head group is non-hydrolyzable, i.e., the Z of X to which the hydrophilic head group is attached is not hydrolyzable. 1 It is a functional group that is stable to its cleavage (eg, chemically or enzymatically) under physiological conditions from the linking moiety and / or pyranose ring.

[0060] The hydrophilic head group is generally a small group such as a heteroatom-containing functional group or a single heterocycle, optionally having a molecular weight of less than 200, such as less than 150, or less than 100.

[0061] In some embodiments, the hydrophilic head group is a phosphonic acid or a bioisostere thereof, such as a carboxylic acid or a malonic acid. In some embodiments, the hydrophilic head group is a thiophosphonic acid.

[0062] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group is not a phosphate, thiophosphate, or dithiophosphate, because such a group would result in a phosphate ester bond to the compound that is unstable under physiological conditions and prone to cleavage (e.g., by phosphatases in biological systems or chemically). For example, the 6-phosphate ester group of M6P exhibits undesirable stability compared to phosphonate analogs or other more stable head groups. The present disclosure provides alternative non-hydrolyzable head groups, in addition to phosphonates, that retain the binding and internalization activity of the resulting M6PR-binding compounds.

[0063] In any one of the embodiments of formulas (II)-(XIII), the hydrophilic head group W is selected from the group consisting of -OH, -CR 2 R 2 OH, -NR 3 P=O(OH)2, -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R 1 OH, -PH(=O)OH, -(CR 2 R 2 )-P=O(OH)2, -SO2OH (i.e., -SO3H), -S(O)OH, -OSO2OH, -COOH, -CN, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4, -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)CO2H, -NHSO2NHR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , -NHSO3H, [ka] or salts thereof; During the ceremony, R 1 and R 2 are independently hydrogen, SR 3 , halo, or CN, R 3 and R 4 are independently H, C 1~6 Alkyl or substituted C 1~6 alkyl (e.g., —CF or —CHCF), A, B, and C are each independently CH or N; Each D is independently O or S.

[0064] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is a phosphate or thiophosphate, e.g., -OP=O(OH), -SP=O(OH), -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH), -OP=O(N(R 3 )2)(OH), or -OP=O(R 3)(OH), or a salt thereof. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is non-hydrolyzable and therefore is not a phosphate or thiophosphate, e.g., -OP=O(OH), -SP=O(OH), -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH), -OP=O(N(R 3 )2)(OH), or -OP=O(R 3 )(OH), or a salt thereof.

[0065] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is charged, e.g., capable of salt formation under aqueous or physiological conditions. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is -NR 3 P=O(OH)2, -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R 1 OH, -PH(=O)OH, -(CR 2 R 2 )-P=O(OH)2, -COOH, -CH(COOH)2, -CR 1 R 2 COOH, and —NHC(O)COH.

[0066] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is a phosphonic acid or thiophosphonic acid (e.g., -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), or -P=S(SH)(OH), or a salt thereof). In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is a phosphonic acid or a salt thereof. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is -CO2H or a salt thereof. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is a malonic acid (e.g., -CH(COOH)2 or a salt thereof).

[0067] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is selected from -SO2OH (i.e., -SO3H), -S(O)OH, -OSO2OH, and -NHSO3H. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is a sulfonic acid (e.g., -SO3H or a salt thereof).

[0068] In some embodiments, the hydrophilic head group W is neutral and hydrophilic. In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is selected from the group consisting of -OH, -CR 2 R 2 OH, -CN, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHSO2NHR 3 , -NHC(O)NHS(O)2R 3 , and -NHSO 2 R 3 is selected from.

[0069] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is [ka] or a salt thereof, wherein A, B, and C are each independently CH or N, and D is each independently O or S.

[0070] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is [ka] or a salt thereof.

[0071] In some embodiments of Formulas (II)-(XIII), the hydrophilic head group W is selected from optionally substituted (C1-C2) alkylene and optionally substituted ethenylene. 1 The pyranose ring is connected via the above Z 1 Z may be selected relative to W to provide the desired spacing between the 5-position of the ring and the charged or polar center of W. For example, if W is malonic acid having a C—H atom connecting two carboxylic acid groups, then Z 1 may be methylene, which together provide the desired two carbon spacer between the ring and the COOH group.

[0072] In some embodiments of Formulas (II)-(XIII), Z 1 is methylene or substituted methylene. In some embodiments of Formulas (II)-(XIII), Z 1 is ethyl or substituted ethyl. In some embodiments of Formulas (II)-(XIII), Z 1 is ethenylene or substituted ethenylene. In some embodiments of Formulas (II)-(XIII), Z 1 is substituted with one or more halogens, for example fluoro.

[0073] In some embodiments of formula (III), the M6PR binding moiety (X) is represented by formulas (IV-1) to (IV-3): [ka] (In the formula, R a , R b , R c , and R d are independently H or F) is represented by one of the following:

[0074] In some embodiments of formulas (IV-1) to (IV-3), Z2 is O.

[0075] In some embodiments of formulas (IV-1) to (IV-3), Z 2 is S.

[0076] In some embodiments of formulas (IV)-1 to (IV-3), Z 2 Ha-NR 21 -It is.

[0077] In some embodiments of formulas (IV-1) to (IV-3), Z 2 -C(R 22 )2-, where each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl. In some embodiments of formulas (IV-1) to (IV-3), Z 2 is -CH2-.

[0078] In some embodiments of formulas (IV-1) to (IV-3), R a , R b , R c , and R d are H respectively.

[0079] In some embodiments of formula (IV-1), R a is H and R b is F. In some embodiments of formula (IV-1), R a and R b are F respectively.

[0080] In some embodiments of formula (IV-2), R c is H. In some embodiments of formula (IV-2), R c is F.

[0081] In some embodiments of formula (IV-3), R d is H. In some embodiments of formula (IV-3), R d is F.

[0082] In some embodiments of Formula (IV-1) and (IV-3), W is selected from -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or a salt thereof. In some embodiments of Formula (IV-1) and (IV-3), W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-1) and (IV-3), W is COOH, or a salt thereof.

[0083] In some embodiments of formula (IV-1), R a and R b are each F, and W is -P=O(OH)2, or a salt thereof. In some embodiments of formula (IV-1), R a and R b are each H, and W is -P=O(OH)2, or a salt thereof. In some embodiments of formula (IV-1), R a is F and R b is H and W is -P=O(OH)2, or a salt thereof.

[0084] In some embodiments of formulas (IV-1) to (IV-3), Z 2 is linked to the anomeric position of the pyranose ring having the α-configuration. In such cases, the M6PR binding moieties (X) of (IV-1) to (IV-3) may be referred to as formulae (IV-A1) to (IV-A3), respectively.

[0085] In some embodiments of formulas (IV-A1) to (IV-A3), Z 2 is S. In some embodiments of formulas (IV-A1) to (IV-A3), Z 2 is O. In some embodiments of formulas (IV-A1) to (IV-A3), Z 2 In some embodiments of formulas (IV-A1) to (IV-A3), Z 2 is -CF2-.

[0086] In some embodiments of Formula (IV-A1) and (IV-A3), W is selected from -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or a salt thereof. In some embodiments of Formula (IV-A1) and (IV-A3), W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-A1) and (IV-A3), W is COOH, or a salt thereof.

[0087] In some embodiments of Formula (IV-A1), R a and R b are each F, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-A1), R a and R b are each H, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-A1), R a is F and R b is H and W is -P=O(OH)2, or a salt thereof.

[0088] In some embodiments of formulas (IV-1) to (IV-3), Z 2 is linked to the anomeric position of the pyranose ring having a β-glycosidic configuration. The present inventors have demonstrated that compounds comprising an M6PR-binding moiety having a β-glycosidic configuration can have at least equivalent binding activity and / or cellular uptake activity compared to conjugates having a corresponding α-glycosidic configuration. In some embodiments, an M6PR-binding moiety having such a β-glycosidic configuration can have improved stability compared to a reference compound having a β-glycosidic configuration. Thus, in some embodiments of formula (IV), the M6PR-binding moiety (X) is represented by formulas (IV-B1) to (IV-B3): [ka] (In the formula, R a , R b , R c , and R dare independently H or F) is represented by one of the following:

[0089] In some embodiments of formulas (IV-B1) to (IV-B3), Z 2 is S. In some embodiments of formulas (IV-B1) to (IV-B3), Z 2 is O. In some embodiments of formulas (IV-B1) to (IV-B3), Z 2 In some embodiments of formulas (IV-B1) to (IV-B3), Z 2 is -CF2-.

[0090] In some embodiments of Formulas (IV-B1) and (IV-B3), W is selected from -P=O(OH), -P=S(OH), -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or a salt thereof.

[0091] In some embodiments of Formula (IV-B1) and (IV-B3), W is selected from -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or a salt thereof. In some embodiments of Formula (IV-B1) and (IV-B3), W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-B1) and (IV-B3), W is COOH, or a salt thereof.

[0092] In some embodiments of Formula (IV-B1), R a and R b are each F, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-B1), R a and R b are each H, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-B1), R a is F and R b is H and W is -P=O(OH)2, or a salt thereof.

[0093] The present inventors have demonstrated that conjugates comprising M6PR-binding moieties with a β-S-glycosidic configuration can have at least equivalent or superior binding and / or cellular uptake activity compared to conjugates with the corresponding α-S-glycosidic or α-O-glycosidic configurations (see Figure 19).

[0094] Thus, in some embodiments of formulas (IV-B1) to (IV-B3), the M6PR binding moiety (X) is represented by formula (IV-BS1) to (IV-BS3): [ka] (In the formula, R a , R b , R c , and R d are independently H or F) is represented by one of the following:

[0095] In some embodiments of formulas (IV-BS1) to (IV-BS3), R a , R b , R c , and R d are H respectively.

[0096] In some embodiments of Formula (IV-BS1), R a is H and R b is F. In some embodiments of Formula (IV-BS1), R a and R b are F respectively.

[0097] In some embodiments of Formula (IV-BS2), R c is H. In some embodiments of Formula (IV-B2), R c is F.

[0098] In some embodiments of Formula (IV-BS3), R dis H. In some embodiments of Formula (IV-BS3), R d is F.

[0099] In some embodiments of formulas (IV-BS1) to (IV-BS3), Z 2 is S. In some embodiments of formulas (IV-BS1) to (IV-BS3), Z 2 is O. In some embodiments of formulas (IV-BS1) to (IV-BS3), Z 2 In some embodiments of formulas (IV-BS1) to (IV-BS3), Z 2 is -CF2-.

[0100] In some embodiments of Formula (IV-BS1) and (IV-BS3), W is selected from -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or a salt thereof. In some embodiments of Formula (IV-BS1) and (IV-BS3), W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-BS1) and (IV-BS3), W is COOH, or a salt thereof.

[0101] In some embodiments of Formula (IV-BS1), R a and R b are each F, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-BS1), R a and R b are each H, and W is -P=O(OH)2, or a salt thereof. In some embodiments of Formula (IV-BS1), R a is F and R b is H and W is -P=O(OH)2, or a salt thereof.

[0102] In some embodiments, the mannose ring or analog thereof of the M6PR binding moiety is linked to a Z bond at the anomeric or 1-position of the sugar ring. 2A linking moiety can be attached to the group to be incorporated into the compounds of the present disclosure.

[0103] In some embodiments, the M6PR binding moiety comprises a Z bonded to a cyclic group A. 3 In the compound of formula (III), Z is incorporated into the compound of the present disclosure by attaching a linker to the group. 2 It is understood that the cyclic group attached to can be considered part of the M6PR binding moiety (X) and can impart desirable binding properties to said M6PR.

[0104] 5.2.2. Cyclic group A The cyclic group A in formulas (III)-(XIII) may be a monocyclic group or a bicyclic group. The bicyclic group in question may be a fused bicyclic group or a bicyclic group comprising two monocyclic rings linked via a covalent bond. The cyclic group A in formulas (III)-(XIII) may be an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle (e.g., a saturated heterocycle), or an optionally substituted cycloalkyl.

[0105] The cyclic group A in Formulas (III)-(XIII) may be a monocyclic aryl group or a monocyclic heteroaryl group. In some embodiments of Formulas (III)-(XIII), A is a 5-membered monocyclic heteroaryl group. In some embodiments of Formulas (III)-(XIII), A is a 6-membered monocyclic aryl or heteroaryl group. In some embodiments of Formulas (III)-(XIII), A may be a polycyclic aryl or polycyclic heteroaryl group, such as a bicyclic aryl or bicyclic heteroaryl group. In some embodiments of Formulas (III)-(XIII), A is a fused bicyclic group. In some embodiments of Formulas (III)-(XIII), A is a bicyclic group comprising two aryl and / or heteroaryl monocyclic rings linked via a covalent bond. In some embodiments of Formulas (III)-(XIII), A is a bicyclic aryl or bicyclic heteroaryl group having two 6-membered rings. In some embodiments of Formulas (III)-(XIII), A is a bicyclic aryl or bicyclic heteroaryl group having one 6-membered ring covalently bonded or fused to a 5-membered ring.

[0106] In some embodiments of Formulas (III)-(XIII), A is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted quinoline, optionally substituted triazole, and optionally substituted phenylenetriazole.

[0107] In some embodiments of Formulas (III)-(XIII), A is not phenyl (also referred to in the context of Formula (III) as phenylene, eg, 1,4-phenylene).

[0108] In some embodiments of Formulas (III)-(XIII), A is substituted with at least one OH substituent. In some embodiments of Formulas (III)-(XIII), A is substituted with one, two, or more OH groups. In some embodiments of Formulas (III)-(XIII), A is substituted with at least one optionally substituted (C1-C6) alkyl.

[0109] In some embodiments of Formulas (III)-(XIII), A is optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, or optionally substituted 2,5-pyridylene.

[0110] In some embodiments of Formulas (III)-(XIII), A is [ka] (In the formula, R 11 ~R 14 are independently H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and NHCOR 25 is selected from R 25 are independently selected from H and optionally substituted (C1-C6) alkyl. is selected from.

[0111] In some embodiments of Formulas (III)-(XIII), A is an optionally substituted fused bicyclic aryl or an optionally substituted fused bicyclic heteroaryl.

[0112] In some embodiments of Formulas (III)-(XIII), A is an optionally substituted naphthalene or an optionally substituted quinoline.

[0113] In some embodiments of Formulas (III)-(XIII), A is [ka] (In the formula, R 11 and R 13 ~R 14 are independently H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 is selected from s is 0 to 3, Each R 25 are independently selected from H and optionally substituted (C1-C6) alkyl. is selected from.

[0114] In some embodiments of Formulas (III)-(XIII), A is [ka] is selected from.

[0115] In some embodiments of Formulas (III)-(XIII), A has the following formula: [ka] (In the formula, Cy is independently a monocyclic aryl or a monocyclic heteroaryl; R 11 ~R 15 are independently H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR25 , and -NHCOR 25 is selected from s is 0 to 4, Each R 25 are independently selected from H and optionally substituted (C1-C6) alkyl. or a salt thereof.

[0116] In some embodiments, when Cy is optionally substituted phenyl, A is a group of the formula: [ka] is an optionally substituted biphenyl of the formula:

[0117] In some embodiments of Formulas (III)-(XIII), A is [ka] is selected from.

[0118] In some embodiments, when Cy is triazole, A is [ka] is selected from.

[0119] In some embodiments, R 11 ~R 15 At least one of is OH (eg, at least two are OH).

[0120] In some embodiments, R 11 ~R 15 are H respectively.

[0121] 5.2.3.Connection part Z 3 The above connecting part Z 3may be any convenient linking moiety that connects the linker L to the cyclic ring A. In some embodiments of Formulas (III)-(XIII), Z 3 has a main chain of three atoms or less.

[0122] In some embodiments of Formulas (III)-(XIII), Z 3 is a covalent bond, -O-, -NR 23 -, -NR 23 CO-, -CONR 23 -, -NR 23 CO2-, -OCONR 23 , -NR 23 C(=X 1 )NR 23 -, -CR 24 =N-, -CR 24 =NX 2 , -N(R 23 )SO2- and -SO2N(R 23 )-(wherein, X 1 and X 2 O, S, and NR 23 and R 23 and R 24 are independently H, C (1~3) -Alkyl (e.g., methyl) and substituted C (1~3) -alkyl) is selected from.

[0123] In some embodiments of Formulas (III)-(XIII), Z 3 is the covalent bond connecting A to L.

[0124] In some embodiments of Formulas (III)-(XIII), Z 3 is an optionally substituted amide, urea, or thiourea.

[0125] In some embodiments of Formulas (III)-(XIII), Z 3 teeth [ka] (In the formula, X1 is O or S, t is 0 or 1, Each R 23 are independently H, C (1~3) -Alkyl (e.g., methyl or ethyl) and substituted C (1~3) -alkyl) Z 3 In some embodiments, X 1 is O. Z 3 In some embodiments, X 1 is S. Z 3 In some embodiments, t is 0 and X 1 is O, so Z 3 is an amide. Z 3 In some embodiments, t is 1, and thus Z 3 is urea or thiourea.

[0126] In some embodiments of Formulas (III)-(XIII), Z 3 -N(R 23 )SO2- or -SO2N(R 23 In some embodiments of Formulas (III)-(XIII), Z 3 is -NHSO2- or -SO2NH-.

[0127] In some embodiments of Formulas (III)-(XIII), Z 3 -N(R 23 )CO- or -CON(R 23 In some embodiments of Formulas (III)-(XIII), Z 3 is -NHCO- or -CONH-.

[0128] In some embodiments of Formulas (III)-(XIII), Z 3 is -NHC(=X 1 )NH-, provided that X 1 is O or S. In some embodiments, X 1 is O (i.e., Z 3is —NHC(═O)NH—). In some embodiments, X 1 is S.

[0129] In some embodiments of Formulas (III)-(XIII), Z 3 is an optionally substituted triazole. 3 When is an optionally substituted triazole, the triazole can be synthetically derived from the conjugation of an azide-containing precursor and an alkyne-containing precursor of the compound via click chemistry.

[0130] In some embodiments, Z 3 is a cyclic group A and / or a linking moiety Z 1 to confer desirable M6PR binding and internalization properties on X.

[0131] In some embodiments of Formulas (III)-(XIII), -AZ 3 -teeth, [ka] [ka] is selected from.

[0132] In some embodiments of Formulas (III)-(XIII), -AZ 3 -teeth, [ka] is selected from.

[0133] In some embodiments of Formulas (III)-(XIII), -AZ 3 -teeth, [ka] is selected from.

[0134] In some embodiments of Formulas (II)-(XIb), -AZ 3 -teeth, [ka] is selected from.

[0135] In some embodiments of Formulas (III)-(XIII), -AZ 3 -teeth, [ka] [ka] is selected from.

[0136] In some embodiments of Formulas (III)-(XIII), Z 2 is O.

[0137] In some embodiments of Formulas (III)-(XIII), Z 2 is S.

[0138] In some embodiments of Formulas (III)-(XIII), Z 2 Ha-NR 21 -It is.

[0139] In some embodiments of Formulas (III)-(XIII), Z 2 -C(R 22 )2-, where each R 22 are independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl. In some embodiments, Z 2 is -CH-. In some embodiments, Z 2 is -CHF-. In some embodiments, Z 2 is -CF2-.

[0140] In some embodiments of Formulas (III)-(XIII), Z 2 -A-Z 3-teeth, [ka] (In the formula, Z 21 is O, S, or -C(R 22 )2- and R 16 is OH or CH3, w is 0 to 4 (e.g., w is 0, 1, or 2) is.

[0141] In some embodiments, Z 21 is S or O. In some embodiments, Z 21 is -CH-. In some embodiments, Z 21 is -CHF-. In some embodiments, Z 21 is -CF-. In some embodiments, R 16 is OH and w is 1. In some embodiments, R 16 is CH3 and w is 1. In some embodiments, w is 0.

[0142] In some embodiments of Formulas (III)-(XIII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0143] In some embodiments of Formulas (III)-(XII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0144] In some embodiments of Formulas (III)-(XIII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0145] In some embodiments of Formulas (III)-(XIII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0146] In some embodiments of Formulas (III)-(XIII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0147] In some embodiments of Formulas (III)-(XIII), -Z 2 -A-Z 3 -teeth, [ka] is.

[0148] 5.2.4. Exemplary M6PR Ligands Exemplary M6PR binding moieties, X, of Formulas (I)-(XIII) that can be utilized in preparing the compounds and conjugates of the present disclosure are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0149] Exemplary synthons, i.e., synthetic precursors, for incorporating a desired target M6PR binding moiety that can be utilized in preparing compounds of the present disclosure are shown in Table 2. It should be understood that alternative synthons, including homologs and analogs of the synthons shown in Table 2, are also possible depending on the M6PR binding moiety and linker selected. The synthons in Table 2 are represented by the following formula: 3 It is understood that the structural precursors of Table 2 may include structural elements that become part of the linker (L) in the compounds and conjugates of the present disclosure. Based on the exemplary synthetic precursors of Table 2, it is understood that compounds of the present disclosure can be prepared utilizing synthons corresponding to any of the M6PR binding moieties of Table 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0150] Other M6PR binding moieties of interest and their synthons, or synthetic precursors, are shown in Table 3. X101-X103 represent compounds with a phosphate or thiophosphate head group. X109-X110 represent exemplary compounds of formula (V). In some embodiments, such M6PR binding moieties are used as reference compounds for evaluation of compounds of formula (XII). [Table 3-1] [Table 3-2]

[0151] 5.2.5. Disaccharides Containing the M6PR Binding Moiety Embodiments of the present disclosure include compounds and conjugates of Formula (I) having an M6PR binding moiety that includes a specific dimannose structure having a first pyranose ring (e.g., the pyranose ring of Formula (II)) attached to a second 2,5-linked pyranose ring that is further attached to a linker.

[0152] Figure 20 shows selected cellular uptake activities comparing conjugates of the compound of formula (III) with compounds containing specific dimannose M6PR-binding moieties. Conjugates of M6PR-binding compounds 660 or 659, each of which has a dimannose structure with a 2,5-linked pyranose ring attached to a linker, were potent and showed activity comparable to that of conjugates of compound 520 (I-7).

[0153] Thus, an embodiment of the present disclosure provides a compound of formula (XV): [ka] (In the formula, W is a non-hydrolyzable hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 4 -Z 14 -, -Z14 -A-, -A-, and -CH2-Z 14 - selected from Z 14 are O, S, NR 21 , and C(R 22 )2, where R 21 are 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; A is an optionally substituted cyclic group (e.g., optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted cycloalkyl); n is 1 to 500; m is 1 to 500; L is a linker, Y is the target part) or a prodrug or salt thereof.

[0154] In some embodiments of Formula (XV), Z 4 Ha-CH2-Z 14 -(However, Z 14 are O, S, NR 21 , and C(R 22 )2) is selected from.

[0155] In some embodiments of Formula (XV), Z 4 is -CH2-A-.

[0156] In some embodiments of Formula (XV), Z 4 is -A-.

[0157] In some embodiments of Formula (XV), A is a cyclic group (e.g., an optionally substituted aryl or an optionally substituted heteroaryl as described above with respect to Formula (III)). In some embodiments of Formula (XV), A is a cyclic group as defined above in Formula (III).

[0158] In some embodiments of Formula (XV), A is triazole.

[0159] In some embodiments of Formula (XV), Z 4 teeth [ka] where "*" represents the bond to the linker L.

[0160] The M6PR binding moiety of formula (XV) can be adapted for use in a variety of compounds and conjugates described herein.

[0161] In some embodiments of Formula (XV), m is 1 to 100, for example, 1 to 5, 5 to 10, 10 to 20, 10 to 100, 20 to 80, or 20 to 50. In some embodiments of Formula (XV), m is 1, 2, 3, 4, or 5.

[0162] Prodrugs Aspects of the present disclosure include prodrugs of any of the M6PR binding moieties described herein that are incorporated into the compounds and conjugates of the present disclosure.

[0163] 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 at physiological pH).

[0164] Prodrug forms of any of the M6PR binding moieties described herein may be useful because they may offer 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 effective dosage required.

[0165] This may be useful in some cases because a prodrug may be easier to administer than the parent drug. For example, a prodrug may be bioavailable by oral administration while the parent drug may not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug.

[0166] Prodrug derivatives of M6PR binding moieties generally contain a promoiety substituent at an appropriate labile site of the compound, e.g., a hydroxy group on the pyranose ring of Formula (II). The promoiety refers to a group that is removed by enzymatic or chemical reaction when the prodrug is converted to a drug in vivo. For example, the promoiety may be an optionally substituted alkyl acyl group attached to a hydroxy group of the compound via an ester bond. An exemplary alkyl acyl promoiety includes acetyl. In some embodiments, prodrug derivatives of one or more hydroxyl groups on the pyranose sugar ring may be incorporated into the compound. For example, an ester promoiety may be incorporated into one or more hydroxyl groups at the 2-, 3-, and / or 4-positions of the sugar ring.

[0167] In some embodiments, prodrug derivatives of the hydrophilic head group (W) may be incorporated into the M6PR binding moieties and compounds of the present disclosure, for example, an ester promoiety may be incorporated into a phosphonic acid or thiophosphonic acid head group, or an ester promoiety may be incorporated into a carboxylic acid or malonic acid head group.

[0168] Linker The terms "linker," "linking moiety," and "linking group" are used interchangeably and refer to a linking moiety that covalently links two or more moieties or compounds, such as an M6PR binding moiety and another moiety of interest. In some cases, the linker is divalent and connects two moieties. In some cases, the linker is a branched linking group that is a trivalent or more highly polyvalent linker. In some cases, the linker connecting two or more moieties has a linear or branched backbone that is 500 atoms or less (e.g., 400 atoms or less, 300 atoms or less, 200 atoms or less, 100 atoms or less, 80 atoms, 60 atoms or less, 50 atoms or less, 40 atoms or less, 30 atoms or less, or even 20 atoms or less) in length, for example, as measured between the two or more moieties. The linking moiety can be a covalent bond connecting two groups, or a straight or branched chain of 1 to 500 atoms in length, e.g., 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 straight, branched, cyclic, or a single atom. In some cases, 1, 2, 3, 4, 5 or more, 10 or more, or even more carbon atoms in the linker backbone are optionally substituted with heteroatoms, e.g., sulfur, nitrogen, or oxygen heteroatoms. In some cases, when the linker includes a PEG group, every third atom in that segment of the linker backbone is substituted with oxygen. The bond between the backbone atoms can be saturated or unsaturated, and typically, there are one, two, or no more than three unsaturated bonds in the linker backbone. The linker may include one or more substituents, such as alkyl, aryl, or alkenyl groups. The linker may include, but is not limited to, one or more of oligo(ethylene glycol), ether, thioether, disulfide, amide, carbonate, carbamate, tertiary amine, alkyl (which may be linear or branched), such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.The linker backbone may include a cyclic group, such as an aryl, heterocycle, cycloalkyl group, or heterocyclic group, where two or more atoms of the cyclic group, such as two, three, or four atoms, are included in the backbone.

[0169] In some embodiments, the "linker" or linking moiety is derived from a molecule having two reactive ends, one for conjugation to a moiety of interest (Y), e.g., a biomolecule (e.g., an antibody), and the other for conjugation to a moiety that binds to cell surface M6PR (designated as X). When Y is a polypeptide, the polypeptide-binding reactive end of the linker is a site that is capable of conjugation to the polypeptide, as the case may be, via a cysteine ​​thiol or lysine amine group on the polypeptide, and thus may be a thiol-reactive group, e.g., maleimide or dibromomaleimide, or as defined herein, or an amine-reactive group such as an active ester (e.g., pentafluorophenyl ester or tetrafluorophenyl ester or NHS ester), or as defined herein.

[0170] 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 amide, urea, or thiourea, carbamate, ester, amino, ether, thioether, sulfhydryl, or other heterofunctional bonds. 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.

[0171] 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.

[0172] 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 L comprises an optionally substituted arylene linked to a cell surface M6PR binding moiety (X), an optionally substituted heteroarylene linked to X, an optionally substituted heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, L is a linker of about 10 Å to about 500 Å, and L comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, L is a linker of about 10 Å to about 400 Å, and L comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, L is a linker of about 10 Å to about 200 Å, and L comprises an optionally substituted arylene linked to X, an optionally substituted heteroarylene linked to X, an optionally substituted heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X.

[0173] In certain embodiments, L separates the cell surface M6PR binding moiety (Y) from Y (or Z) by a main chain comprising at least 10 consecutive atoms. Optionally, the main chain is at least 12 consecutive atoms. Optionally, the main chain is at least 14 consecutive atoms. Optionally, the main chain is at least 16 consecutive atoms. Optionally, the main chain is at least 18 consecutive atoms. Optionally, the main chain is at least 20 consecutive atoms. Optionally, the main chain is at least 22 consecutive atoms. Optionally, the main chain is at least 24 consecutive atoms. Optionally, the main chain is at least 26 consecutive atoms. Optionally, the main chain is at least 28 consecutive atoms. Optionally, the main chain is at least 30 consecutive atoms. Optionally, the main chain is at least 32 consecutive atoms. Optionally, the main chain is at least 34 consecutive atoms. In some cases, the backbone is at least 36 consecutive atoms. In some cases, the backbone is at least 38 consecutive atoms. In some cases, the backbone is at least 40 consecutive atoms. In some cases, the backbone is at most 50 consecutive atoms. In some cases, the backbone is at most 60 consecutive atoms. In some cases, the backbone is at most 70 consecutive atoms. In some cases, the backbone is at most 80 consecutive atoms. In some cases, the backbone is at most 90 consecutive atoms. In some cases, the backbone is at most 100 consecutive atoms.

[0174] In certain embodiments, linker L separates X and Y (or Z) by a chain of 4 to 500 contiguous atoms. In certain embodiments, linker L separates the cell surface M6PR binding moiety (X) and Y (or Z) by a chain of 4 to 50 contiguous atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 6 to 50 contiguous atoms, by a chain of 11 to 50 contiguous atoms, by a chain of 16 to 50 contiguous atoms, by a chain of 21 to 50 contiguous atoms, by a chain of 26 to 50 contiguous atoms, by a chain of 31 to 50 contiguous atoms, by a chain of 36 to 50 contiguous atoms, by a chain of 41 to 50 contiguous atoms, or by a chain of 46 to 50 contiguous atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 6 to 50 contiguous atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 11 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 16 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 21 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 26 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 31 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 36 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 41 to 50 consecutive atoms. In certain embodiments, the linker L separates X and Y (or Z) by a chain of 46 to 50 contiguous atoms.

[0175] In certain embodiments, the linker L separates X and Y (or Z) by a chain of 4 or 5 contiguous atoms, by a chain of 6-10 contiguous atoms, by a chain of 11-15 contiguous atoms, by a chain of 16-20 contiguous atoms, by a chain of 21-25 contiguous atoms, by a chain of 26-30 contiguous atoms, by a chain of 31-35 contiguous atoms, by a chain of 36-40 contiguous atoms, by a chain of 41-45 contiguous atoms, or by a chain of 46-50 contiguous atoms.

[0176] In certain embodiments, the linker L separates X and Y (or Z) by a chain of 50 or 55 consecutive atoms, by a chain of 56-60 consecutive atoms, by a chain of 61-65 consecutive atoms, by a chain of 66-70 consecutive atoms, by a chain of 71-75 consecutive atoms, by a chain of 76-80 consecutive atoms, by a chain of 81-85 consecutive atoms, by a chain of 86-90 consecutive atoms, by a chain of 91-95 consecutive atoms, or by a chain of 96-100 consecutive atoms.

[0177] In certain embodiments, the linker L is a chain of 5 to 500 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 heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, the linker L is a chain of 7 to 500 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 heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, the linker L is a chain of 10 to 500 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 heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X. In certain embodiments, the linker L is a chain of 15 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 heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X.

[0178] In certain embodiments, linker L is a chain of 5 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted arylene linked to X or an optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 7 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted arylene linked to X or an optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 10 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted arylene linked to X or an optionally substituted heteroarylene linked to X. In certain embodiments, the linker L is a chain of 15 to 400 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted arylene linked to X or an optionally substituted heteroarylene linked to X.

[0179] In certain embodiments, the linker L is a chain of 5 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted phenylene linked to X. In certain embodiments, the linker L is a chain of 7 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted phenylene linked to X. In certain embodiments, the linker L is a chain of 10 to 500 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted phenylene linked to X. In certain embodiments, the linker L is a chain of 15 to 400 contiguous atoms separating X and Y (or Z) and comprises an optionally substituted phenylene linked to X.

[0180] In certain 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 heterocyclene linked to X, or an optionally substituted cycloalkylene linked to X.

[0181] The linker may be a linker between the Z of the M6PR binding moiety (X) (e.g., as described herein). 3 or Z 4 It is understood that the linker may be considered to be directly attached to the Z group. In some embodiments of formula (III) or (V), the linker may be 3 or Z 4 Alternatively, the linker formula -Z may be considered to be directly attached to the -Z group. 3 -L 1 -group or -Z 4 -L 1 -groups (e.g., as described herein) can be Z 3 or Z 4 may be considered part of the linking moiety that connects Y. The present disclosure is intended to include all such configurations of M6PR binding moieties (X) and linkers (L).

[0182] In some embodiments of Formulas (XI)-(XIII), L is a group represented by Formula (VII): [ka] (In the formula, L 1 and L 3 are independently linkers, and L 2 is a branched chain linking moiety, where 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 X's Z 1 via L 1 represents the point of attachment to *** represents the point of attachment to Y; when n is 1, a is 1 and b is 0; If n is >1, then a is 1 and b is 1. is a linker.

[0183] In certain embodiments of the linker of formula (VII), L 1 ~L 3 are each independently, -C 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 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, as described herein), amino acid residue (natural or non-naturally occurring amino acid residue), -NH-, and -NMe- (wherein each p is independently 1 to 50).

[0184] In certain embodiments of the linker of formula (VII), L 1 ~L 3contains repeating ethylene glycol moieties (e.g., -CH2CHO- or -OCH2CH2-). In certain cases, the linker of formula (VII) above 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 cases, the linker of formula (VII) above 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.

[0185] In certain embodiments of the linker of formula (VII), L 1 ~L 3 In some cases, the linker comprises one or more 1,2,3-triazole linking moieties. In certain cases, the one or more 1,2,3-triazole moieties have the following structure: [ka] (wherein w1, u1, and q1 are independently selected from one of 1 to 25 (eg, 1 to 12, for example, 1 to 6)).

[0186] In certain embodiments of the linker of formula (VII) above, n is 1 and therefore b is 0, and the linker has formula (VIIa): [ka] (In the formula, L 1 and L 3 are independently a linker (e.g., as described herein), provided that L 1 ~L 3 together provide a linear linker between X and Y, a is "1" c is 0 or 1, ** is X's Z 1 via L 1 represents the point of attachment to *** indicates the point of attachment to Y) is a linker.

[0187] In certain embodiments of the linker of formula (VIIa) above, the linear linker is Z 1 In certain embodiments of Formula (VIIa), the linear linker has a main chain of 20 or more consecutive atoms, e.g., 25 or more consecutive atoms, or 30 or more consecutive atoms, and in some cases, up to 100 consecutive atoms, covalently linking X to Y (or Z) via a chain of 20 to 50 consecutive atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 21 to 50 consecutive atoms, by a chain of 22 to 50 consecutive atoms, by a chain of 23 to 50 consecutive atoms, by a chain of 24 to 50 consecutive atoms, by a chain of 25 to 50 consecutive atoms, by a chain of 26 to 50 consecutive atoms, by a chain of 27 to 50 consecutive atoms, by a chain of 28 to 50 consecutive atoms, or by 29 to 50 consecutive atoms. 1 In certain embodiments of Formula (VIIa), the linear linker separates X and Y (or Z) by a chain of 30 to 60 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 31 to 60 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 32 to 60 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 33 to 60 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 34 to 60 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 35 to 50 contiguous atoms. 1In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 36 to 50 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 41 to 50 contiguous atoms. 1 In certain embodiments, the linear linker separates X and Y (or Z) by a chain of 46 to 50 contiguous atoms. 1 ) and separate.

[0188] In certain other embodiments of Formula (VII), n is 2 or greater and L 1 ~L 3 together provide a branched linker between X and Y.

[0189] In certain embodiments of Formula (VII), n is 2 or greater and L 2 teeth, [ka] (wherein each x and y independently represents 1 to 10) is selected from.

[0190] In certain embodiments of formula (VII), L 1 ~L 2 comprises a main chain 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.

[0191] In certain embodiments of formula (VII) or (VIIa), L 3 comprises a main chain of 10 to 80 consecutive atoms, for example, 12 to 70, 12 to 60, or 12 to 50 consecutive atoms.

[0192] In certain embodiments of formula (VII) or (VIIa), L 3 is C 10 ~C 20 -Alkylene (e.g., C 12 -alkylene), or -(OCH2CH2)p -(wherein p is 1 to 25, e.g., 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25, or 20 to 24).

[0193] In certain embodiments, L is of formula (VIIb): [ka] (In the formula, Each L 1 ~L 5 are independently, and both are Z 1 and Y, a, b, c, d, and e are each independently 0, 1, or 2; ** is X's Z 1 via L 1 represents the point of attachment to *** represents the point of attachment to Y; when n is 1, a is 1 and c is 0; If n>1, then a is 1 and c is 1) It is L.

[0194] In certain embodiments of the linker of formula (VIIb) above, L 1 ~L 5 are each independently, -C 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) pand 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, as described herein), amino acid residue (natural or non-naturally occurring amino acid residue), -NH-, and -NMe- (wherein each p is independently 1 to 50).

[0195] In certain embodiments of Formula (VIIb), -(L 1 ) a - includes an optionally substituted alkyl or ethylene glycol linking moiety. 1 is optionally replaced by -C 1~6 In certain cases, L 1 contains an ethylene glycol linking moiety.

[0196] In certain embodiments of Formula (VIIb), L 1 are independent, -C 1~6 -Alkylene-, -(CH2CH2O) t -, -C 1~6 -Alkylene-NR 4 CO-, -C 1~6 -alkylene CONH-, or OCH2, where t is 1 to 20; R 4 is independently selected from H and optionally substituted (C1-C6) alkyl. In certain cases, L 1 Ha-C 1~6 -Alkylene-, for example, -C 1~3 -alkylene-. In certain cases, L 1 Ha-(CH2CH2O) t -, where 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 cases, L 1 Ha-C 1~6 -Alkylene-NR 4CO-. In certain cases, L 1 Ha-C 1~6 -alkyleneCONH-. In certain cases, L 1 is OCH2.

[0197] In some embodiments of Formula (VIIb), one or more L 1 are independently -CH2O-, -(CH2CH2O) t -, -NR 4 CO-, -C 1~6 -alkylene-, [ka] (In the formula, 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 is optionally further substituted) is.

[0198] In certain embodiments of Formula (VIIb), L 2 are independently, -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 cases, L 2 Ha-NR4 CO-C 1~6 -alkylene-. In certain cases, L 2 -CONR 4 -C 1~6 - alkylene.

[0199] In certain cases, L 2 teeth [ka] (wherein w is 1 and u is 0 or 1) is.

[0200] In certain cases, L 2 teeth [ka] (wherein w is 1 and u is 0 or 1) is.

[0201] In certain cases, L 2 teeth [ka] (wherein w is 1, u is 0 or 1, and q is 1) is.

[0202] In certain cases, L 2 teeth [ka] (wherein u is 0 or 1) is.

[0203] In certain cases, L 2 teeth [ka] is.

[0204] In certain embodiments, L 2is —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 cases, q is 2 to 8, for example, 2 to 6, 4 to 6, or 2 to 4.

[0205] In certain embodiments of Formula (VIIb), L 4 is absent or independently, -C 1~6 -Alkylene-, -(CH2CH2O) t -, -C 1~6 -Alkylene-NHCO-, -C 1~6 -alkyleneCONH-, or OCH2, where t is 1 to 20. 4 does not exist. In certain cases, L 4 Ha-C 1~6 -alkylene-. In certain cases, L 4 Ha-(CH2CH2O) t -, and 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 cases, L 4 Ha-C 1~6 -alkylene-NHCO-. In certain cases, L 4 Ha-C 1~6 -alkyleneCONH-. In certain cases, L 4 is OCH2.

[0206] In some embodiments of the subject compounds, n is 1 and L in formula (VIIb) 3 does not exist.

[0207] In certain embodiments of the subject compounds, n is 2 or greater and L of formula (VIIb) 3 is the branched chain bond portion.

[0208] Thus, in some embodiments of formula (VIIb), L 3is a branched linking moiety, e.g., a trivalent linking moiety. For example, L 3 The linking moiety has the following general formula: [ka] It may be one of the linking moieties.

[0209] In some embodiments of Formula (VIIb), the branched linking moiety may be a higher valency linking moiety and has the general formula: [ka] (Wherein, any two L 3 The groups may be directly linked or attached via an optional linear linking moiety (e.g., as described herein). etc.

[0210] In some embodiments of Formula (VIIb), the branched linking moiety may include one, two, or more L 3 and optionally containing linking moieties, each of which is a trivalent moiety that, when linked together, provides multiple branching points for covalent attachment of ligands and has the general formula: [ka] (wherein t is 0 to 500, for example, 0 to 100, 0 to 20, or 0 to 10) may be represented by one of:

[0211] In some embodiments, the branched chain linking moiety (e.g., L 3 ) includes one or more amino acid residues (e.g., Asp, Lys, Orn, Glu, Ser), N-substituted amide (-N(-)C(=O)-), tertiary amino, polyol (e.g., O-substituted glycerol), and the like.

[0212] In some embodiments of Formula (VIIb), one or more L 3 teeth, [ka] wherein each x and y is independently 1 to 10, e.g., 1 to 6, 1 to 3, e.g., 1 or 2. In some cases, each x is 1, 2, or 3, e.g., 2. is a branched chain moiety selected from

[0213] In some embodiments of Formula (VIIb), one or more L 5 are independently -CH2O-, -(CH2CH2O) t -, -NR 4 CO-, -C 1~6 -alkylene-, [ka] (In the formula, 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 is optionally further substituted) is.

[0214] In certain cases, L 5 is -CH2O-. In certain cases, L 5 Ha-(CH2CH2O) t -, and t is 1 to 20, e.g., 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In certain cases, L 5 Ha-NR 4 CO- and R 4 is H or optionally substituted (C1-C6) alkyl. In certain cases, L 5 Ha-C 1~6 -alkylene-.

[0215] In certain cases, 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). is.

[0216] In certain cases, 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 is.

[0217] In certain cases, L 5 teeth [ka] (wherein r is 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 is.

[0218] In certain cases, L 5 teeth [ka] (wherein r is 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 is.

[0219] In certain cases, L 5 teeth [ka] (wherein r is 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 is.

[0220] In certain cases, L 5 teeth [ka] (wherein r is independently 0 to 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5). is.

[0221] In certain cases, 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). is.

[0222] In certain cases, 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). is.

[0223] In certain cases, 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). is.

[0224] In certain cases, 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). is.

[0225] In certain embodiments of Formula (VIIb), a is 1. In certain cases, at least one of b, c, d, and e is not 0. In certain cases, b is 1 or 2. In certain cases, c is 1 or 2. In certain cases, e is 1 or 2. In certain cases, b, d, and e are independently 1 or 2. In certain cases, a, b, d, and e are each 1, and c is 0.

[0226] In some embodiments of Formula (VIIb), L 5 includes one or more amino acid residues (e.g., Asp, Lys, Orn, Glu, Ser), amino acid analogs, N-substituted amides (-N(-)C(=O)-), tertiary amino acids, polyols (e.g., O-substituted glycerol), etc. Amino acid analogs include, but are not limited to, unnatural amino acids, as well as other modifications known in the art. The amino acids may include L-amino acids, D-amino acids, or both, and may include any of a variety of amino acid modifications or analogs known in the art.

[0227] In some embodiments of Formula (VIIb), L 1 ~L 5 is in the following units: [ka] (In the formula, R a is (C1-C6) alkyl or substituted (C1-C6) alkyl, for example, (C1-C6) alkyl optionally substituted with an amine, a tertiary amine, optionally substituted alkoxy, optionally substituted carboxyl, optionally substituted aryl, or optionally substituted heteroaryl. Contains one or more of the following: R aIt is to be understood that may be linked to the M6PR binding moiety.

[0228] In certain embodiments of Formula (VIIb), a is 1. In certain cases, at least one of b, c, d, and e is not 0. In certain cases, b is 1 or 2. In certain cases, c is 1 or 2. In certain cases, e is 1 or 2. In certain cases, b, d, and e are independently 1 or 2. In certain cases, a, b, d, and e are each 1 and c is 0.

[0229] In certain embodiments of Formula (VII), (VIIa), or (VIIb), the linker comprises 20 to 100 consecutive atoms, e.g., 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 cases, the linker comprises 25 to 100 consecutive atoms, e.g., 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.

[0230] In certain embodiments of Formula (VII), (VIIa), or (VIIb), the linker comprises 25 or more consecutive atoms, e.g., 26 or more, 27 or more, 28 or more, 29 or more, or 30 or more consecutive atoms. In certain embodiments of Formula (VII), (VIIa), or (VIIb), the linker comprises 30 or more consecutive atoms, e.g., 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37 or more, 38 or more, 39 or more, 40 or even more consecutive atoms.

[0231] In certain embodiments where the linker of formula (VII) or (VIIb) is a branched linker, each branch of the linker may be Z 1In certain cases, each branched chain of the linker comprises a linear linker of 14 or more consecutive atoms covalently linking each X moiety to a branch point of the linker via a linear linker of 15 or more consecutive atoms to the branch point. In certain cases, each branched chain of the linker comprises a linear linker of 16 or more consecutive atoms to the branch point. In certain cases, each branched chain of the linker comprises a linear linker of 18 or more consecutive atoms to the branch point. In certain cases, each branched chain of the linker comprises a linear linker of 20 or more consecutive atoms to the branch point. In certain cases, each branched chain of the linker comprises a linear linker of 22 or more consecutive atoms to the branch point.

[0232] In certain embodiments of formula (VII) or (VIIb), the linker is Z 1 and a linear linker covalently connecting the branch point to Y. In certain cases, the linear linker covalently connecting the branch point to Y is 12 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 15 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 20 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 25 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 30 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 40 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 50 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 60 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 70 or more consecutive atoms. In certain cases, the linear linker covalently connecting the branch point to Y is 80 or more consecutive atoms.

[0233] In some embodiments, the linker comprises a polypeptide scaffold in which some or all of the side chain groups of its amino acid residues have been modified to bind to an M6PR binding moiety (e.g., as described herein). It should be understood that an M6PR binding moiety (e.g., as described herein) can be conjugated to amino acid residues such as Asp, Lys, Orn, Glu, and Ser of a polypeptide comprising the linker via 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 can be a randomly polymerized polymer having an average length, or a polymer of a defined length, e.g., prepared in a controlled, stepwise manner. In some cases, the length of the polypeptide linker segment is 10 to 100 amino acid residues, e.g., 20 to 90 amino acid residues, 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). In some embodiments, the N- or C-terminus of the polypeptide linker segment is modified with one or more linking units (e.g., as described herein) suitable for attachment to a Y, moiety of interest.

[0234] In some embodiments, the linker has formula (VIIIa) or (VIIIb): [ka] (In the formula, L 0is a linking moiety (e.g., one or more amino acid residues), a linked M6PR binding moiety, an optionally substituted alkyl, or an optionally substituted aryl or heteroaryl; R a is a (C1-C6) alkyl or substituted (C1-C6) alkyl (e.g., a (C1-C6) alkyl optionally substituted with an amine, a tertiary amine), an optionally substituted alkoxy, an optionally substituted carboxyl, an optionally substituted aryl, or an optionally substituted heteroaryl, a derivative of an amino acid side chain group (e.g., lysine, serine, aspartic acid, glutamic acid, ornithine, etc.), or a linked M6PR binding moiety; r is 1 to 10 (e.g., r is 1 to 5), t is 1 to 11 (e.g., t is 1 to 5), u is 0 to 5 (e.g., u is 0, 1, or 2); s is 1 to 50 (e.g., s is 1 to 20, 1 to 10, or 1 to 5) Includes a scaffold.

[0235] It is understood that the C-terminal carboxylic acid group of formulas (VIIIa)-(VIIIb) can provide for coupling (e.g., via a chemoselective linking group) to an additional linking moiety (e.g., one or more amino acid residues) and / or to a moiety of interest (Y) (e.g., as described herein).

[0236] In some embodiments of (VIIIa) or (VIIIb), r is 1 to 3. In some embodiments of (VIIIa) or (VIIIb), t is 3 to 11, for example, 3 to 5. In some embodiments of (VIIIa) or (VIIIb), u is 1. In some embodiments of (VIIIa) or (VIIIb), s is at least 2. In some embodiments of (VIIIa) or (VIIIb), s is 2 to 10, for example, 2 to 5, for example, 2 or 3.

[0237] In some embodiments of (VIIIa) or (VIIIb), r is 1 to 3, t is 3 to 5, u is 0 or 1, and s is 2 to 5 (eg, 2 or 3).

[0238] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 1, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 1, and u is 0.

[0239] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 2, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 2, and u is 0.

[0240] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 3, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 1, r is 3, and u is 0.

[0241] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 1, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 1, and u is 0.

[0242] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 2, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 2, and u is 0.

[0243] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 3, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 2, r is 3, and u is 0.

[0244] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 1, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 1, and u is 0.

[0245] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 2, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 2, and u is 0.

[0246] In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 3, and u is 1. In some embodiments of (VIIIa) or (VIIIb), t is 3, s is 3, r is 3, and u is 0.

[0247] 5.3.1. Exemplary Linkers and Linking Moieties Exemplary linkers and linking moieties that can be utilized in preparing compounds of the present disclosure (e.g., linkers and linking moieties that connect the M6PR binding moiety (X) to the moiety of interest (Y) in formulas (XI)-(XV)) are shown in Tables 4-6.

[0248] In certain embodiments, the linker comprises a linear linker or linking moiety shown in Table 4. In certain embodiments, the linker comprises a linear linker or linking moiety shown in Table 5. In certain embodiments, the linker comprises a linear linker or linking moiety shown in Table 6. It is understood that a variety of terminal modifications to the exemplary linking moieties can be incorporated based on the synthetic procedure and / or conjugation chemistry utilized in preparing the present compounds.

[0249] Table 4 shows various example linkers or linking moieties used in the compounds described herein. In some embodiments of Formulas (XI)-(XV), the compound includes any one of the linkers or linking moieties shown in Table 4. [Table 4-1] [Table 4-2] [Table 4-3] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0250] Table 6 shows exemplary synthetic precursors of linker components used to prepare compounds of the present disclosure, for example, by conjugation chemistry. It is understood that various analogs of the structures shown in Table 6, which provide linkers of various lengths, are also encompassed by the present disclosure. It is understood that alternative chemoselective linking groups and other chemical functionalities can be incorporated as needed to prepare the desired linker. [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]

[0251] 5.4. Chemoselective Linking Groups In certain embodiments of Formulas (XI)-(XV), Y is a chemoselective linking group or a precursor thereof. A chemoselective linking group is a group or functional group having a reactive functionality that allows for conjugation to a compatible group of a second moiety. For example, the chemoselective linking 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-Pictet-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, dialkyl squarate chemistry, etc.

[0252] Table 6 shows exemplary synthetic precursors of linker components with various chemoselective linking groups that have been used to prepare compounds of the present disclosure. Various other chemical functional groups can also be incorporated to prepare desired linkers, as needed.

[0253] Chemoselective linking groups that can be used to link two moieties include, but are not limited to, amino (e.g., the N-terminal amino or lysine side chain group of a polypeptide), azide, arylazide, 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, hydrazide, maleimide, vinyl sulfone, 2-sulfonylpyridine, cyano-alkyne, thiol (e.g., cysteine ​​residue), disulfide or protected thiol, isocyanate, isothiocyanate, aldehyde, ketone, alkoxyamine, hydrazide, aminooxy, phosphine, HIPS hydrazinyl-indolyl group, or aza-HIPS hydrazinyl-pyrrolo-pyridinyl group, tetrazine, cyclooctene, squarate, and the like.

[0254] In some cases, the chemoselective linking group is capable of spontaneously conjugating to a compatible chemical group when the two groups are contacted under suitable conditions (e.g., copper-free click chemistry conditions). In some cases, the chemoselective linking group is capable of conjugating to a compatible chemical group when the two groups are contacted in the presence of a catalyst or other reactant (e.g., copper-catalyzed click chemistry conditions).

[0255] In some embodiments, the chemoselective linking group is a photoactive linking group. For example, upon irradiation with ultraviolet light, the diazirine group can form a reactive carbene that can insert into the C-H, N-H, and O-H bonds of a second moiety.

[0256] In some cases, Y is a reactive functional group or a precursor of a functional group capable of conjugation to a compatible group on a second moiety. For example, a carboxylic acid is a precursor to an active ester chemoselective linking group.

[0257] In certain embodiments, Y is a reactive moiety capable of forming a covalent bond to a polypeptide (e.g., with an amino acid side chain of the polypeptide bearing a compatible reactive group), which reactive moiety may be referred to as a chemoselective linking group.

[0258] Exemplary chemoselective linking groups, and their synthetic precursors, that can be adapted for use in the compounds of the present disclosure are shown in Table 6B. [Table 6B-1] [Table 6B-2] [Table 6B-3]

[0259] In Table 6B: [ka] may represent the point of attachment of Y to the linking moiety or to the linked X moiety (e.g., M6PR binding moiety).

[0260] 5.5. Conjugates Aspects of the present disclosure include conjugates of compounds described herein, such as compounds of Formula (XIII), where Y is a chemoselective linking group, with another moiety of interest. When such conjugates are prepared, one or more M6PR ligand-linker compounds can be attached or conjugated to another moiety of interest. For example, if the moiety of interest is a biomolecule, the chemoselective linking group of the M6PR ligand-linker compound can be conjugated to one or several sites on the biomolecule. It should be understood that such biomolecule conjugates of the present disclosure may be encompassed by Formulas (XI), (XII), and (II)-(III), as well as the formulae described below.

[0261] In some embodiments, the conjugate of the present disclosure has formula (XII): [ka] (In the formula, W is a non-hydrolyzable hydrophilic head group; Z 1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene; Z 2 are O, S, NR 21 , and C(R 22 )2, where each R 21 are 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; each A is independently a cyclic group (e.g., an optionally substituted aryl or heteroaryl linking moiety); each Z 3 are independently linking moieties, n is 1 to 500; m is 1 to 100; L is a linker, Y is a biomolecule) or a prodrug thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0262] In some embodiments of Formula (XII), A is phenyl and Z 2 If is O, then (i) W is -P(O)(OH)2, or (ii) the linker L comprises a backbone of at least 16 contiguous atoms and Y is a target binding moiety.

[0263] In some embodiments of Formula (XII), the cell surface mannose-6-phosphate receptor (M6PR) binding conjugate has the formula (XIIa): [ka] It is a conjugate of

[0264] In some embodiments of Formula (XII), the cell surface mannose-6-phosphate receptor (M6PR) binding conjugate has the formula (XIIa): [ka] It is a conjugate of

[0265] In some embodiments, the moiety of interest to which the M6PR binding moiety is linked is a biomolecule. In some embodiments, the moiety of interest is a biomolecule. In some embodiments, the biomolecule is selected from a polypeptide (e.g., a peptide or protein), a polynucleotide, a polysaccharide, a glycan, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment.

[0266] 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. In some embodiments, m is 1 when one M6PR binding moiety is linked to Y.

[0267] In some embodiments, one Y biomolecule is conjugated via a linker L to a single moiety (X) that specifically binds to cell surface M6PR. In some embodiments, one Y biomolecule is conjugated via a linker L to a single moiety (X) that specifically binds to cell surface M6PR. n and when n=1, it is conjugated to a (X n The (X -L)- group is said to be monovalent, and when n>1, n In some embodiments of the formulas described herein where Y is a biomolecule, Y is a group having two or more (X n -L)- group, and each (X n It is understood that the (-L)- group may itself be monovalent or polyvalent (e.g., divalent, trivalent, etc.). In such cases, the linked (Xn The ratio of -L)- groups to biomolecules may be referred to as 2 or greater.

[0268] In some embodiments of Formula (XII), the conjugate is produced from the conjugation of a compound of Formula (XIII), where Y is a chemoselective linking group with a biomolecule, and the conjugate has the formula (XXI): [ka] (In the formula, n is 1 to 3, m is the load number from 1 to 20, L is a linker, P is a biomolecule that specifically binds to a target protein, Z 5 is the remaining linking moiety resulting from the covalent bond between the chemoselective linking group located at the terminus of the linker of formula (XIII) and the compatible group of P. or a prodrug thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (XXI), Z 2 is attached to the anomeric position of the pyranose ring having a β-configuration. Depending on the chemoselective linking group and conjugation chemistry used, m may be an average loading number (also referred to herein as DAR), or m may be a specific loading number (e.g., m is 1 or 2).

[0269] In some embodiments of Formula (XXI), the conjugate has the formula (XXIa): [ka] It is a conjugate of

[0270] In some embodiments of Formula (XXI), the conjugate has the formula (XXIa): [ka] It is a conjugate of

[0271] In some embodiments of Formulas (XXI)-(XXIb), n is 1.

[0272] In some embodiments of Formulas (XXI)-(XXIb), n is 2.

[0273] In some embodiments of Formulas (XXI)-(XXIb), n is 3.

[0274] In some embodiments of Formulas (XXI)-(XXIb), n is 4.

[0275] In some embodiments of Formulas (XXI) to (XXIb), n is 5 or greater, e.g., n is 5 to 500, 5 to 100, 5 to 50, 5 to 20, or 5 to 10. In some embodiments of Formulas (XXI) to (XXIb), n is 5. In some embodiments of Formulas (XXI) to (XXIb), n is 10 to 100, e.g., 10 to 50, 10 to 20, or 20 to 50. In some embodiments of Formulas (XXI) to (XXIb), L comprises a polypeptide, e.g., a polylysine or polyserine derivative. In some embodiments of Formulas (XXI) to (XXIb), L is a polypeptide-containing linker in which one M6PR binding moiety (X) is bound to L for each amino acid residue of the polypeptide.

[0276] In some embodiments of Formulas (XXI)-(XXIb), m is the average loading number of M6PR binding moieties (X) on the biomolecule P. For example, it is understood that when lysine conjugation chemistry is used to link X to P and P contains multiple lysine residues, m will refer to the average loading number.

[0277] In some embodiments of Formulas (XXI)-(XXIb), m is 1 to 10, for example, 1 to 8, 1 to 7, or 1 to 6. In some embodiments of Formulas (XXI)-(XXIb), m is 2 to 20, for example, 2 to 10, 2 to 8, 2 to 7, or 2 to 6. In some embodiments of Formulas (XXI)-(XXIb), m is at least 3. In some embodiments of Formulas (XXI)-(XXIb), m is at least 4.

[0278] In some embodiments of Formulas (XXI)-(XXIb), m is about 8, about 7, about 6, about 5, about 4, about 3, or about 2.

[0279] In some embodiments of Formulas (XXI)-(XXIb), n is 1 and m is 1 to 10. In some embodiments of Formulas (XXI)-(XXIb), m is 2 to 8 (e.g., 2 to 6, or 3 to 5). In some embodiments of Formulas (XXI)-(XXIb), m is about 4.

[0280] In some embodiments of Formulas (XXI)-(XXIb), m is the specific loading number of the M6PR binding moiety (X) on the biomolecule P. For example, it is understood that m refers to the specific loading number when site-specific conjugation chemistry is used to link X to P via a linker. In some embodiments of Formulas (XXI)-(XXIb), m is 1. In some embodiments, the biomolecule P is a polypeptide having a single conjugation site. In some embodiments of Formulas (XXI)-(XXIb), m is 2. In some embodiments, the biomolecule P is an antibody. In some embodiments, the biomolecule P is an antibody fragment.

[0281] In some embodiments of Formulas (XXI)-(XXIb), n is 2 and m is 1 to 6 (e.g., 2 to 6, or 3 to 5). In some embodiments of Formulas (XXI)-(XXIb), m is about 4.

[0282] In some embodiments of Formulas (XXI)-(XXIb), n is 3 and m is 1 to 6 (eg, 2 to 6, or 3 to 5).

[0283] In some embodiments of Formulas (XXI)-(XXIb), Z 5 represents the moiety remaining from the covalent attachment of a thiol-reactive chemoselective linking group (e.g., maleimide) to one or more cysteine ​​residue(s) of P, e.g., [ka] (In the formula, [ka] represents the point of attachment to the linker L, [ka] represents the point of attachment to P)) is.

[0284] In some embodiments of Formulas (XXI)-(XXIb), Z 5 is the moiety remaining from the covalent attachment of an amine-reactive chemoselective linking group (e.g., PFP ester or TFP ester or NHS ester) to one or more lysine residue(s) of P, i.e., the amide bond -CONH-.

[0285] Further remaining part Z 5 and a chemoselective linking group, Z 5 The chemoselective linking groups from which are derived are described herein.

[0286] In some embodiments of Formulas (XXI)-(XXIb), L is Z 3 In some embodiments of Formulas (XXI)-(XXIb), L is a linear linker having a backbone of 16 or more consecutive atoms (e.g., a backbone of 16 to 100, 18 to 100, or 20 to 100 consecutive atoms) covalently linking Z to P. 3and a branched linker having a main chain of 14 or more consecutive atoms (e.g., 14 to 50, or 14 to 30 atoms, etc.) between the branched atom of the linker.

[0287] 5.5.1.Target binding moiety In a preferred embodiment, the moiety of interest is a molecule that specifically binds to a target of interest, i.e., a target-binding moiety. Therefore, the compound of the present disclosure may be referred to as a targeted protein degradation compound or conjugate. In such cases, the conjugate of the present disclosure can take up the target into cells after the target is non-covalently bound to the conjugate, followed by degradation in the lysosome. The present inventors have demonstrated that the conjugate of the present disclosure, which has a specific M6PR-binding moiety with a desired affinity and includes a linker with a desired valency and length, can simultaneously specifically bind to both M6PR and the target with high affinity. Therefore, the conjugate of the present disclosure can internalize and sequester the bound target protein in the lysosome of the cell, followed by degradation of the target protein.

[0288] The target binding moiety can be any moiety that has an affinity for the 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. In some embodiments, the affinity of the target binding moiety for the target protein is 10 nM or less, e.g., 1 nM or less.

[0289] 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 polypeptide (e.g., a peptide or protein), a polynucleotide, a polysaccharide, a glycan, an antibody, an antibody fragment, and a glycoprotein. The term polypeptide should be understood to encompass antibodies, antibody fragments, and glycoproteins.

[0290] 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.

[0291] In some embodiments, the target binding moiety is a glycan. In some embodiments, the target binding moiety comprises a glycan epitope of an autoantibody.

[0292] Polypeptides For example, in some embodiments of Formula (XXI), the target-binding moiety is a polypeptide (e.g., a peptide or protein target-binding motif, a protein domain, an engineered protein, a glycoprotein, an antibody, or an antibody fragment) that specifically binds to a target molecule, such as a target protein. In some embodiments, the target-binding moiety of a bifunctional compound of the present disclosure comprises a polypeptide that binds to a soluble (e.g., secreted) target protein of interest. In some embodiments, the target-binding moiety is a polypeptide ligand for a target, including a receptor ligand, or a receptor-binding portion or fragment of a receptor ligand, that binds to a target cell surface receptor.

[0293] Target-binding polypeptides may contain L-amino acids, D-amino acids, or both, depending on the source, and may contain any of a variety of natural amino acids, unnatural amino acids, and / or amino acid modifications or analogs known in the art. Useful modifications include N-terminal acetylation, amidation, methylation, etc.

[0294] In certain embodiments, the polypeptide (P) of the conjugate comprises a polypeptide that binds to a soluble (e.g., secreted) target protein of interest. In certain embodiments, for example, the target protein of interest is a ligand that binds to a cell surface receptor, and P comprises a ligand-binding portion of the cell surface receptor, or a biological equivalent thereof, e.g., the extracellular domain of the cell surface receptor, e.g., the ligand-binding domain of the extracellular domain of the cell surface receptor. In certain embodiments, the target protein of interest is a cell surface receptor, and P comprises a ligand that binds to the cell surface receptor, or a receptor-binding portion of the ligand, or a biological equivalent thereof.

[0295] In some embodiments, the polypeptide (P) of the conjugate of the present disclosure is a synthetic D protein binder of a target protein of interest, such as the VEGF-A-binding or PD1-binding D proteins described in WO2020198074 and WO2020198075.

[0296] Conjugates of polypeptides (i.e., Y is P), such as conjugates of antibodies (Ab) and compounds (X-LY, where Y is a chemoselective linking group), 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 may be prepared using any suitable method disclosed in the art (see, e.g., Bioconjugate Techniques (Hermanson ed., 2d ed. 2008)).

[0297] In certain embodiments of the conjugates described herein, L is attached to a lysine residue of P via an amide bond. In certain embodiments of the conjugates described herein, L is attached to a cysteine ​​residue of P via a thioether bond.

[0298] 5.5.1.2. Antibodies For example, in some embodiments of Formula (XXI), the target binding moiety is an antibody or antibody fragment that specifically binds to a target moiety, such as a target protein.

[0299] Thus, in this specification, the following formula (XXII): [ka] (In the formula, n is 1 to 20, m is the average load number from 1 to 80, each X is a moiety that binds to cell surface M6PR (e.g., X is X of formula (III) described herein); each L is a linker; each Z 5 is the moiety remaining from the covalent attachment of the chemoselective linking group to a compatible group on the Ab, Ab is an antibody or antibody fragment that specifically binds to the target protein. or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments of Formula (XXII), L is a linker (e.g., as described herein). In some embodiments of Formula (XXII), Xn-LZ 5 - is derived from a compound of formula (XIII) (eg, as described herein) where Y is a chemoselective linking group.

[0301] In some embodiments of Formula (XXII), L has the formula: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 5 , a, b, c, d, e, and n are defined herein) is a linker.

[0302] In certain embodiments of Formula (XXII), L is selected from the linkers in Tables 4-5.

[0303] In formula (XXII), Z 5 may be any convenient moiety remaining from the covalent attachment or conjugation of the chemoselective linking group (Y) to a compatible reactive group of the antibody (Ab). In some cases, the compatible reactive group of the antibody (Ab) is a group that may be a natural part of the biomolecule. In some cases, the compatible reactive group of the antibody (Ab) is a group that is introduced or incorporated into the biomolecule prior to conjugation. In such cases, the antibody (Ab) may be a modified version of the biomolecule. For example, a functional group (e.g., an amino group, a carboxylic acid group, or a thiol group) of the biomolecule may be modified to introduce a compatible chemoselective linking group (e.g., using a chemical reagent such as 2-haloacetyl or 2-iminothiolane, or via coupling of a linker group containing a chemoselective linking group such as an azide or alkyne).

[0304] In some embodiments of Formula (XXII), Z 5 teeth, [ka] (In the formula, [ka] represents the point of attachment to the linker L, [ka] represents the point of attachment to the Ab, W is CH, N, O, or S; Ab is antibody) is selected from.

[0305] In certain embodiments of Formula (XXII), Z 5 teeth, [ka] (In the formula, [ka] represents the point of attachment to the linker L, [ka] represents the point of attachment to the Ab, Ab is antibody) is selected from.

[0306] In certain embodiments of Formula (XXII), Z 5 teeth, [ka] (In the formula, [ka] represents the point of attachment to the linker L, [ka] indicates the point of attachment to Ab) is selected from.

[0307] In certain embodiments of formulas (XXI)-(XXII), Z 5 is derived from a chemoselective linking group disclosed herein.

[0308] In certain embodiments of Formulas (XXI)-(XXII), n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.

[0309] The M6PR-binding moiety may be site-specifically covalently linked to the antibody or antibody fragment via an optional linking moiety. The M6PR-binding moiety may be covalently linked to the antibody or antibody fragment via a site-specific cysteine ​​modification (e.g., L443C) on the antibody or antibody fragment and a thiol-reactive chemoselective linking group. The M6PR-binding moiety may be covalently linked to the antibody or antibody fragment via one or more lysine residues on the antibody or antibody fragment and an amine-reactive chemoselective linking group.

[0310] The M6PR binding moiety may be linked to the target-binding antibody or antibody fragment by a chimeric protein fusion, optionally via a spacer sequence.

[0311] In some embodiments, the conjugates of the present disclosure comprise 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.

[0312] In some embodiments, the antibody or antibody fragment specifically binds to a cancer antigen.

[0313] In some embodiments, the antibody or antibody fragment specifically binds to a hepatocyte antigen.

[0314] In some embodiments, the antibody or antibody fragment specifically binds to an antigen presented on a macrophage.

[0315] In some embodiments, the antibody or antibody fragment specifically binds to intact complement or a fragment thereof, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitope(s) within intact complement or a fragment thereof.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] In some embodiments, the antibody or antibody fragment specifically binds to a vascular endothelial growth factor (VEGF) protein, e.g., a human VEGF protein, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the VEGF protein.

[0320] 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.

[0321] In some embodiments, the antibody or antibody fragment specifically binds to fibroblast growth factor (FGF), e.g., human FGF, hi some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the FGF protein.

[0322] In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor (FGFR), such as human FGFR. In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor 2 (FGFR2) protein, such as human FGFR2 protein, such as FGFR2b protein. In some embodiments, the antibody or antibody fragment specifically binds to a fibroblast growth factor receptor 3 (FGFR3) protein, such as 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.

[0323] 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.

[0324] 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.

[0325] In some embodiments, the antibody specifically binds to an immune checkpoint inhibitor. In some embodiments, the antibody binds to one or more immunodominant epitopes within an 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 epitopes within the PD-1 protein.

[0326] 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.

[0327] In some embodiments, the antibody binds to TIM3. In some embodiments, the antibody binds to one or more immunodominant epitope(s) within TIM3.

[0328] In some embodiments, the antibody specifically binds to a lectin. In some embodiments, the antibody specifically binds to one or more immunodominant epitopes within a lectin. In some embodiments, the antibody binds to SIGLEC. In some embodiments, the antibody binds to one or more immunodominant epitopes within SIGLEC. In some embodiments, the antibody binds to a cytokine receptor. In some embodiments, the antibody binds to one or more immunodominant epitopes within a cytokine receptor. In some embodiments, the antibody binds to sIL6R. In some embodiments, the antibody binds to one or more immunodominant epitopes within sIL6R. In some embodiments, the antibody binds to a cytokine. In some embodiments, the antibody binds to one or more immunodominant epitopes 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.

[0329] 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.

[0330] In some embodiments, the target-binding moiety is a biological agent that is an antagonist of a TNF protein (e.g., TNF-α). Many biological agents (e.g., monoclonal antibody drugs) have been developed to inhibit the binding of TNF to TNF receptors and have been shown to be clinically effective in many autoinflammatory diseases.

[0331] In certain embodiments of the conjugates described herein, L is attached to a lysine residue of P via an amide bond. In certain embodiments of the conjugates described herein, L is attached to a cysteine ​​residue of P via a thioether bond. In certain embodiments of the conjugates described herein, L is attached to a lysine residue of Ab via an amide bond, as described above. In certain embodiments of the conjugates described herein, L is attached to a cysteine ​​residue of Ab via a thioether bond, as described above. In certain embodiments of the conjugates described herein, L is attached to two cysteine ​​residues of Ab via two thioether bonds, the two cysteine ​​residues being derived from cleaved cysteine-cysteine ​​disulfide bonds of Ab, as described above. In certain embodiments, the cleaved cysteine-cysteine ​​disulfide bonds are interchain disulfide bonds.

[0332] In certain embodiments of the conjugates described herein, when L is attached to a lysine residue of P 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.

[0333] In certain embodiments, conjugation to a polypeptide P or antibody Ab may be via site-specific conjugation. Site-specific conjugation can, for example, result in uniform loading and minimize conjugate subpopulations with potentially altered antigen binding or pharmacokinetics. In certain embodiments, for example, conjugation can involve engineering cysteine ​​substitutions at positions on the polypeptide or antibody, such as positions on the heavy and / or light chains of an antibody, that provide reactive thiol groups and do not disrupt folding and assembly of the polypeptide or antibody, or that alter binding of the polypeptide or antigen (see, e.g., Junutula et al., J. Immunol. Meth. 2008;332:41-52, and Junutula et al., Nature Biotechnol. 2008;26:925-32, and see also WO2006 / 034488, which is incorporated by reference in its entirety. In another non-limiting approach, selenocysteine ​​is co-translationally inserted into a polypeptide or antibody sequence by recoding the stop codon UGA from a termination to a selenocysteine ​​insertion, allowing site-specific covalent conjugation with 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, for example, engineering unnatural amino acids, including 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, 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 contents of each of which are incorporated by reference in their entirety. See also US2019 / 0060481A1 and US2016 / 0060354A1, the contents of each of which are incorporated by reference in their entirety. All such methodologies are contemplated for use in connection with making the conjugates described herein.

[0334] The loading number of compounds of Formulae (I) and (III)-(IIIb) onto a polypeptide (e.g., an antibody) described herein is represented by "m" in various formulas 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 number of a conjugate. The number of "X" moieties (e.g., M6P moieties) per each "Xn-L-" or "Xn-" unit is represented by "n" in the formulas. As used herein, the term "valency(ies)" refers to the number of "X" moieties ("n") per unit. It will be understood that the loading number or DAR is not necessarily equivalent to 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, then there is 1 x 1 = 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 are 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(ies)" refers to the total number of "X" moieties (n x m; total valency) per conjugate molecule.

[0335] The DAR (loading number) ranges from 1 to 80 units per conjugate. The conjugates provided herein can include a collection of polypeptides, antibodies, or antigen-binding fragments conjugated with a range of units, e.g., 1 to 80. The average number of units per polypeptide or antibody in a conjugate preparation from a conjugation reaction can be characterized by conventional means, such as mass spectrometry. The quantitative distribution of DAR (loading number) with respect to m can also be measured. In some cases, separation, purification, and characterization of homogeneous conjugates with a particular value of m can be achieved by means, such as electrophoresis.

[0336] In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 80. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 70. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 60. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 50. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 40. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 35. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 30. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 25. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 20. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 18. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 15. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 12. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 10. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 9. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 8. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 7. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 6. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 5. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 4. In certain embodiments, the DAR of the conjugates provided herein ranges from 1 to 3. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 12.In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 10. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 9. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 8. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 7. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 6. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 5. In certain embodiments, the DAR of the conjugates provided herein ranges from 2 to 4. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 12. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 10. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 9. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 8. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 7. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 6. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 5. In certain embodiments, the DAR of the conjugates provided herein ranges from 3 to 4.

[0337] 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.

[0338] In certain embodiments, the DAR of 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 of 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.

[0339] In some embodiments, the DAR of the conjugates provided herein is in the range of 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 of the conjugates provided herein is in the range of 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 of the conjugates provided herein is about 1. In some embodiments, the DAR of the conjugates provided herein is about 2. In some embodiments, the DAR of the conjugates provided herein is about 3. In some embodiments, the DAR of the conjugates provided herein is about 4. In some embodiments, the DAR of the conjugates provided herein is about 3.8. In some embodiments, the DAR of the conjugates provided herein is about 5. In some embodiments, the DAR of the conjugates provided herein is about 6. In some embodiments, the DAR of the conjugates provided herein is about 7. In some embodiments, the DAR of the conjugates provided herein is about 8. In some embodiments, the DAR of the conjugates provided herein is about 9. In some embodiments, the DAR of the conjugates provided herein is about 10. In some embodiments, the DAR of the conjugates provided herein is about 11. In some embodiments, the DAR of the conjugates provided herein is about 12. In some embodiments, the DAR of the conjugates provided herein is about 13. In some embodiments, the DAR of the conjugates provided herein is about 14. In some embodiments, the DAR of the conjugates provided herein is about 15. In some embodiments, the DAR of the conjugates provided herein is about 16. In some embodiments, the DAR of the conjugates provided herein is about 17. In some embodiments, the DAR of the conjugates provided herein is about 18.In some embodiments, the DAR of the conjugates provided herein is about 19. In some embodiments, the DAR of the conjugates provided herein is about 20.

[0340] In some embodiments, the DAR of the conjugates provided herein is about 25. In some embodiments, the DAR of the conjugates provided herein is about 30. In some embodiments, the DAR of the conjugates provided herein is about 35. In some embodiments, the DAR of the conjugates provided herein is about 40. In some embodiments, the DAR of the conjugates provided herein is about 50. In some embodiments, the DAR of the conjugates provided herein is about 60. In some embodiments, the DAR of the conjugates provided herein is about 70. In some embodiments, the DAR of the conjugates provided herein is about 80.

[0341] In certain embodiments, fewer than the theoretical maximum number of units are conjugated to a polypeptide, e.g., an antibody, during a conjugation reaction. The polypeptide may contain, for example, lysine residues that do not react with a compound or a linker reagent. Generally, for example, antibodies do not contain many free and reactive cysteine ​​thiol groups that can be linked to a Drug unit; in fact, most cysteine ​​thiol residues of antibodies exist as disulfide bridges. In certain embodiments, antibodies can be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) under partial or total reducing conditions to generate reactive cysteine ​​thiol groups. In certain embodiments, the antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine. In some embodiments, a 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.

[0342] In certain embodiments, the amino acid that binds to the unit is present in the heavy chain of the antibody. In certain embodiments, the amino acid that binds to the unit is present in the light chain of the antibody. In certain embodiments, the amino acid that binds to the unit is present in the hinge region of the antibody. In certain embodiments, the amino acid that binds to the unit is present in the Fc region of the antibody. In certain embodiments, the amino acid that binds to the unit is present in the constant region of the antibody (e.g., CH1, CH2, or CH3 of the heavy chain, or CH1 of the light chain). In yet other embodiments, the amino acid that binds to the unit or Drug Unit is present in the VH framework region of the antibody. In yet other embodiments, the amino acid that binds to the unit is present in the VL framework region of the antibody.

[0343] The DAR (loading number) of the conjugate can be controlled in different ways, for example, by (i) limiting the molar excess of the compound or conjugation reagent compared to the polypeptide, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limited reducing conditions for cysteine ​​thiol modifications, or (iv) manipulating the amino acid sequence of the polypeptide by recombinant techniques such that the number and position of cysteine ​​residues are altered to adjust the number and / or position of linker-drug bonds (such as thiomab prepared as disclosed in WO2006 / 034488, which is incorporated herein by reference in its entirety).

[0344] It should be understood that the preparation of the conjugates described herein may produce a mixture of conjugates with a distribution of one or more units that bind to polypeptides, such as antibodies.Individual conjugate molecules in the mixture can be identified by mass spectrometry and separated by HPLC, for example, hydrophobic interaction chromatography, including such methods known in the art.In certain embodiments, homogeneous conjugates with a single DAR (loading number) value can be isolated from the conjugation mixture by electrophoresis or chromatography.

[0345] 5.5.1.3.Small molecules 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 a ligand of the target protein. The small molecule target-binding moiety may be covalently linked to one or more M6PR-binding moieties via a linker. The linker may be attached to the small molecule via substitution at any suitable site on the small molecule such that binding to the target protein is substantially maintained.

[0346] 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 a target of interest may be adapted for use in the subject compounds and conjugates.

[0347] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of VEGF. In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of PD-L1.

[0348] 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.

[0349] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of a TNF protein (e.g., TNF-alpha). TNF-alpha (TNFα) is a soluble cytokine produced by monocytes and macrophages as part of immune and inflammatory processes and is involved in a diverse range of cellular responses, including differentiation, proliferation, inflammation, and cell death. TNFα is a type II transmembrane protein that may be cleaved and secreted in 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 regulation of intracellular NF-κB, JNK, and p38-MAPK signaling pathways.

[0350] 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. Compounds of the present disclosure can include potent TNFα inhibitors, e.g., 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 in TNFα and stabilizes the trimer unit in an asymmetric conformation that causes the TNFα trimer to recruit only two of the three copies of a TNF receptor (TNFR, e.g., TNFR1), resulting in an incompetent TNFα-TNFR signaling complex.

[0351] 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, which discloses an analysis of the X-ray co-crystal structure of exemplary inhibitors bound to TNFα. Allosteric desymmetrized TNFα inhibitors act via specific mechanisms of action and can exhibit potent inhibitory activity. For example, (a) the binding site of TNFα inhibitors is a cavity within the TNFα trimer created 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, largely disrupting one TNFR-binding site and slightly disrupting a second site, while leaving the third site intact, and (d) allosteric desymmetrizing TNFα inhibitors regulate TNF-R activity through an allosteric mechanism rather than direct competition with TNFR. Thus, binding of allosteric desymmetrizing TNFα inhibitors to a symmetric TNFα trimer can result in the formation of an asymmetric trimer that prevents the recruitment of the three TNF receptor molecules required for signal transduction.

[0352] 5.5.2.Target As summarized above, the bifunctional compounds of the present disclosure may include a moiety of interest (Y) that specifically binds to a target molecule, which may be a cell surface molecule or an extracellular molecule.

[0353] In some embodiments of the compounds and methods of the present disclosure, the target molecule is a cell surface molecule. By "cell surface molecule" is meant a target molecule that is associated with a cell membrane, for example, because 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 may be any cell surface molecule for which targeted degradation via the endosomal / lysosomal pathway is desirable. In some embodiments, the cell surface molecule is a cell surface receptor.

[0354] 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.

[0355] In some embodiments, the moiety of interest (Y) specifically binds to a cell surface molecule that mediates its effect through bulk biophysical or aggregation effects rather than through specific molecular interactions (and therefore less susceptible to blocking). 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, etc.

[0356] In some embodiments, when the 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, which can be characterized by, for example, one or more of aberrant cell growth, aberrant cellular 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 any suitable indicator of cellular transformation. "Cancer cell" may be used interchangeably herein with "tumor cell," "malignant cell," or "cancerous cell" and includes cancer cells such as solid tumors, semi-solid tumors, hematological malignancies (e.g., leukemia cells, lymphoma cells, myeloma cells, etc.), primary tumors, and metastatic tumors. In some embodiments, the cell surface molecule present on the cancer cell is a tumor-associated antigen or a tumor-specific antigen. In certain aspects, when the moiety of interest (Y) specifically binds 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 the 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 may be inhibited according to the methods of the present disclosure include sialic acid-binding Ig-like lectin (Siglec) receptors, such as Siglec 7 and Siglec 9. Further examples of inhibitory immunoreceptors that may be inhibited according to the methods of the present disclosure include C-type lectins, including, but not limited to, CLEC4A (DCIR), Ly49Q, and MICL. More information regarding inhibitory immunoreceptors can be found, for example, in Steevels et al. (2011) Eur. J. Immunol. 41(3):575-587. In some embodiments, the cell surface molecule present on the immune cell is a ligand of an inhibitory immunoreceptor. In certain aspects, the cell surface molecule present on the immune cell is an immune checkpoint molecule. Non-limiting examples of immune checkpoint molecules to which the moiety of interest (Y) may specifically bind include PD-1, PD-L1, CTLA4, TIM3, LAG3, TIGIT, and members of the B7 family.

[0357] In some embodiments of the compounds and methods of the present disclosure, the target molecule is an extracellular molecule. By "extracellular molecule" is meant a soluble molecule that is located outside the cell membrane of any cell in the vicinity of the soluble molecule. The extracellular molecule may be any extracellular molecule for which targeted degradation via the endosomal / lysosomal pathway is desirable.

[0358] 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), any chemokine or cytokine (e.g., 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., for peanut allergy), a protein toxin (e.g., snake venom hyaluronidase, etc.), an autoantibody, etc.

[0359] In some embodiments, the target molecule is an extracellular molecule that is an antibody, e.g., an antibody that specifically binds 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, the 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 expressed on immune effector cells to initiate inflammatory responses. Abnormal IgA expression is involved in 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 bind 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 IG4-associated diseases. In some embodiments, the target is human immunoglobulin E (IgE). IgE is a type of immunoglobulin that plays an important role in type I hypersensitivity, which can manifest in a variety of allergic disorders and diseases.

[0360] 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 b (TGF-b) (including certain subtypes of such cytokines)), hormones, etc. In certain embodiments, the moiety of interest (Y) specifically binds to apolipoprotein E4 (ApoE4).

[0361] 5.5.3. Moieties of Interest for Intracellular Delivery In some embodiments, the moiety of interest is a molecule that does not bind to an extracellular target, but rather is itself a molecule desirable for intracellular delivery, 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, or a therapeutic antibody.

[0362] 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, and the like.

[0363] In some embodiments, the moiety of interest Y is a nanoparticle suitable for delivery of one or more drugs or cargo within the nanoparticle.

[0364] 5.5.3.1. Conjugates for Enzyme Replacement Therapy In some embodiments, the moiety of interest is a lysosomal enzyme for delivery to cells for use in enzyme replacement therapy, such as acid α-glucosidase (GAA). Lysosomal enzymes of interest that can be adapted for use in the conjugates of the present disclosure include acid α-glucosidase, acid β-galactosidase-1, acid sphingomyelinase, α-D-mannosidase, α-fucosidase, α-galactosidase A, α-glucosaminide acetyltransferase, α-glucosidase, α-L-iduronidase, α-N-acetylgalactosaminidase, α-acetylglucosaminidase, α-D-neuraminidase, arylsulfatase A, arylsulfatase B, β-galactosidase, β-glucuronidase, β-mannosidase, cathepsin D, cathepsin K, ceramidase, cystinosin, ganglioside activator GM2, These include, but are not limited to, galactocerebrosidase, glucocerebrosidase, heparan sulfatase, hexosaminidase A, hexosaminidase B, hyaluronidase, iduronate-2-sulfatase, LAMP2, lysosomal acid lipase, N-acetylglucosamine-1-phosphotransferase, N-acetylgalactosamine-6-sulfatase, N-acetylglucosamine-1-phosphotransferase, N-acetylglucosamine-6-sulfatase, N-aspartyl-β-glucosaminidase, palmitoylthioesterase-1, acid phosphatase, protective protein / cathepsin A (PPCA), sialin, and tripeptidyl peptidase 1.

[0365] Conjugation to an enzyme can be achieved using the methods described herein for preparing polypeptide and antibody conjugates.

[0366] 5.5.3.2. Modified Virus Compositions for Viral Transduction In certain embodiments, Y is a viral composition comprising 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. Conjugation of one or more compounds of the present disclosure to the viral composition produces a modified viral composition that exhibits enhanced viral transduction compared to an unlabeled viral composition.

[0367] 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 envelope protein), linked (e.g., directly or indirectly (e.g., via an intervening linker sequence)) to an M6PR-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).

[0368] 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., capsid protein or envelope protein, or fragment thereof, described herein.

[0369] In certain embodiments, the viral compositions described herein may comprise viral particles. The terms "virus particle," "viral particle," "virus vector," or "viral vector" are used interchangeably herein. A "viral particle" refers to a viral capsid and a polynucleotide (DNA or RNA), which may comprise the viral genome, a portion of the viral genome, or a polynucleotide derived from the viral genome (e.g., one or more ITRs), which optionally comprises a transgene. In certain cases, a viral particle further comprises an envelope (generally comprising a lipid portion and envelope proteins) surrounding or partially surrounding the capsid.

[0370] Viral particles may also be referred to as "recombinant viral particles" or "recombinant virus particles," as that term is used herein to refer to viral particles that have been genetically altered, 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 optional outer envelope) within which is encapsulated a polynucleotide sequence that includes sequences of viral and non-viral origin (i.e., a polynucleotide heterologous to the virus). This polynucleotide sequence is generally the sequence that is the subject of cellular genetic alteration.

[0371] In certain aspects, the viral compositions described herein, when referred to herein in the context of viruses, may comprise a "viral capsid," "empty viral particle," "empty virus particle," or "capsid," or "empty particle," 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.

[0372] 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).

[0373] In some embodiments, lentiviral vectors can be used for CAR-T gene delivery, vaccines, or research tools (e.g., to introduce genes into mature T cells to elicit immunity against cancer through delivery of chimeric antigen receptors (CARs) or cloned T cell receptors).

[0374] Naturally occurring AAV forms viral particles that include a three-dimensional capsid coat or shell ("capsid") composed of capsid proteins (VP1, VP2, and VP3) and the AAV viral genome contained within the capsid.

[0375] The modified AAV compositions provided herein, e.g., AAV conjugates or fusions, may comprise any AAV composition described herein, e.g., any AAV particle, capsid, or capsid protein described herein, or a fragment thereof. The term "AAV capsid protein" or "AAV cap protein" refers to a protein encoded by an AAV capsid gene (e.g., VP1, VP2, and VP3) or a variant or fragment thereof. The 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 from any AAV serotype, such as AAV1, AAV2, AAV2i8, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAVrhlO, AAV11, AAV12, AAV13, AAV-DJ, AAV3b, AAVLK03, AAVrh74, AAVAnc81, Anc82, Anc83, Anc84, AncllO, Ancll3, Anc126, or Anc127, AAV_go.1, AAVhu.37, or AAVrh.8, or variants thereof.

[0376] 5.5.3.3. Bridging Moieties Binding to Viral Compositions In some embodiments, Y is a bridging moiety that specifically binds to the viral composition, e.g., a viral particle, a viral capsid, a viral envelope, or a viral protein (e.g., a viral capsid protein or an envelope protein), provided that the binding is not via a covalent bond. Such conjugates may be useful for enhancing intracellular delivery and viral transduction of targeted viral compositions.

[0377] 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) may be adapted for use in the cross-linking moiety conjugates of the present disclosure.

[0378] 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, such as 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 binds to a viral capsid protein or a viral envelope protein.

[0379] 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, via binding to the viral protein incorporated into the viral particle. Similarly, in certain embodiments, a bridging moiety that binds to a viral particle may also bind to the 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.

[0380] 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).

[0381] Antibodies or antigen-binding fragments that can be utilized in connection with the modified virus compositions provided herein, for example, in connection with the crosslinking compositions and crosslinking moieties provided herein, include, but are not limited to, monoclonal antibodies, antibody compositions with specificity for multiple epitopes or for a single epitope, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies, so long as they exhibit the desired biological activity) formed from at least two intact antibodies, single-chain antibodies, and fragments thereof (e.g., domain antibodies).

[0382] 5.6. Exemplary Conjugates Exemplary monomeric compounds of the present disclosure containing chemoselective linking groups are shown in Table 7 and can be used to prepare conjugates of desired moieties. [Table 7]

[0383] Exemplary dimeric (n=2) compounds of the present disclosure containing chemoselective linking groups are shown in Table 8 and can be used to prepare conjugates of moieties of interest. [Table 8]

[0384] Structures of exemplary monomeric (n=1) compounds of the present disclosure containing chemoselective linking groups are shown in Table 9 and can be used to prepare conjugates of moieties of interest. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 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] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 11]

[0385] Structures of exemplary multivalent (n>1) compounds of the present disclosure are shown in Table 12 and can be used to prepare conjugates of moieties of interest. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8]

[0386] Structures of exemplary multivalent (n>1) compounds of the present disclosure are shown in Table 12B and can be used to prepare conjugates of moieties of interest. [Table 12B-1] [Table 12B-2] [Table 12B-3] [Table 12B-4] [Table 12B-5] [Table 12B-6] [Table 12B-7] [Table 12B-8] [Table 12B-9] [Table 12B-10] [Table 12B-11] [Table 12B-12] [Table 12B-13] [Table 12B-14] [Table 12B-15]

[0387] 5.7. Further Experimental Observations Without being bound by any particular mechanism or theory, within certain desired ranges, the binding affinity of an M6PR ligand may be inversely correlated with a longer half-life of the resulting compounds and conjugates, and selecting a desired binding affinity may be useful for tuning (e.g., altering) the pharmacokinetic properties of the conjugates described herein. In certain embodiments, compounds or conjugates having structures described herein may be selected to have a binding affinity for cell-surface M6PR that is sufficiently stable to internalize and / or degrade the target while providing the desired pharmacokinetic properties (e.g., sufficient half-life).

[0388] Pharmaceutical Compositions In another embodiment, provided herein is a pharmaceutical composition comprising one or more conjugates disclosed herein and a pharmaceutically acceptable carrier.

[0389] In certain embodiments, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of one or more of the conjugates provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. The pharmaceutical compositions may be useful for the prevention, treatment, management, or amelioration of a disease or disorder described herein, or one or more symptoms thereof.

[0390] Pharmaceutical carriers suitable for administration of the conjugates provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0391] The conjugates described herein may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

[0392] 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 as transdermal patches and dry powder inhalants.

[0393] In the compositions provided herein, the conjugates described herein may be mixed with a suitable pharmaceutical carrier, and the concentration of the conjugate in the composition may be, for example, effective to deliver an amount upon administration that treats, prevents, or ameliorates a disease or disorder described herein, or a symptom thereof.

[0394] In certain embodiments, the pharmaceutical compositions provided herein are formulated for single-dose administration. To formulate the compositions, a weight fraction of the conjugate is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration such that the disease being treated is alleviated, prevented, or one or more symptoms are ameliorated.

[0395] The concentration of the conjugate in the pharmaceutical compositions provided herein will depend, for example, on the physicochemical properties of the conjugate, the administration schedule and amount administered, as well as other factors known to those of skill in the art.

[0396] 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 a suitable 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, including 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 or multiple dosage forms. As used herein, unit dosage form refers to an individually packaged, physically discrete unit suitable for human or animal (e.g., mammalian) subjects, 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 and syringes, and individually packaged capsules. Unit dosage forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container, and administered in separate unit-dosage form.Examples of multiple-dose forms include vials, bottles of capsules, or bottles.Therefore, in certain embodiments, a multiple-dose form is a plurality of unit doses that are not separated by packaging.

[0397] In certain embodiments, the conjugates herein are in the form of liquid pharmaceutical formulations. Liquid pharmaceutically administrable formulations can be prepared, for example, by dissolving, dispersing, or otherwise mixing the conjugate and any pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, glycols, etc., to form a solution or suspension. In certain embodiments, the pharmaceutical compositions provided herein to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents.

[0398] 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 containing between 0.005% and 100% antibody can be made, with the remainder consisting of a non-toxic carrier.

[0399] Parenteral administration, in certain embodiments, is characterized by subcutaneous, intramuscular, or intravenous injection, and is also contemplated herein. Injectables can be prepared in conventional forms as liquid solutions or suspensions, in solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. Other routes of administration may include enteral administration, intracerebral administration, intranasal administration, intraarterial administration, intracardiac administration, intraosseous injection, intrathecal administration, and intraperitoneal administration.

[0400] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders ready to be mixed with a solvent immediately before use, such as subcutaneous tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be mixed with a vehicle immediately before use, and sterile emulsions. The solutions may be either aqueous or non-aqueous.

[0401] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0402] 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.

[0403] Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0404] In certain embodiments, intravenous or intraarterial infusion of a sterile aqueous solution containing a conjugate described herein is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing a conjugate described herein, injected as needed to produce the desired pharmacological effect.

[0405] In certain embodiments, the pharmaceutical formulations are lyophilized powders, which can be reconstituted for administration as solutions, emulsions, and other mixtures. They may also be reconstituted and formulated as solids or gels.

[0406] The lyophilized powder is prepared by dissolving the conjugate provided herein in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The suitable solvent may contain an excipient that improves the stability or other pharmacological properties of the powder or a reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The suitable solvent may also contain a buffer such as phosphate citrate, sodium phosphate, or potassium phosphate, or, in certain embodiments, other such buffers known to those of skill in the art 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 dispensed into vials for lyophilization. The lyophilized powder can be stored under appropriate conditions, for example, at about 4°C to room temperature.

[0407] Reconstitution of this lyophilized powder with water for injection provides a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier.

[0408] In certain embodiments, the conjugates provided herein may be formulated for topical administration or application, for example, in the eye, for example, for topical application to the skin and mucous membranes, in the form of gels, creams, and lotions, as well as for application to the eye, or for intracisternal or intrathecal application. Topical administration is also contemplated for transdermal delivery, and for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0409] 5.9.How to use 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 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.

[0410] Removal of a target protein can refer to the reduction or depletion of the target protein from the cell surface or extracellular space, or the extracellular environment, i.e., the reduction or depletion of the amount of the target protein on the cell surface or in the extracellular environment. In some embodiments, the method is a method of reducing the amount or level of a target protein in a biological system or cell sample.

[0411] In one aspect, provided herein is a method for sequestering a polypeptide of interest (target protein) in the lysosomes of a cell using the conjugates 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 the conjugates described herein and degrading the polypeptide of interest.

[0412] In one aspect, provided herein are methods for degrading a polypeptide of interest (target protein) using the conjugates described herein.

[0413] 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.

[0414] In another aspect, the present invention provides a method for depleting the polypeptide of interest (target protein) described herein by administering to a subject in need thereof an effective amount of the conjugate or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein.In certain embodiments, the subject is a mammal (e.g., human).

[0415] In certain embodiments, the target protein is a membrane-bound protein, in certain embodiments, the target protein is a cell surface receptor, or in certain embodiments, the target protein is an extracellular protein.

[0416] In certain embodiments, the target protein is a VEGF protein, an EGFR protein, a VEGFR protein, a PD-L1 protein, an FGFR2 protein, or an FGFR3 protein.

[0417] In another aspect, a subject, e.g., a human in need thereof, is administered an effective amount of a conjugate or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein. Provided herein are methods for treating a disease or disorder by administering

[0418] 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), for example, by mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery, and / or any other method of physical delivery described herein or known in the art. In certain embodiments, administration is by intravenous infusion.

[0419] 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 the onset of, reduce the severity and / or duration of, and / or ameliorate a given disease, disorder, or condition, and / or its associated symptoms. These terms also encompass the amount necessary to alleviate, slow, or ameliorate the progression or progression of a given disease, alleviate, slow, or ameliorate the recurrence, development, or onset of a given disease, and / or improve or enhance the prophylactic or therapeutic effect(s) of another therapy, or act as a bridge to another therapy. In some embodiments, "effective amount" as used herein also refers to the amount of a conjugate described herein to achieve a particular result.

[0420] 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 treat the cancer. "Treatment" or "treatment" of cancer includes one or more of the following: (1) limiting / inhibiting cancer growth, e.g., limiting its occurrence; (2) reducing / preventing the spread of cancer, e.g., reducing / preventing metastasis; (3) Reducing cancer, e.g., causing cancer regression; (4) reducing / preventing cancer recurrence, and (5) Relieving cancer symptoms.

[0421] The terms "subject" and "patient" are used interchangeably. A subject may 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 provided herein. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In certain embodiments, the subject is a human.

[0422] The term "therapy(s)" can refer to any protocol(s), method(s), composition(s), formulation(s), and / or agent(s) that can be used in the prevention, treatment, management, or amelioration of 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 term "therapy(s)" refers to drug therapy, adjuvant therapy, radiation, 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 described herein or a pharmaceutical composition thereof.

[0423] In certain embodiments, the disease or disorder is treated by depletion of the target protein by degradation via the lysosomal pathway.

[0424] In certain embodiments, the disease or disorder is treated by depletion of certain proteins, e.g., soluble proteins, e.g., secreted proteins, cell surface proteins (e.g., cell surface receptor proteins, e.g., tyrosine kinase receptors, soluble cytokine receptors, and immune checkpoint receptors, e.g., EGFR, VEGFR, FGFR, and PD-L1), lectins, complement, lipoproteins, transport proteins, MHC class I and class II molecules, cytokines, chemokines, and / or receptors, or fragments or subunits of any of the foregoing.

[0425] In certain embodiments, the disease or disorder is cancer.

[0426] 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 neoplasms, non-small cell lung cancer (NSCLC), Ewing's sarcoma, and Hodgkin's lymphoma.

[0427] In certain embodiments, the cancer is a solid tumor.

[0428] In certain embodiments, the disease or disorder is an inflammatory or autoimmune disease.

[0429] In certain embodiments, the disease or disorder is an inflammatory disease.

[0430] In certain embodiments, the disease or disorder is an autoimmune disease.

[0431] 5.10.Definition It is to be understood that the present disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0432] 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.

[0433] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes a single compound as well as a combination of two or more compounds, reference to a "substituent" includes a single substituent as well as two or more substituents, etc.

[0434] In describing and claiming the present invention, certain terminology will be used in accordance with the definitions set out below. It will be understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may be included within more than one definition of a term.

[0435] As used herein, the phrases "for example," "for instance," "such as," or "including" are intended to introduce examples that further clarify a more general subject matter. These examples are presented solely as an aid in understanding the disclosure and are not intended to be limiting in any way.

[0436] 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 invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0437] The terms "protein" and "polypeptide" are used interchangeably. A protein may include moieties other than amino acids (e.g., it may be a glycoprotein, etc.) and / or may be otherwise processed or modified. Those of skill in the art will understand that a "protein" may refer to 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 may comprise multiple protein chains, for example, linked noncovalently or covalently, e.g., by one or more disulfide bonds, or associated by other means. In certain embodiments, a polypeptide may exist as a single chain or as two or more associated chains, e.g., as a multimer, e.g., a dimer, a trimer. The term also encompasses amino acid polymers that have been modified, either naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or other manipulation or modification. Also included within the definition are 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, and the like. 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.

[0438] The terms "antibody" and "immunoglobulin" are terms of art and may be used interchangeably herein in their broadest sense, including a specific type of immunoglobulin molecule that contains one or more antigen-binding domains that specifically bind to an antigen or epitope.

[0439] In certain embodiments, an isolated antibody (e.g., a monoclonal antibody) described herein, or an antigen-binding fragment thereof that specifically binds to a protein of interest, e.g., EGFR, is conjugated to one or more lysosomal targeting moieties, e.g., via a linker.

[0440] An "antigen" is a moiety or molecule containing an epitope to which an antibody can specifically bind. Thus, an antibody also specifically binds to an antigen. 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).

[0441] "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 two or more non-contiguous regions of amino acids of the antigen.

[0442] The terms "binds," "binds to," "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 generally bind to other polypeptides with lower affinity, as measured, 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 refers to the affinity (K) with which the molecule binds to another antigen. d ) at least 2, 2.5, 3, or 4 logs lower thand In another specific embodiment, a molecule that specifically binds to an antigen does not cross-react with other proteins. In another specific embodiment, where EGFR is the protein of interest, a molecule that specifically binds to an antigen does not cross-react with other non-EGFR proteins.

[0443] Antibodies include, in particular, full-length antibodies (e.g., intact immunoglobulins), antibody fragments, monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain / antibody heavy chain pairs, antibodies having two light chain / heavy chain pairs (e.g., identical pairs), antibody fragments, and the like. Examples of antibodies include, but are not limited to, 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.

[0444] An antibody may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, the antibodies described herein are IgG antibodies (e.g., human IgG), or classes thereof (e.g., human IgG1, IgG2, IgG3, or IgG4), or subclasses thereof.

[0445] In certain embodiments, the antibody is a four-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs, wherein the amino acid sequences of the H chains are identical and the amino acid sequences of the L chains are identical. In certain embodiments, the H chain and L chain comprise a constant region, e.g., a human constant region. In even more particular 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.

[0446] The term "constant region" or "constant domain" is a well-known antibody term in the art (sometimes referred to as "Fc") and 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 may exhibit various effector functions, such as interaction with Fc receptors. These terms refer to portions of immunoglobulin molecules that generally have more conserved amino acid sequences compared to immunoglobulin variable domains.

[0447] The term "heavy chain" when used in reference to an antibody can refer to any of the different types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, including the IgG subclasses, e.g., IgG1, IgG2, IgG3, and IgG4, respectively, based on the amino acid sequence of the constant domain.

[0448] The term "light chain" when 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 its constant domain. Light chain amino acid sequences are well known in the art. In certain embodiments, the light chain is a human light chain.

[0449] 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 any particular method for producing the antibody. Generally, a population of monoclonal antibodies can be produced by a cell, a population of cells, 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 a host cell producing a recombinant antibody), which specifically binds to an epitope, as measured, for example, by ELISA or other antigen-binding or competitive binding assays known in the art or in the Examples provided 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 or multispecific antibody (e.g., a bispecific antibody).

[0450] The term "variable region" or "variable domain" refers to a portion of an antibody, generally a portion of either the light or heavy chain, usually from the amino terminus, approximately 110-120 amino acids in the mature heavy chain and approximately 90-100 amino acids in the mature light chain. The variable region comprises complementarity-determining regions (CDRs) flanked by framework regions (FRs). Generally, the spatial orientation of the CDRs and FRs, from N-terminus to C-terminus, is as follows: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen and the specificity of the antibody for the epitope. In certain embodiments, the numbering of the amino acid positions of the antibodies described herein is according to the EU index, such as 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.

[0451] 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, US Department of Health and Human Services, NIH Publication No. 91-3242), or (ii) the Chothia numbering scheme (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), herein referred to as "Chothia CDRs." 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 Dubel, 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., 1996, J. Mol. Biol., 262: The AbM CDRs can be determined according to the AbM numbering system, set forth in pp. 732-745, herein referred to 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) the contact numbering system, referred to herein as "contact CDRs," where the contact definitions are 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).

[0452] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody in a substantially intact form, and not an antibody fragment as defined below. These terms specifically refer to antibodies having heavy chains that include an Fc region.

[0453] An "antibody fragment" comprises only a portion of an intact antibody, which portion retains at least one, two, three, or most or all of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises the antigen-binding site of an intact antibody and thus retains the ability to bind to an antigen. In another embodiment, an antibody fragment, such as 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, antibody half-life modulation, 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 comprise a single 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.

[0454] "Polynucleotide" or "nucleic acid" are used interchangeably herein and refer 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. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides can also contain modified nucleotides, such as methylated nucleotides and their analogs. The nucleic acid molecule can be an aptamer.

[0455] The term "purified" refers to the isolation of a substance (compound, polynucleotide, protein, polypeptide, polypeptide composition) of interest such that the substance constitutes a majority of a sample containing said substance. Typically, a substantially purified component of a sample constitutes 50%, 80%-85%, 90-99%, e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% 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.

[0456] The terms "treatment," "treating," and the like refer to obtaining a desired pharmacological and / or physiological effect, such as reducing tumor burden. The effect may be prophylactic, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that the disease and / or side effects caused by the disease are partially or completely cured. As used herein, "treatment" encompasses any treatment of a disease in a mammal, particularly a human, and includes (a) preventing the onset of the disease or symptoms of the disease in a subject who is susceptible to the disease but has not yet been diagnosed with the disease (including, for example, diseases that may be associated with or caused by the primary disease, such as liver fibrosis that may occur in the context 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., reducing tumor burden).

[0457] The terms "individual," "host," "subject," and "patient" are used interchangeably herein and refer to animals including, but not limited to, humans and non-human primates, including apes and humans; rodents, including rats and mice, cows, horses, sheep, cats, dogs, etc. "Mammal" means a member or members of any mammalian species, including, for example, dogs, cats, horses, cows, sheep, rodents, etc., and primates, e.g., non-human primates, and humans. Non-human animal models, e.g., mammals, e.g., non-human primates, rats, rabbits, etc., may be used in experimental studies.

[0458] "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, illness, or disorder, is sufficient to effect such treatment for the disease, illness, or disorder. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated.

[0459] Unless otherwise specified, in cases where a compound can 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, if a compound is described as a particular optical isomer, D- or L-, both optical isomers are intended to be encompassed herein. For example, if a compound is described as having one of two tautomeric forms, both tautomers are intended to be encompassed herein. 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 provided herein may undergo epimerization in vivo. Thus, one of skill in the art will recognize that, for compounds that undergo epimerization in vivo, administering a compound in its (R) form is equivalent to administering the compound in its (S) form.

[0460] The present disclosure also encompasses all suitable isotopic variants of the compounds of the present disclosure, whether 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 having the same atomic number but an atomic mass different from the atomic mass that is usually or predominantly present in nature.Examples of isotopes that can be incorporated into compounds of the present disclosure include 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, and131 I is an isotope of I. Certain isotopic variants of the compounds of 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. 3 H, 14 C, and / or 18 Compounds labeled with F isotopes are suitable for this purpose. Additionally, the incorporation of isotopes, such as deuterium, may lead to certain therapeutic advantages as a result of greater metabolic stability of the compound, such as an increased half-life in the body or a reduced required active dose. In some embodiments, hydrogen atoms in the compounds described herein can 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 an amount substantially greater than its natural abundance, unless otherwise indicated. Isotopic variants of the compounds according to the present disclosure can be prepared in various ways, for example, by using corresponding isotopic modifications of certain reactants and / or starting compounds therein in the methods and examples described below.

[0461] Therefore, any of the embodiments described herein are intended to encompass salts, single stereoisomers, mixtures of stereoisomers, and / or isotopic forms of the compounds.

[0462] "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 are useful in the preparation of pharmaceutical compositions, including excipients, diluents, carriers, and adjuvants that are acceptable for veterinary as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipients, diluents, carriers, and adjuvants" includes both one and more of such excipients, diluents, carriers, and adjuvants.

[0463] "Pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that could induce an undesirable reaction in the subject (e.g., the compound(s) in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need of such composition via many different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, etc.

[0464] The term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0465] The term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with the tissues of humans and lower animals without causing undue toxicity, irritation, allergic reactions, etc. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Such salts can be prepared in situ during the final isolation and purification of the conjugate compound, or separately by reacting the free base functional group of the compound with an appropriate organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts or salts of amino groups formed with inorganic acids.

[0466] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O))-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, "C(O)-," "heterocyclyl-C(O)-," and "substituted heterocyclyl-C(O)-," where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. For example, acyl includes the "acetyl" group CHC(O)-.

[0467] The term "alkyl" refers to a branched or unbranched saturated hydrocarbon group (i.e., a monoradical) typically (but not necessarily) containing from 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl and cyclohexyl. Alkyl groups herein generally (but not necessarily) may contain from 1 to about 18 carbon atoms, and such groups may contain from 1 to about 12 carbon atoms. The term "lower alkyl" refers to an alkyl group of 1 to 6 carbon atoms. "Substituted alkyl" refers to an alkyl substituted with one or more substituents, including instances in which two hydrogen atoms are replaced from the same carbon atom in an alkyl substituent, such as in a carbonyl group (i.e., a substituted alkyl group may contain a -C(=O)- moiety). The terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl substituent in which at least one carbon atom is replaced with a heteroatom, as described in more detail below. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include straight-chain, branched-chain, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively.

[0468] The term "substituted alkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms in the alkyl chain are optionally replaced with a heteroatom, such as -O-, -N-, -S-, -S(O)n- (n is 0-2), -NR- (wherein R is hydrogen or alkyl), and includes alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thio is meant to include the above alkyl groups having 1 to 5 substituents selected from the group consisting of all, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and NRaRb (wherein R' and R'' are the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocycle).

[0469] The term "alkenyl" refers to a straight-chain, branched-chain, or cyclic hydrocarbon group containing at least one double bond and having 2 to about 24 carbon atoms, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Alkenyl groups herein generally (although not necessarily) may contain from 2 to about 18 carbon atoms, e.g., from 2 to 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to an alkenyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl, respectively.

[0470] The term "alkynyl" refers to a straight- or branched-chain hydrocarbon group containing 2 to 24 carbon atoms, such as ethynyl, n-propynyl, and the like, and containing at least one triple bond. Alkynyl groups herein generally (although not necessarily) may contain from 2 to about 18 carbon atoms, although such groups may also contain from 2 to 12 carbon atoms. The term "lower alkynyl" contemplates an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to an alkynyl substituted with one or more substituents, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to an alkynyl having at least one carbon atom replaced with a heteroatom. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" include straight-chain, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively.

[0471] The term "alkoxy" refers to an alkyl group attached through a single, terminal ether linkage. That is, an "alkoxy" group can be represented as -O-alkyl, where alkyl is as defined above. A "lower alkoxy" group refers to an alkoxy group having from 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. Substituents herein identified as "C1-C6 alkoxy" or "lower alkoxy" can contain, for example, 1 to 3 carbon atoms; as a further example, such substituents can contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0472] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0473] The term "aryl," unless otherwise specified, generally (though not necessarily) refers to an aromatic substituent containing 5 to 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings fused, directly linked, or indirectly linked together (such that different aromatic rings are bonded to a common group, such as a methylene or ethylene moiety). An aryl group may contain, for example, 5 to 20 carbon atoms; as a further example, an aryl group may contain 5 to 12 carbon atoms. For example, an aryl group may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc.). Examples include phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, etc. "Substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to an aryl substituent in which at least one carbon atom has been replaced with a heteroatom, as described in more detail below. Aryl includes stable cyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated C-C 14 Moieties are intended to include, but are not limited to, phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazolyl, pyrimidinyl, and oxazolyl, which may be further substituted with 1 to 5 members selected from the group consisting of hydroxy, C1-C8 alkoxy, C1-C8 branched or straight chain alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halogen, trifluoromethyl, cyano, and carboxyl (see, e.g., Katritzky, Handbook of Heterocyclic Chemistry). Unless otherwise indicated, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0474] The term "aralkyl" refers to an alkyl group having an aryl substituent, and the term "alkaryl" refers to an aryl group having an alkyl substituent, where "alkyl" and "aryl" are defined above. Generally, aralkyl and alkaryl groups herein contain 6 to 30 carbon atoms. Aralkyl and alkaryl groups can, for example, contain 6 to 20 carbon atoms, and as a further example, such groups can contain 6 to 12 carbon atoms.

[0475] The term "alkylene" refers to a diradical alkyl group. Unless otherwise indicated, such groups include saturated hydrocarbon chains containing 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may contain heteroatoms. "Lower alkylene" refers to an alkylene linkage containing 1 to 6 carbon atoms. Examples include methylene (--CH--), ethylene (--CHCH--), propylene (--CHCHCH--), 2-methylpropylene (--CH--CH(CH)--CH--), hexylene (--(CH)--), and the like.

[0476] Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and "alkarylene" refer to the diradical alkenyl, alkynyl, aryl, aralkyl, and alkaryl groups, respectively.

[0477] The term "amino" refers to the group -NRR', where R and R' are independently hydrogen or non-hydrogen substituents, including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and / or heteroatom-containing variants thereof.

[0478] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.

[0479] "Carboxyl", "carboxy", or "carboxylate" refers to -CO2H or its salts.

[0480] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0481] The term "substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0482] The term "heteroatom-containing," as in "heteroatom-containing alkyl group" (also referred to as "heteroalkyl" group) or "heteroatom-containing aryl group" (also referred to as "heteroaryl" group), refers to a molecule, bond, or substituent in which one or more carbon atoms have been replaced with an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent containing a heteroatom; the term "heterocycloalkyl" refers to a cycloalkyl substituent containing a heteroatom; the terms "heterocyclic" or "heterocycle" refer to cyclic substituents containing heteroatoms; the terms "heteroaryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents, respectively, that contain heteroatoms; and so forth. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyls, N-alkylated aminoalkyls, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, and the like; examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl, and the like.

[0483] "Heteroaryl" refers to an aromatic group having 1 to 15 carbon atoms in the ring, e.g., 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups can have a single ring (such as pyridinyl, imidazolyl, or furyl) or multiple condensed rings in the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring in the ring system is aromatic, provided that the point of attachment is through an atom in the aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atom(s) of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. The term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained in the definition of a heteroaryl substituent, such heteroaryl groups are optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl, and trihalomethyl.

[0484] The terms "heterocycle," "heterocyclic," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings (including fused bridged and spiro ring systems) and having 3 to 15 ring atoms, including 1 to 4 heteroatoms. These ring heteroatoms are selected from nitrogen, sulfur, and oxygen; in fused ring systems, one or more of the rings may be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atom(s) of a heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0485] Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenanthroline, phenanthiazole, phenanthroline ... These include, but are not limited to, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0486] Unless otherwise constrained in the definition of a heterocyclic substituent, such heterocyclic groups are optionally substituted with 1 to 5 or 1 to 3 substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0487] "Hydrocarbyl" refers to a monovalent hydrocarbyl radical, such as an alkyl group, an alkenyl group, or an aryl group, containing 1 to about 30 carbon atoms, including 1 to about 24 carbon atoms, including 1 to about 18 carbon atoms, and including about 1 to 12 carbon atoms, and including straight-chain, branched-chain, cyclic, saturated, and unsaturated species. The hydrocarbyl may be substituted with one or more substituents. The term "heteroatom-containing hydrocarbyl" refers to a hydrocarbyl in which at least one carbon atom has been replaced with a heteroatom. Unless otherwise indicated, the term "hydrocarbyl" should be interpreted as including substituted and / or heteroatom-containing hydrocarbyl moieties.

[0488] "Substituted," as in "substituted hydrocarbyl," "substituted alkyl," "substituted aryl," etc., as mentioned in some of the definitions above, means that at least one hydrogen atom bonded to a carbon (or other) atom in a hydrocarbyl, alkyl, aryl, or other moiety has been replaced with one or more non-hydrogen substituents. Examples of such substituents include, but are not limited to, functional groups and hydrocarbyl moieties, C1-C24 alkyl (including C1-C18 alkyl, further including C1-C12 alkyl, and further including C1-C6 alkyl), C2-C24 alkenyl (including C2-C18 alkyl, further including C2-C12 alkenyl, and further including C2-C6 alkenyl), C2-C24 alkynyl (including C2-C18 alkynyl, further including C2-C12 alkynyl, and further including C2-C6 alkynyl), C5-C30 aryl (including C5-C20 aryl, further including C5-C12 aryl), and C6-C30 aralkyl (including C6-C20 aralkyl, and further including C6-C12 aralkyl). The aforementioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically listed. Unless otherwise indicated, any group described herein should be interpreted as including substituted and / or heteroatom-containing moieties in addition to unsubstituted moieties.

[0489] "Sulfonyl" refers to the groups SO-alkyl, SO-substituted alkyl, SO-alkenyl, SO-substituted alkenyl, SO-cycloalkyl, SO-substituted cycloalkyl, SO-cycloalkenyl, SO-substituted cycloalkenyl, SO-aryl, SO-substituted aryl, SO-heteroaryl, SO-substituted heteroaryl, SO-heterocyclic, and SO-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Sulfonyl, by way of example, includes methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0490] The term "functional group" refers to halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (e.g., C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X (where X is halo). )), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH2), monosubstituted C1-C24 alkylcarbamoyl (-(CO)-NH(C1-C24 alkyl)), disubstituted alkylcarbamoyl (-(CO)-N(C1-C24 alkyl)2), monosubstituted arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbami amide (-NH-(CO)-NH2), cyano (-C≡N), isocyano (-N≡C-), cyanato (-OC≡N), isocyanato (-O-N≡C-), isothiocyanato (-SC≡N), azido (-N=N≡N-), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), mono- and di-(C1-C24 alkyl) substituted amino, mono- and di-(C5-C20 aryl) substituted amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C5-C20 arylamido (-NH-(CO)-aryl) aryl), imino (-CR=NH (where R=hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C20 alkaryl, C6-C20 aralkyl, etc.)), alkylimino (-CR=N(alkyl) (where R=hydrogen, alkyl, aryl, alkaryl, etc.)), arylimino (-CR=N(aryl) (where R=hydrogen, alkyl, aryl, alkaryl, etc.)), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl;"Ci-C alkylsulfinyl" refers to chemical groups such as C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), and phosphino (-PH2), mono- and di-(C1-C24 alkyl)-substituted phosphino, mono- and di-(C5-C20 aryl)-substituted phosphines. Furthermore, the aforementioned functional groups may be further substituted with one or more additional functional groups, or one or more hydrocarbyl moieties, such as those specifically listed above, if the particular group allows.

[0491] "Linkage" or "linker," as in "linking group," "linker moiety," etc., refers to a linking moiety that connects two groups via a covalent bond. The linker may be linear, branched, cyclic, or a single atom. Examples of such linking groups include alkyl, alkenylene, alkynylene, arylene, alkarylene, aralkylene, and linking moieties that contain functional groups, including, but not limited to, amide (-NH-CO-), ureylene (-NH-CO-NH-), imide (-CO-NH-CO-), epoxy (-O-), epithio (-S-), epidioxy (-OO-), carbonyldioxy (-O-CO-O-), alkyldioxy (-O-(CH2)nO-), epoxyimino (-O-NH-), epimino (-NH-), carbonyl (-CO-), and the like. In certain cases, one, two, three, four, or five or more carbon atoms of the linker backbone may be optionally substituted with sulfur, nitrogen, or oxygen heteroatoms. The bonds between the backbone atoms may be saturated or unsaturated, and typically there will be no more than one, two, or three unsaturated bonds in the linker backbone. The linker may include one or more substituents, such as alkyl, aryl, or alkenyl groups. Linkers may include, but are not limited to, poly(ethylene glycol) unit(s) (e.g., —(CH—CH—O)—), ether, thioether, amine, alkyl (e.g., (C1-C 12 ) alkyl) (which may be straight or branched, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), etc.). The linker backbone may comprise a cyclic group, e.g., an aryl, heterocycle, or cycloalkyl group, where two or more atoms, e.g., 2, 3, or 4 atoms, of the cyclic group are included in the backbone. Linkers may be cleavable or non-cleavable. Any convenient arrangement and / or attachment of the linker to the groups to be linked may be used.

[0492] When the term "substituted" appears before a list of possible substituents, it is intended that the term apply to all groups that make up that group. For example, the phrase "substituted alkyl and aryl" should be interpreted as "substituted alkyl and substituted aryl."

[0493] Further to the disclosure herein, the term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each independently replaced with the same or different substituents, as defined below.

[0494] In addition to the groups disclosed for each individual term herein, substituents replacing one or more hydrogens on a saturated carbon atom in a specified group or radical (any two hydrogens on a single carbon can be replaced by ═O, ═NR, etc.) are also included. 70 , =N-OR 70 , =N2, or =S) is, unless otherwise specified, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)O - M + , -C(O)OR 70, -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)O - M + , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 where R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; each R 70 are independently hydrogen or R 60 and each R 80 are independently R 70 Or, two R 80 together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl, which optionally contains 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S, wherein N may have —H or C1-C3 alkyl substitution; each M + is a counterion with a net single positive charge.+ are independent, e.g., K + , Na + , Li + Alkaline ions such as; + N(R 60 ) 4; or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The "subscript 0.5" contemplates that one of the counterions to such divalent alkaline earth ions may be an ionized form of a compound of the invention and the other may be a common counterion such as chloride, or a doubly ionized compound disclosed herein may serve as a counterion to such divalent alkaline earth ion, or a doubly ionized compound of the invention may serve as a counterion to such divalent alkaline earth ion.) Specific examples include -NR 80 R 80 is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methylpiperazin-1-yl, and N-morpholinyl.

[0495] Further to the disclosure herein, the substitution of hydrogen on an unsaturated carbon atom in a "substituted" alkene, alkyne, aryl, and heteroaryl group is represented by -R unless otherwise specified. 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3-2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 where R 60 , R 70 , R 80 , and M + is as defined above, except that in the case of a substituted alkene or alkyne, the substituent may be -O - M + , -OR 70 , -SR 70 , or -S - M+ isn't it.

[0496] In addition to the groups disclosed for each individual term herein, the substituents of the hydrogen on the nitrogen atom in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O - M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O - M + , -OS(O)2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 where R 60 , R 70 , R 80 , and M + is as defined above.

[0497] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0498] Unless otherwise indicated, substituents not explicitly defined herein are named by naming the terminal portion of the functional group, followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0499] With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include substitutions or patterns that are sterically impractical and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0500] In certain embodiments, substituents may contribute to the optical isomerism and / or stereoisomerism of the compound. Salts, solvates, hydrates, and prodrug forms of the compound are also of interest. All such forms are encompassed by the present disclosure. Thus, the compounds described herein encompass salts, solvates, hydrates, prodrugs, and isomers of the compound, including pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and isomers of the compound. In certain embodiments, the compound may be metabolized to a pharmaceutically active derivative.

[0501] Unless otherwise specified, a reference to an atom is intended to include isotopes of that atom. For example, a reference to H is 1 H, 2 H (i.e., D), and 3 is intended to encompass H (i.e., T), and reference to C is 12 C and all isotopes of carbon ( 13 C, etc.

[0502] Unless otherwise indicated, the term "about" or "approximately" refers to an acceptable error of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1%, or 0.05% of a given value or range. In certain embodiments requiring an integer, the term "about" means within ±10% of a given value or range, rounded up or down to the nearest integer.

[0503] In the description herein, if there is any discrepancy between a chemical name and a chemical structure, the chemical structure shall prevail.

[0504] Definitions of other terms and concepts are set forth throughout the detailed description.

[0505] M6PR binding compounds and conjugates are described in International Application No. PCT / US2021 / 012846, filed January 8, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0506] 5.11. Further Embodiments Further embodiments of the present disclosure are also described in the following clauses.

[0507] Article 1. Formula: [ka] or a salt thereof, During the ceremony, each W is independently a hydrophilic head group; each Z 1 are independently selected from optionally substituted (C-C)alkylene and optionally substituted ethenylene; each Z 2 However, independently, O, S, NR 21 , and C(R 22 )2, and each R 21 is independently selected from H and optionally substituted (C-C) alkyl, and each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C-C) alkyl; each Ar is independently an optionally substituted aryl or heteroaryl linking moiety (e.g., an optionally substituted monocyclic or bicyclic aryl or heteroaryl); each Z 3 are independently linking moieties, n is 1 to 500; L is a linker, Y is the target part, When m is 1 and Ar is phenyl, then: i) L comprises a backbone chain of at least 16 contiguous atoms; ii) Y is a biomolecule; and / or ii) Z 3 is an amide, sulfonamide, urea, or thiourea.

[0508] Clause 2. The compound of clause 1, wherein each Ar is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted triazole, and optionally substituted phenylene-triazole.

[0509] Clause 3. The compound of clause 2, wherein Ar is selected from optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, or optionally substituted 2,5-pyridylene.

[0510] Clause 4. The compound has the formula [ka] or a salt thereof, During the ceremony, Each R 11 ~R 14 are independently H, halogen, OH, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkoxy, COOH, NO, CN, NH, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 is selected from Each R 25 The compound of clause 3, wherein is independently selected from H and optionally substituted (C1-C6) alkyl.

[0511] Clause 5. The compound according to clause 1, wherein Ar is an optionally substituted fused bicyclic aryl or fused bicyclic heteroaryl.

[0512] Clause 6. The compound according to clause 5, wherein Ar is optionally substituted naphthalene or optionally substituted quinoline.

[0513] Clause 7. The compound has the formula: [ka] or a salt thereof, During the ceremony, Each R 11 and R 13 ~R 14 are independently H, halogen, OH, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkoxy, COOH, NO, CN, NH, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 is selected from s is 0 to 3, Each R 25 The compound of clause 6, wherein is independently selected from H and optionally substituted (C1-C6) alkyl.

[0514] Clause 8. The compound has the formula: [ka] 8. The compound according to clause 7, which is one of the compounds of the formula:

[0515] Clause 9. The compound according to claim 1, wherein Ar is an optionally substituted bicyclic aryl or an optionally substituted bicyclic heteroaryl, and the compound has the formula: [ka] or a salt thereof, During the ceremony, each Cy is independently monocyclic aryl or monocyclic heteroaryl; Each R 11 ~R 15are independently H, halogen, OH, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkoxy, COOH, NO, CN, NH, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 is selected from s is 0 to 4, Each R 25 is independently selected from H and optionally substituted (C1-C6) alkyl.

[0516] Clause 10. The compound according to claim 1, wherein Ar is an optionally substituted biphenyl, Cy is an optionally substituted phenyl, and the compound has the formula: [ka] 10. The compound according to clause 9, which is a compound of formula (I) or a salt thereof.

[0517] Clause 11. The compound has the following formula: [ka] 11. The compound according to clause 10, which is one of the compounds of the formula:

[0518] Clause 12. A compound according to any one of clauses 1 to 10, wherein Ar is substituted with at least one OH substituent.

[0519] Article 13.R 11 ~R 15 and n is H.

[0520] Article 14.R 11 ~R 15 The compound of any one of clauses 4, 6, 7, 9, and 10, wherein at least one of is OH (e.g., at least two are OH).

[0521] Article 15.Z 3 is a covalent bond, -O-, -NR 23 -, -NR 23 CO-, -CONR 23 -, -NR 23 CO2-, -OCONR 23 , -NR 23 C(=X 1 )NR 23 -, -CR 24 =N-, -CR 24 =NX 2 , -N(R 23 )SO2- and -SO2N(R 23 )-selected from X 1 and X 2 O, S, and NR 23 is selected from R 23 and R 24 However, independently, H, C (1-3) -Alkyl (e.g., methyl), and substituted C (1-3) 15. The compound according to any one of clauses 1 to 14, wherein the compound is selected from the group consisting of -alkyl, -sulfonyl, -sulfonyl, -isopropyl ...

[0522] Article 16.Z 3 but: [ka] During the ceremony, X 1 is O or S, t is 0 or 1, Each R 23 However, independently, H, C (1-3) -Alkyl (e.g., methyl), and substituted C (1-3) 16. The compound according to any one of clauses 1 to 15, wherein the alkyl is selected from the group consisting of -alkyl, -a-alkyl, -a-alkyl, -b ...

[0523] Article 17.Z 3 But -NHC(=X 1 )NH- and X 1 is O or S, Item 17. The compound according to item 16.

[0524] Clause 18. Ar is a triazole and the compound has the following formula: [ka] 15. The compound according to any one of clauses 1 to 14, wherein the compound is one of the compounds:

[0525] Article 19.Z 3 is an optionally substituted triazole and the compound has the formula: [ka] or a salt thereof, During the ceremony, Each R 11 ~R 14 are independently H, halogen, OH, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkoxy, COOH, NO, CN, NH, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 is selected from Each R 25 is independently selected from H and optionally substituted (C1-C6) alkyl.

[0526] Article 20.-Ar-Z 3 20. The compound according to any one of clauses 1 to 19, wherein - is selected from: [ka] [ka]

[0527] Clause 21. The compound of any one of clauses 1 to 20, wherein m is at least 2 and L is a branched linker covalently linking each Ar group to Y.

[0528] Clause 22. The compound according to clause 21, wherein m is 2 to 20 (eg, m is 2 to 6, such as 2 or 3).

[0529] Clause 23.m is between 20 and 500 (e.g., between 20 and 400, between 20 and 300, or between 20 and 200, or between 50 and 500, or between 100 and 500), L is an α-amino acid polymer (e.g., poly-L-lysine) and a number of -Ar-Z 3 22. The compound of clause 21, wherein the -group is covalently attached to the polymer backbone via a side chain group (e.g., via conjugation to the side chain amino group of a lysine residue).

[0530] Article 24.m is at least 2 and each Z 3 The linking moiety is connected to every other Z via the linker L by a chain of at least 16 contiguous atoms (e.g., by a chain of at least 20, at least 25, or at least 30 contiguous atoms, and in some cases by a chain of up to 100 contiguous atoms). 3 24. The compound of any one of clauses 21 to 23, separated from the binding moiety.

[0531] Clause 25. The compound has the formula: [ka] or a salt thereof, During the ceremony, n is 1 to 500 (e.g., n is 1 to 20, 1 to 10, 1 to 6, or 1 to 5); Each L 1 ~L 7 But independently, n Z 2 and Y. The -(L 1 ) a - comprises a linking moiety Ar, wherein - is an optionally substituted aryl or heteroaryl group; a is 1 or 2, 25. The compound of any one of clauses 1-24, wherein b, c, d, e, f, and g are each independently 0, 1, or 2.

[0532] Clause 26. The linear or branched linker is connected to each Z by a chain of at least 16 contiguous atoms (e.g., at least 20 contiguous atoms, at least 30 contiguous atoms, or 16 to 100 contiguous atoms). 2 and Y.

[0533] Clause 27. The compound according to any one of clauses 25 or 26, wherein n is 1 to 20.

[0534] Clause 28. The compound of any one of clauses 25 to 27, wherein n is at least 2 (eg, n is 2 or 3).

[0535] Clause 29.d is >0 and L 4 is the branched chain linking moiety, and each L 1 29. The compound of clause 28, covalently attached to a binding moiety.

[0536] Clause 30. The compound has the formula: [ka] is a compound of During the ceremony, Ar is an optionally substituted aryl or heteroaryl group (e.g., a monocyclic, bicyclic, or tricyclic aryl or heteroaryl group); Z 11 is a linking moiety (e.g., a covalent bond, a heteroatom, a group having a main chain of 1 to 3 atoms in length, or a triazole); r is 0 or 1, 30. The compound according to any one of clauses 25 to 29, wherein n is 1 to 6.

[0537] Clause 31. The compound according to clause 30, wherein Ar is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted quinoline, optionally substituted triazole, optionally substituted phenyl-triazole, optionally substituted biphenyl-triazole, and optionally substituted naphthalene-triazole.

[0538] Clause 32. The compound according to clause 31, wherein Ar is optionally substituted 1,4-phenylene.

[0539] Clause 33. A compound according to any one of clauses 30 to 32, wherein Ar is substituted with at least one hydroxy.

[0540] Article 34.L 1 or -Ar-(Z 11 ) r - is selected from the following: [ka] During the ceremony, Cy is monocyclic aryl or heteroaryl; r is 0 or 1, s is 0 to 4, R 11 ~R 14 and each R 15 are independently H, halogen, OH, optionally substituted (C-C) alkyl, optionally substituted (C-C) alkoxy, COOH, NO, CN, NH, -N(R 25 )2, -OCOR 25 , -COOR 25 , -CONHR 25 , and -NHCOR 25 Each R 25 However, independently, H, C (1-6) -alkyl and substituted C (1-6) -alkyl, Z 11 is a covalent bond, -O-, -NR 23-, -NR 23 CO-, -CONR 23 -, -NR 23 CO2-, -OCONR 23 , -NR 23 C(=X 1 )NR 23 -, -CR 24 =N-, -CR 24 =NX 2 - and optionally substituted triazole; X 1 and X 2 O, S, and NR 23 Selected from R 23 and R 24 However, independently, H, C (1-3) -Alkyl (e.g., methyl), and substituted C (1-3) 34. The compound according to any one of clauses 25 to 33, wherein the compound is selected from the group consisting of -alkyl, -sulfonyl, -sulfonyl, -isopropyl ...

[0541] Article 35.L 1 35. The compound according to clause 34, wherein: [ka]

[0542] Article 36.L 1 35. The compound according to clause 34, wherein: [ka]

[0543] Article 37.L 1 35. The compound according to clause 34, wherein is selected from: [ka]

[0544] Clause 38. The compound according to any one of clauses 34 to 37, wherein r is 0.

[0545] Article 39.r is 1 and Z 11 -O-, -NR 23-, -NR 23 CO-, CONR 23 -, -NR 23 CO2-, -OCONR 23 -, -NR 23 C(=X 1 )NR 23 -, -CR 24 =N- and -CR 24 =NX 2 - Selected from X 1 and X 2 O, S, and NR 23 Each R 23 and R 24 However, independently, H, C (1-3) -Alkyl (e.g., methyl), and substituted C (1-3) 38. The compound according to any one of clauses 34 to 37, wherein the compound is selected from the group consisting of -alkyl, -sulfonyl, -sulfonyl, -isopropyl ...

[0546] Article 40.r is 1 and Z 11 but: [ka] During the ceremony, X 1 is O or S, t is 0 or 1, Each R 23 However, independently, H, C (1-3) -Alkyl (e.g., methyl), and substituted C (1-3) 38. The compound according to any one of clauses 34 to 37, wherein the compound is selected from the group consisting of -alkyl, -sulfonyl, -sulfonyl, -isopropyl ...

[0547] Article 41.Z 11 But -NHC(=X 1 )NH- and X 1 is O or S.

[0548] Article 42.r is 1 and Z 11 38. The compound according to any one of clauses 34 to 37, wherein is a triazole.

[0549] Clause 43. The compound according to any one of clauses 1 to 42, wherein Y is selected from a small molecule, a dye, a fluorophore, a monosaccharide, a disaccharide, a trisaccharide, and a chemoselective linking group, or a precursor thereof.

[0550] Clause 44. A compound according to any one of clauses 1 to 42, wherein Y is a biomolecule.

[0551] Clause 45. The compound according to clause 44, wherein the biomolecule is selected from a peptide, a protein, a polynucleotide, a polysaccharide, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment.

[0552] Clause 46. A compound according to any one of clauses 1 to 45, wherein Y is a moiety that specifically binds to a target protein.

[0553] Clause 47. The compound according to clause 46, wherein the target protein is a membrane-bound protein.

[0554] Clause 48. The compound according to clause 46, wherein the target protein is an extracellular protein.

[0555] Clause 49. The compound of any one of clauses 46 to 49, wherein Y is selected from an antibody, an antibody fragment (e.g., an antigen-binding fragment of an antibody), a chimeric fusion protein, an engineered protein domain, a protein D binder of a target protein, an aptamer, a peptide, an enzyme substrate, and a small molecule inhibitor or ligand.

[0556] Clause 50. Y is an antibody or antibody fragment that specifically binds to a target protein and the compound has the formula: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n is 1 to 20; m is the average load between 1 and 80; Ab is an antibody or antibody fragment that specifically binds to the target protein; 50. The compound of clause 49, wherein Z is a residue moiety resulting from the covalent attachment of a chemoselective linking group to a compatibility group of an Ab.

[0557] Clause 51. The compound of clause 49, wherein Y is a small molecule inhibitor or ligand of the target protein.

[0558] Clause 52. The hydrophilic head group W is -OH, -CR 2 R 2 OH, -OP=O(OH)2, -SP=O(OH)2, -NR 3 P=O(OH)2, -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH)2, -OP=O(N(R 3 )2)(OH), -OP=O(R 3 )(OH), -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R 1 OH, -PH(=O)OH, -(CR 2 R 2 )-P=O(OH)2, -SO2OH (i.e., -SO3H), -S(O)OH, -OSO2OH, -COOH, -CN, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 ,-NHC(O)CO2H, -NHSO2NHR 3 , -NHC(O)NHS(O)2R 3, -NHSO2R 3 , -NHSO3H, [ka] or a salt thereof, During the ceremony, R 1 and R 2 are independently hydrogen, SR 3 , halo, or CN, R 3 and R 4 However, independently, H, C 1-6 Alkyl or substituted C 1-6 alkyl (e.g., —CF or —CHCF), A, B, and C are each independently CH or N; 52. The compound of any one of clauses 1-51, wherein each D is independently O or S.

[0559] Clause 53. The compound according to clause 52, wherein W is selected from -P=O(OH)2, -SO3H, -COOH, and -CH(COOH)2, or a salt thereof.

[0560] Article 54.Z 1 But -(CH2) j -or-(C(R 22 )2) j - and each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C-C) alkyl; 54. The compound according to any one of clauses 1 to 53, wherein j is 1 to 3.

[0561] Article 55.Z 1 54. The compound according to any one of clauses 1 to 53, wherein is -CH=CH-.

[0562] Article 56.Z 2 is O or S.

[0563] Article 57.Z 2 But, -NR21 56. The compound according to any one of clauses 1 to 55, wherein

[0564] Article 58.Z 2 But -C(R 22 )2-, and each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0565] Article 59.Z 1 But -(CH2) j -, substituted (C1-C3) alkylene, and -CH=CH-; j is 1 to 3, Z 2 54. The compound according to any one of clauses 1 to 53, wherein is selected from O and CH2.

[0566] Article 60. Z 1 is -(CH2)2-, -CH2-CF2-, or -CH2-CHF-; Z 2 61. The compound according to clause 60, wherein

[0567] Article 61.Z 1 is -(CH2)2-, -CH2-CF2-, or -CH2-CHF-; Z 2 61. The compound according to clause 60, wherein is CH2.

[0568] Article 62.Z 1 is -CH=CH-, Z 2 61. The compound according to clause 60, wherein

[0569] Article 63.Z 1 is -CH=CH-, Z 2 61. The compound according to clause 60, wherein is CH2.

[0570] Article 64.X: [ka] 64. The compound according to any one of clauses 1 to 63, selected from:

[0571] Clause 65. n is 1 to 6 (e.g., n is 1 to 5, or 2 to 6, or 1, 2, or 3); when d is 0, n is 1; when d is 1, n is 1 to 3; 65. The compound according to any one of clauses 25 to 64, wherein when d is 2, n is 1 to 6.

[0572] Article 66. Each L 2 But independently, -C 1-6 -Alkylene-, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -O(CH2) p - and -(OCH2CH2) p and p is selected from 1 to 10; Each L 3 But independently, [ka] , and -(OCH2CH2) q -, wherein q is 1 to 10, u is 0 to 10 and w is 1 to 10.

[0573] If clause 67.n is 2 or more, at least one L 4 67. The compound of any one of clauses 25 to 66, wherein is present and is a branched chain linking moiety.

[0574] Article 68. Each L 4 But independently, -OCH2CH2-, [ka] , selected from 68. The compound of any one of clauses 25 to 67, wherein each x and y is independently 1 to 10.

[0575] Article 69. Each L 5 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -alkylene-, [ka] , or -(OCH2CH2) r - and Each L 6 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, or -(OCH2CH2) s - and Each L 7 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, -(OCH2CH2) t - or -OCH2-, Any one of clauses 25 to 68, wherein r, s, and t are each independently 1 to 20. The compound described in

[0576] The compound according to any one of clauses 25 to 69, wherein clause 70.a is 1.

[0577] Clause 71. The compound according to any one of clauses 25 to 70, wherein at least one of b, c, e, f, and g is not 0.

[0578] Clause 72. A compound according to any one of clauses 25 to 71, wherein at least one of b or c is not 0 and at least one of e, f and g is not 0.

[0579] Clause 73. The compound of any one of clauses 25 to 72, wherein a, b, and c are each independently 1 or 2.

[0580] Clause 74. The compound according to any one of clauses 1 to 73, wherein the linker L is selected from any one of the structures in Tables 2-3.

[0581] Clause 75. The compound according to any one of clauses 1 to 74, wherein the compound is selected from the compounds of Tables 5 to 9.

[0582] Article 76. Cell surface receptor binding conjugate of formula (I): [ka] or a salt thereof, During the ceremony, X is a moiety that binds to the cell surface mannose-6-phosphate receptor (M6PR); n is 1 to 500 (e.g., n is 1 to 20, 1 to 10, 1 to 6, or 1 to 5); L is a linker, Y is a biomolecule that specifically binds to a target protein; The above conjugate or a salt thereof.

[0583] Article 77. The conjugate has the formula: [ka] or a pharmaceutically acceptable salt thereof During the ceremony, n is 1 to 20; m is the average load between 1 and 80; Ab is an antibody or antibody fragment that specifically binds to the target protein; 77. The conjugate of clause 76, wherein Z is a residue moiety resulting from the covalent attachment of the chemoselective linking group to a compatibility group of the Ab.

[0584] Clause 78. A conjugate according to clause 76 or 77, wherein n is 1 to 6.

[0585] Clause 79. A conjugate according to clause 76 or 77, wherein n is 2 or less.

[0586] Clause 80. A conjugate according to clause 79, wherein n is 1.

[0587] Clause 81. A conjugate according to clause 76 or 77, wherein n is at least 2.

[0588] Clause 82. The conjugate according to clause 81, wherein n is 2.

[0589] Clause 83. The conjugate according to clause 81, wherein n is 3.

[0590] Clause 84. A conjugate according to clause 81, wherein n is 4.

[0591] Clause 85. The conjugate according to any one of clauses 76 to 84, wherein m is 1 to 20.

[0592] The conjugate according to any one of clauses 76 to 84, wherein clause 86.m is 1 to 12.

[0593] Clause 87. The conjugate according to any one of clauses 76 to 86, wherein m is at least about 2.

[0594] Clause 88. The conjugate of any one of clauses 76 to 86, wherein m is at least about 3.

[0595] Clause 89. The conjugate of any one of clauses 76 to 86, wherein m is at least about 4.

[0596] Clause 90. A conjugate according to any one of clauses 77 to 89, wherein Z is a residue moiety resulting from the covalent attachment of a thiol-reactive chemoselective linking group to one or more cysteine ​​residue(s) of the Ab.

[0597] Clause 91. A conjugate according to any one of clauses 76 to 89, wherein Z is a residue moiety resulting from the covalent attachment of an amine-reactive chemoselective linking group to one or more lysine residue(s) of Ab.

[0598] Clause 92.X is a moiety that binds to M6PR, and X of the formula: [ka] or a salt thereof, During the ceremony, each W is independently a hydrophilic head group; each Z 1 are independently selected from optionally substituted (C-C)alkylene and optionally substituted ethenylene; each Z 2 However, independently, O, S, NR 21 , and C(R 22 )2, and each R 21 is independently selected from H, optionally substituted (C-C) alkyl, and each R 22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl.

[0599] Clause 93. The hydrophilic head group W is -OH, -CR 2 R 2 OH, -OP=O(OH)2, -SP=O(OH)2, -NR 3 P=O(OH)2, -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH)2, -OP=O(N(R 3 )2)(OH), -OP=O(R 3 )(OH), -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R 1 OH, -PH(=O)OH, -(CR 2 R 2)-P=O(OH)2, -SO2OH (i.e., -SO3H), -S(O)OH, -OSO2OH, -COOH, -CN, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)CO2H, -NHSO2NHR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , -NHSO3H, [ka] or a salt thereof; During the ceremony, R 1 and R 2 are independently hydrogen, SR 3 , halo, or CN, R 3 and R 4 However, independently, H, C 1-6 Alkyl or substituted C 1-6 alkyl (e.g., —CF or —CHCF), A, B, and C are each independently CH or N; The conjugate of clause 92, wherein each D is independently O or S.

[0600] Clause 94. A conjugate according to Clause 93, wherein W is selected from -P=O(OH)2, -SO3H, -CO2H, and -CH(CO2H)2, or salts thereof.

[0601] Article 95.Z 1 But -(CH2) j - and j is 1 to 3.

[0602] Article 96.Z 1 96. The conjugate according to any one of clauses 92 to 95, wherein is -CH=CH-.

[0603] Article 97.Z 2 is O or S.

[0604] Article 98.Z 2 But, -NR 21 97. The conjugate of any one of clauses 92 to 96, wherein

[0605] Article 99.Z 2 But -C(R 22 97. The conjugate of any one of clauses 92 to 96, wherein

[0606] Article 100.Z 1 But -(CH2) j -, substituted (C1-C3) alkylene, and -CH=CH-; j is 1 to 3, Z 2 The conjugate of any one of clauses 92 to 94, wherein is selected from O and CH2.

[0607] Article 101.Z 1 is -(CH2)2-, -CH2-CF2-, or -CH2-CHF-; Z 2 The conjugate according to clause 100, wherein

[0608] Article 102.Z 1 is -(CH2)2-, -CH2-CF2-, or -CH2-CHF-; Z2 The conjugate of clause 100, wherein is CH2.

[0609] Article 103.Z 1 is -CH=CH-, and Z 2 The conjugate according to clause 100, wherein

[0610] Article 104.Z 1 is -CH=CH-, and Z 2 The conjugate of clause 100, wherein is CH2.

[0611] Clause 105. A conjugate according to any one of clauses 92 to 104, wherein X is selected from the following: [ka]

[0612] Clause 106. The linker L is represented by formula (IIa): [ka] (In the formula, Each L 1 ~L 7 are independently linking moieties and together provide a linear or branched linker between X and Y; a is 1 or 2, b, c, d, e, f, and g are each independently 0, 1, or 2; n is 1 to 6 (e.g., n is 1 to 5, or 2 to 6, or 1, 2, or 3) The conjugate according to clauses 76 to 105, wherein the linker is

[0613] If clause 107.d is 0, then n is 1; when d is 1, n is 1 to 3; When d is 2, n is 1 to 6. A conjugate according to clause 108.

[0614] Article 111.-(L1 ) a 111. The conjugate of clause 109 or 110, wherein - comprises an optionally substituted aryl or heteroaryl linking moiety.

[0615] Article 112. Each L 1 But independently, [ka] 112. The conjugate of clause 111, wherein v is 0 to 10 and z is 0 to 10.

[0616] Article 113. Each L 2 But independently, -C 1-6 -Alkylene-, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -O(CH2) p - and -(OCH2CH2) p and p is selected from 1 to 10; Each L 3 But independently, [ka] , and -(OCH2CH2) q -, wherein q is 1 to 10, u is 0 to 10 and w is 1 to 10.

[0617] If clause 114.n is 2 or more, at least one L 4 114. The conjugate of any one of clauses 109 to 113, wherein is present and is a branched linking moiety.

[0618] Article 115. Each L 4 But independently, -OCH2CH2-, [ka] is selected from 115. The conjugate of any one of clauses 109-114, wherein each x and y is independently 1 to 10.

[0619] Article 116. Each L 5 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -alkylene-, [ka] , or -(OCH2CH2) r - and Each L 6 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, or -(OCH2CH2) s - and Each L 7 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, -(OCH2CH2) t - or -OCH2-, 116. The conjugate of any one of clauses 109-115, wherein r, s, and t are each independently 1 to 20.

[0620] The conjugate according to any one of clauses 109 to 116, wherein clause 117.a is 1.

[0621] Clause 118. A conjugate according to any one of clauses 109 to 117, wherein at least one of b, c, e, f and g is not 0.

[0622] Clause 119. A conjugate according to any one of clauses 109 to 118, wherein at least one of b or c is not 0 and at least one of e, f and g is not 0.

[0623] Clause 120. The conjugate according to any one of clauses 109 to 119, wherein a, b, and c are each independently 1 or 2.

[0624] Clause 121. The conjugate according to any one of clauses 109-120, wherein the linker L is selected from any one of the structures in Tables 2-3.

[0625] Article 122. i) a conjugate derived from the conjugation of any one of the compounds of the structure in the Table of Compounds described herein with a biomolecule; ii) a conjugate derived from the conjugation of any one of the compounds of the structures in the Table of Compounds set forth herein to a polypeptide, or iii) A conjugate derived from the conjugation of any one of the compounds of the structure in the Compound Table described herein with an antibody or antibody fragment. 78. The conjugate of clause 76 or 77, selected from:

[0626] Clause 123. The conjugate of any one of clauses 77 to 122, wherein the antibody or antibody fragment is an IgG antibody.

[0627] Clause 124. The conjugate of any one of clauses 77 to 122, wherein the antibody or antibody fragment is a humanized antibody.

[0628] Clause 125. A conjugate according to any one of clauses 77 to 124, wherein the antibody or antibody fragment specifically binds to a secreted or soluble protein.

[0629] Clause 126. A conjugate according to any one of clauses 77 to 124, wherein the antibody or antibody fragment specifically binds to a cell surface receptor.

[0630] Clause 127. A method for internalizing a target protein into a cell containing the M6PR cell surface receptor, comprising contacting the cell and a cell sample containing the target protein with an effective amount of a compound according to any one of claims 1 to 75 or a conjugate according to any one of claims 76 to 132, wherein the compound or conjugate specifically binds to the target protein and specifically binds to the cell surface receptor to promote cellular uptake of the target protein.

[0631] Clause 128. The method of Clause 127, wherein the target protein is a membrane-bound protein.

[0632] Clause 129. The method of Clause 127, wherein the target protein is an extracellular protein.

[0633] Clause 130. The method of any one of clauses 127 to 129, wherein the compound or conjugate comprises an antibody or antibody fragment (Ab) that specifically binds to the target protein.

[0634] Clause 131. A method for reducing the level of a target protein in a biological system, comprising contacting the biological system with an effective amount of a compound according to any one of clauses 1 to 75 or a conjugate according to any one of clauses 76 to 126, wherein the compound or conjugate specifically binds to the target protein and specifically binds to the M6PR cell surface receptor of cells in the biological system to promote cellular uptake and degradation of the target protein.

[0635] Clause 134. The method of any one of clauses 131 to 133, wherein the biological system is a human subject.

[0636] Clause 135. The method of any one of clauses 131 to 133, wherein the biological system is an in vitro cell sample.

[0637] Clause 136. The method of any one of clauses 131 to 135, wherein the target protein is a membrane-bound protein.

[0638] Clause 137. The method of any one of clauses 131 to 135, wherein the target protein is an extracellular protein.

[0639] Clause 138. A method for treating a disease or disorder associated with a target protein, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 1 to 75 or a conjugate according to any one of clauses 76 to 126, wherein the compound or conjugate specifically binds to the target protein.

[0640] Clause 139. The method according to clause 138, wherein the disease or disorder is an inflammatory disease.

[0641] Clause 140. The method of clause 138, wherein the disease or disorder is an autoimmune disease.

[0642] Clause 141. The method according to clause 138, wherein the disease or disorder is cancer.

[0643] Article 151. A compound of formula (I): [ka] or a salt thereof, single stereoisomer, mixture of stereoisomers, or isotopic form thereof, During the ceremony, X is a moiety that binds to the M6PR cell surface receptor; L is a linker of the formula: [ka] During the ceremony, Each L 1 But independently, [ka] and Each L 2 But independently, -C 1-6 -Alkylene-, -NHCO-C 1-6 -Alkylene-, -CONH-C1-6 -Alkylene-, -(OCH2) p - or -(OCH2CH2) p - and Each L 3 But independently, [ka] , or -(OCH2CH2) q - and Each L 4 are independently -OCH2CH2-, [ka] and Each L 5 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -alkylene-, [ka] , or -(OCH2CH2) r - and Each L 6 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, or -(OCH2CH2) s - and Each L 7 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, -(OCH2CH2) t - or -OCH2-, p, q, r, s, and t are each independently an integer of 1 to 20, a is 1 or 2, b, c, d, e, f, and g are each independently 0, 1, or 2, and u, v, w, x, y, and z are each independently an integer of 1 to 10; n is an integer of 1 to 5, and when d is 0, n is 1, and when d is 1, n is an integer of 1 to 3, and when d is 2, n is an integer of 1 to 5; Y is, [ka] and a moiety selected from the group consisting of [ka] represents the point of attachment to L; R is hydrogen or fluorine, each R' is independently hydrogen or halo; G is selected from -F, -Cl, -Br, -I, -O-mesyl, and -O-tosyl; J is -Cl, -Br, -I, -F, -OH, -ON-succinimide, -O-(4-nitrophenyl), -O-pentafluorophenyl, -O-tetrafluorophenyl, and -OC(O)-OR; J’ Selected from R J’ is -C1-C8 alkyl or -aryl, or a salt, single stereoisomer, mixture of stereoisomers, or isotopic form thereof.

[0644] The compound according to clause 151, wherein clause 154.a is 1.

[0645] Clause 155. A compound according to clause 151, wherein at least one of b, c, e, f and g is not zero.

[0646] Clause 156. A compound according to clause 151, wherein at least one of b or c is not 0 and at least one of e, f and g is not 0.

[0647] Clause 157. The compound according to Clause 151, wherein a, b, and c are each independently 1 or 2.

[0648] Clause 158. Each X is independently selected from one of the following formulas: [ka] During the ceremony, R'' is -OH, -CR 1 R 2 OH, -P=O(OH)2, P(=O)R 1 OH, -PH(=O)OH, -(CR 1 R 2 )-P=O(OH)2, -SO2OH, -S(O)OH, -OSO2OH, -COOH, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , [ka] is selected from the group consisting of j is an integer from 1 to 3, R 1 and R 2 are each independently hydrogen, halo, or CN; R 3 and R 4 However, each independently, C 1-6 is alkyl, A, B, and C are each independently CH or N; D is independently O or S; A compound as defined in clause 151.

[0649] Clause 159. Each X is independently selected from one of the following formulas: [ka] During the ceremony, R'' is -OH, -CR 1 R 2 OH, -P=O(OH)2, P(=O)R 1 OH, -PH(=O)OH, -(CR 1 R 2 )-P=O(OH)2, -SO2OH, -S(O)OH, -OSO2OH, -COOH, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , [ka] is selected from the group consisting of j is an integer from 1 to 3, R 1 and R 2 are each independently hydrogen, halo, or CN; R 3 and R 4 However, each independently, C 1-6 is alkyl, A, B, and C are each independently CH or N; D is independently O or S; A compound as defined in clause 151.

[0650] Article 161. Conjugates of the following formula: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is a moiety that binds to the M6PR cell surface receptor; L is a linker of the formula: [ka] During the ceremony, Each L 1 But independently, [ka] and Each L 2 But independently, -C 1-6 -Alkylene-, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -(OCH2) p - or -(OCH2CH2) p - and Each L 3 But independently, [ka] , or -(OCH2CH2) q - and Each L 4 are independently -OCH2CH2-, [ka] and Each L 5 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -alkylene-, [ka] , or -(OCH2CH2) r - and Each L 6 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, or -(OCH2CH2) s - and Each L 7 But independently, -NHCO-C 1-6 -Alkylene-, -CONH-C1-6-Alkylene-, C 1-6 -Alkylene-, -(OCH2CH2) t - or -OCH2-, p, q, r, s, and t are each independently an integer of 1 to 20, a is 1 or 2, b, c, d, e, f, and g are each independently 0, 1, or 2, and u, v, w, x, y, and z are each independently an integer of 1 to 10; n is an integer of 1 to 5, and when d is 0, n is 1, and when d is 1, n is an integer of 1 to 3, and when d is 2, n is an integer of 1 to 5; Z, [ka] is selected from the group consisting of [ka] represents the point of attachment to L; [ka] represents the point of attachment to P, X is CH, NH, O, or S; P is a polypeptide; The above conjugate or a pharmaceutically acceptable salt thereof.

[0651] Clause 162. A conjugate according to clause 161, wherein P comprises an antibody or an antigen-binding fragment of an antibody.

[0652] Article 163. Conjugates of the following formula: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is a moiety that binds to the M6PR cell surface receptor; L is a linker of the formula: [ka] During the ceremony, Each L 1 But independently, [ka] and Each L 2 But independently, -C 1-6 -Alkylene-, -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -(OCH2) p - or -(OCH2CH2) p - and Each L 3 But independently, [ka] , or -(OCH2CH2) q - and Each L 4 are independently -OCH2CH2-, [ka] and Each L 5 But -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -alkylene-, [ka] , or -(OCH2CH2) r - and Each L 6 But -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, or -(OCH2CH2) s - and Each L 7 But -NHCO-C 1-6 -Alkylene-, -CONH-C 1-6 -Alkylene-, -C 1-6 -Alkylene-, -(OCH2CH2) t - or -OCH2-, p, q, r, s, and t are each independently an integer of 1 to 20, a is 1 or 2, b, c, d, e, f, and g are each independently 0, 1, or 2, u, v, w, x, y, and z are each independently 1, 2, 3, 4, 5, or 6, n is an integer of 1 to 5, and when d is 0, n is 1, and when d is 1, n is an integer of 1 to 3, and when d is 2, n is an integer of 1 to 5; m is an integer from 1 to 8, Z, [ka] is selected from the group consisting of [ka] represents the point of attachment to L; [ka] but, [ka] represents the point of attachment to [ka] is an antibody, or a pharmaceutically acceptable salt thereof.

[0653] Clause 166. Each X is independently selected from one of the following formulas: [ka] During the ceremony, R'' is -OH, -CR 1 R 2 OH, -P=O(OH)2, P(=O)R 1 OH, -PH(=O)OH, -(CR 1 R 2 )-P=O(OH)2, -SO2OH, -S(O)OH, -OSO2OH, -COOH, -CONH2, -CONHR 3 , -CONR 3 R 4 ,- CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , [ka] is selected from the group consisting of j is an integer from 1 to 3, R 1 and R 2 are each independently hydrogen, halo, or CN; R 3 and R 4 However, each independently, C 1-6 is alkyl, A, B, and C are each independently CH or N; D is independently O or S; 166. The conjugate according to any one of clauses 161 to 165.

[0654] Clause 167. Each X is independently selected from one of the following formulas: [ka] During the ceremony, R'' is -OH, -CR 1 R 2 OH, -P=O(OH)2, P(=O)R 1 OH, -PH(=O)OH, -(CR 1 R 2 )-P=O(OH)2, -SO2OH, -S(O)OH, -OSO2OH, -COOH, -CONH2, -CONHR 3 , -CONR 3 R 4 , -CONH(OH), -CONH(OR 3 ), -CONHSO2R 3 , -CONHSO2NR 3 R 4 , -CH(COOH)2, -CR 1 R 2 COOH, -SO2R 3 , -SOR 3 R 4 , -SO2NH2, -SO2NHR 3 , -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHC(O)NHS(O)2R 3 , -NHSO2R 3 , [ka] is selected from the group consisting of j is an integer from 1 to 3, R 1 and R 2 are each independently hydrogen, halo, or CN; R 3 and R 4However, each independently, C 1-6 is alkyl, A, B, and C are each independently CH or N; D is independently O or S; 166. The conjugate according to any one of clauses 161 to 165.

[0655] Clause 169. A pharmaceutical composition comprising the conjugate or pharmaceutically acceptable salt according to any one of clauses 161 to 168 and a pharmaceutically acceptable carrier.

[0656] Clause 170. A pharmaceutical composition according to clause 169, wherein m is an integer from 4 to 8.

[0657] Clause 171. A pharmaceutical composition comprising a conjugate or a pharmaceutically acceptable salt according to clause 170, wherein m is 4.

[0658] Clause 172. The method according to any one of clauses 163 to 168, wherein the antibody is an IgG antibody. Conjugates.

[0659] Clause 173. The conjugate of any one of clauses 163 to 168, wherein the antibody is a humanized antibody.

[0660] Clause 174. The conjugate of any one of clauses 163 to 168, wherein the antibody specifically binds to a secreted or soluble protein.

[0661] Clause 175. The conjugate of any one of clauses 163 to 168, wherein the antibody specifically binds to a cell surface receptor.

[0662] Clause 176. The conjugate of any one of clauses 163 to 168, wherein the antibody specifically binds to the Programmed Death-Ligand-1 (PD-L1) protein.

[0663] Clause 177. The conjugate according to any one of clauses 163 to 168, wherein the antibody specifically binds to the vascular endothelial growth factor (VEGF) protein.

[0664] Clause 178. The conjugate of any one of clauses 163 to 168, wherein the antibody specifically binds to fibroblast growth factor receptor 2 (FGFR2) protein or fibroblast growth factor receptor 3 (FGFR3) protein.

[0665] Clause 179. The conjugate of any one of clauses 163 to 168, wherein the antibody is cetuximab.

[0666] Clause 180. The conjugate of any one of clauses 163 to 168, wherein the antibody is matuzumab.

[0667] Clause 181. The conjugate of any one of clauses 163 to 168, wherein the antibody is atezolizumab.

[0668] Clause 182. A method of treating a disease or disorder by administering to a subject in need thereof an effective amount of a conjugate or pharmaceutically acceptable salt thereof according to any one of clauses 163 to 168 or a pharmaceutical composition according to clause 169.

[0669] Clause 183. The method according to clause 182, wherein the disease or disorder is an inflammatory disease.

[0670] Clause 184. The method of clause 182, wherein the disease or disorder is an autoimmune disease.

[0671] Clause 185. The method according to clause 182, wherein the disease or disorder is cancer. [Example]

[0672] 6. Working Example The examples in this section are offered by way of illustration, not by way of limitation.

[0673] 6.1. Preparation of Compounds Below are illustrative schemes and examples of how the compounds described herein can be prepared and tested. While the examples may represent only some embodiments, it should be understood that the following examples are illustrative and not limiting. All substituents are as defined above unless otherwise indicated. Reagents and starting materials are readily available to one of ordinary skill in the art. Certain synthetic steps for each of the routes described may be combined in different forms or with steps from different schemes to prepare the compounds described herein.

[0674] Synthetic methods for preparing M6PR binding moieties, their precursors, and conjugates thereof that can be adapted for use in preparing the compounds and synthons thereof of the present disclosure are described in International Application No. PCT / US2021 / 012846, published as WO2021 / 142377, and PCT Publication WO2020132100, the disclosures of which are incorporated herein by reference in their entireties.

[0675] 6.1.1. Preparation of M6PR binding moiety synthons Synthesis of Synthon A-10 and Compound A. (2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-isothiocyanatophenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphonic acid (Compound A) [ka]

[0676] (((2R,3S,4S,5R,6R)-2-(4-nitrophenoxy)-6(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane) (A-2)

[0677] A solution of (2R,3S,4S,5S,6R)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (A-1) (1.0 equiv., 26.0 g, 86.37 mmol) in DMF (500 mL) was cooled to 0 °C. Then, triethylamine (6.4 equiv., 288 mL, 552.0 mmol) and trimethylsilyl chloride (24.0 equiv., 70 mL, 2071.0 mmol) were added to the above solution under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and purified by silica gel chromatography (0–5% ethyl acetate / hexanes) to give Intermediate A-2 as a colorless oil. Yield: 36.8g (72.3%); 1 H NMR(400MHz,CDCl3)δ8.18(dd,J=12.36,3.16Hz,2H),7.16(dd,J=12.4,3.12Hz,2H),5.37(d ,J=2.36Hz,1H),3.99-3.87(m,3H),3.72-3.69(m,2H),3.50-3.48(m,1H),0.2-0.07(m,36H).

[0678] ((2R,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol (A-3)

[0679] To a stirred solution of intermediate A-2 (1.0 equiv., 10.0 g, 16.97 mmol) in a mixture of DCM:methanol (8:2 ratio, 100 mL) was added ammonium acetate (1.5 equiv., 1.96 g, 25.46 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (20-30% ethyl acetate / hexanes) to give intermediate A-3 as a white solid. Yield: 7.0 g (80%); LC-MS m / z 516.13 [M-1] - .

[0680] (2S,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-carbaldehyde (A-4)

[0681] To a stirred solution of oxalyl chloride (1.1 equiv., 0.5 mL, 5.31 mmol) in DCM (5 mL) was added a solution of DMSO (2.2 equiv., 0.76 mL, 10.62 mmol) in DCM (5 mL) over 5 min at −78° C. After stirring for 20 min at −78° C., a solution of Intermediate A-3 (1.0 equiv., 2.5 g, 4.83 mmol) in DCM (10 mL) was added to the mixture. The reaction mixture was further stirred at −78° C. for 60 min, followed by the addition of triethylamine (5.0 equiv., 3.4 mL, 24.15 mmol). The resulting mixture was allowed to reach room temperature over 1 h. The cloudy mixture was diluted with DCM and washed with water followed by brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under high vacuum to give intermediate A-4 (2.2 g, crude) as a light brown gel, which was used in the next step without further purification.

[0682] ((E)-2-((2R,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)vinyl)diethyl phosphonate (A-5)

[0683] A stirred suspension of tetraethyl methylenebis(phosphonate) (1.5 equiv., 1.85 g, 6.40 mmol) in anhydrous THF (20 mL) was cooled to -78 °C, and a 2.0 M solution of n-BuLi in hexane (1.25 equiv., 2.6 mL, 5.33 mmol) was added. The resulting mixture was stirred at -78 °C for 1 h, followed by the addition of a solution of Intermediate A-4 (1.0 equiv., 2.2 g, 4.27 mmol) in anhydrous THF (10 mL) at -78 °C. The bath was removed, and the reaction mixture was allowed to warm to room temperature and continued stirring for 12 h. Saturated aqueous NH4Cl was added, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water followed by saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (30–40% ethyl acetate / hexane) to give Intermediate A-5 as a colorless gel. Yield (1.3g, 48%); LC-MS m / z 650.57 [M+1] + .

[0684] ((E)-2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-nitrophenoxy)tetrahydro-2H-pyran-2-yl)vinyl)diethyl phosphonate (A-6)

[0685] To a stirred solution of intermediate A-5 (1.0 equiv., 1.3 g, 1.54 mmol) in methanol (15 mL) was added Dowex 50WX8 hydrogen form at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was filtered, washed with methanol, and the filtrate was concentrated in vacuo to give diethyl ((E)-2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-nitrophenoxy)tetrahydro-2H-pyran-2-yl)vinyl)phosphonate (6) as a white solid. Yield: 0.78 g (90%); LC-MS m / z 434.17 [M+1] + .

[0686] (2R,3R,4S,5S,6R)-2-((E)-2-(diethoxyphosphoryl)vinyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (A-7)

[0687] To a stirred solution of Intermediate A-6 (1.00 equiv., 0.78 g, 1.80 mmol) in pyridine (10 mL) was added dropwise acetic anhydride (10.0 equiv., 1.8 mL, 18.0 mmol) under nitrogen at 0° C. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 16 hours. The pyridine was removed under high vacuum, and the residue was partitioned between ethyl acetate and 1N aqueous HCl. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (2.5% methanol / dichloromethane) to give Intermediate A-7 as a white solid. Yield: 1.0 g (100%); LC-MS m / z 560.17 [M+1] + .

[0688] (2R,3S,4S,5R,6R)-2-(4-aminophenoxy)-6-(2-(diethoxyphosphoryl)ethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (A-8)

[0689] To a stirred solution of intermediate A-7 (1.0 equiv., 1.0 g, 1.78 mmol) in methanol (15 mL) was added 10% palladium on carbon (0.200 g) at room temperature under nitrogen. The resulting mixture was stirred at room temperature under hydrogen gas pressure (100 psi) for 16 hours. The reaction mixture was filtered through a bed of celite, washed with methanol, and the filtrate was concentrated in vacuo to give intermediate A-8 as a brown sticky gel. Yield: 0.700 g (73.6%); LC-MS m / z 532.21 [M+1] + .

[0690] (2-((2R,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(4-aminophenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphonic acid (A-9)

[0691] To a stirred solution of Intermediate A-8 (1.00 equiv., 2.0 g, 5.73 mmol) in acetonitrile (15 mL) under nitrogen at 0° C., bromotrimethylsilane (5.0 equiv., 3.8 mL, 28.65 mmol) was added dropwise. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 16 h. The volatiles were removed on a rotary evaporator, and the residue was dried under high vacuum. The crude residue was triturated with diethyl ether and dried under high vacuum to give Intermediate A-9 as a brown solid. Yield: 2.2 g, crude. LC-MS m / z 476.0 [M+1] + .

[0692] (2-((2R,3S,4S,5S,6R)-6-(4-aminophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)ethyl)phosphonic acid (A-10)

[0693] To a stirred solution of Intermediate A-9 (1.0 equiv., 2.0 g, 4.21 mmol) in a mixture of methanol and water (8:2, 15 mL) under nitrogen at 0 °C, triethylamine (5.0 equiv., 2.93 mL, 21.05 mmol) was added dropwise. The cold bath was removed, and the resulting mixture was stirred at room temperature for 16 h. Methanol was removed on a rotary evaporator, and the residue was dried under high vacuum. The residue was taken up in water and purified by preparative HPLC (2–10% acetonitrile / water with 5 mM ammonium acetate). Fractions containing the desired product were combined and lyophilized to dryness to give Intermediate A-10 as a brown solid. Yield: 0.350 g (25%); LC-MS m / z 348.0 [M−H] - .

[0694] (2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-isothiocyanatophenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphonic acid (Compound A)

[0695] To a stirred solution of intermediate A-10 (1.0 equiv., 1.75 g, 5.01 mmol) in ethanol:water (7:3) (20 mL) under nitrogen at 0 °C, thiophosgene (5.00 equiv., 1.92 mL, 25.05 mmol) was added dropwise. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 3 h. The volatiles were removed on a rotary evaporator, and the residue was dried under high vacuum. The residue was taken up in water and purified by preparative HPLC (20-40% acetonitrile / water with 5.0 mmol of ammonium acetate). Fractions containing the desired product were combined and lyophilized to dryness to give compound A as a white solid. Yield: 0.135 g (6.8%). LC-MS m / z 392.08 [M+1] + ; 1 H NMR(400MHz, D2O) δ 7.32 (d, J=8.92Hz, 2H ), 7.12 (d, J=8.96Hz, 2H ), 5.57 (s, 1H ), 4.13 (s, 1H ), 3.96 (dd, J=9.16, 3.44Hz, 1H ),3.59-3.48 (m, 2H ), 2.03-1.88 (m, 1H ), 1.68-1.54 (m, 2H ), 1.27-1.15 (m, 1H ).

[0696] Preparation of synthon 8D [ka]

[0697] To a stirred solution of (2R,3R,4S,5S,6S)-2-(2-(diethoxyphosphoryl)ethyl)-6-hydroxytetrahydro-2H-pyran-3,4,5-triyl triacetate (8A) (1.00 equiv., 1.48 g, 3.36 mmol) and trichloroacetonitrile (10.0 equiv., 3.4 mL, 33.6 mmol) in DCM (30 mL) was added DBU (0.05 equiv., 0.025 mL, 0.168 mmol) under nitrogen at 0°C. The resulting mixture was stirred under nitrogen at 0°C. An additional aliquot of DBU (0.0500 equiv., 0.025 mL, 0.168 mmol) was added and the cold bath was removed. The resulting mixture was stirred at room temperature for 45 min. Most of the solvent was removed on a rotary evaporator. The residue was loaded onto a silica gel loading column pre-equilibrated with 0.1% triethylamine / dichloromethane and purified by silica gel chromatography (column pre-equilibrated with 0.1% triethylamine / (30% ethyl acetate / hexane)) (30-100% ethyl acetate / hexane). Fractions containing the desired product were combined and concentrated on a rotary evaporator. The residue was stripped twice with anhydrous dichloromethane, dried under high vacuum for 30 minutes, and then stored at -80°C under nitrogen to give compound 8B as a colorless semi-solid. Yield: 1.26 g, 64%. 1 H NMR (300MHz,chloroform-d) δ 8.74 (s, 1H), 6.21 (s, 1H), 5.45 (s, 1H), 5.34 (t, J=11.2Hz, 1H), 5.20 (t, J=10.0Hz, 1H), 4.16-4.00 (m, 4H), 4.00-3.88 (m, 1H), 2.18 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.95-1.64 (m, 4H), 1.31 (t, J=7.3Hz, 6H).

[0698] Compound 8B (1.00 equiv., 1.25 g, 2.14 mmol) was dissolved in anhydrous DCM (10 mL) with stirring under nitrogen. But-3-en-1-ol (2.00 equiv., 0.32 mL, 4.28 mmol) was added, and the resulting mixture was cooled to −78° C. with stirring under nitrogen. A solution of boron trifluoride diethyl etherate (0.500 equiv., 0.13 mL, 1.07 mmol) in dichloromethane (5 mL) was added slowly. The −78° C. cooling bath was removed, and the reaction mixture was allowed to warm slowly under nitrogen for 50 minutes. The reaction mixture was cooled in a water / ice bath and stirred at 0° C. under nitrogen for an additional 30 minutes before workup. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted again with dichloromethane. The combined organics were dried over sodium sulfate, filtered, and purified by silica gel chromatography (20-100% ethyl acetate / dichloromethane) to give compound 8C as a colorless viscous oil. Yield: 408 mg, 39%; LC-MS m / z 493.4 [M+1] + ; 1 H NMR (300MHz, chloroform-d) δ 5.35-5.19 (m, 2H), 5.09 (t, J=9.9Hz, 1H), 4.79 (s, 1H), 4.21-3.98 (m, 4H), 3.91-3.68 (m, 2H),3.64-3.50 (m, 1H), 2.55-2.44 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H), 2.07-1.62 (m, 5H), 1.32(t, J=7.2Hz, 6H).

[0699] To a stirred solution of compound 8C (1.00 equiv., 352 mg, 0.715 mmol) in MeCN (7 mL) at 0°C under nitrogen, bromotrimethylsilane (5.00 equiv., 0.47 mL, 3.57 mmol) was slowly added. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 3.5 hours. The volatiles were removed on a rotary evaporator, and the residue was briefly dried under high vacuum. The residue was dissolved in methanol (7 mL) with stirring under nitrogen, and sodium methoxide (25 wt % in methanol) (2.50 equiv., 0.41 mL, 1.79 mmol) was added. The resulting mixture was stirred under nitrogen at room temperature for 1 hour. Acetic acid (3.00 equiv., 0.12 mL, 2.14 mmol) was added, and then the volatiles were removed on a rotary evaporator. The residue was scooped up into water and purified by preparative HPLC (0-15% acetonitrile / water with 0.1% TFA). Most of the solvent was removed on a rotary evaporator at 30 °C, and the remainder was then lyophilized to dryness to give compound 8D as a white solid. Yield: 208 mg, 94%; LC-MS m / z 311.3 [M+1] + ; 1 H NMR (300MHz, deuterium oxide) δ 4.88-4.80 (m, 1H), 3.93 (s, 1H), 3.84-3.70 (m, 2H), 3.70-3.56 (m, 2H), 3.48 (t, J=9.7Hz, 1H), 2.57-2.44 (m, 2H), 2.37 (s, 1H), 2.15-1.61 (m, 4H).

[0700] Synthesis of Compound B [ka]

[0701] Compound B is synthesized using the procedure described for compound 8D, using but-3-yn-1-amine instead of but-3-yn-1-ol.

[0702] Alternatively, intermediate B-2 can be prepared by adding pyridine to a solution of intermediate B-1 in excess acetic anhydride. The resulting mixture is stirred at 20° C. for 16 hours. The reaction solution is concentrated in vacuo, and residual pyridine is removed by azeotropic distillation with toluene, followed by drying under high vacuum, to give intermediate B-2.

[0703] Other M6PR binding moiety synthons containing an amino linking group at position 1 of the pyranose ring can be prepared by adapting the method shown below.

[0704] Synthesis of synthon 38C [ka]

[0705] To a round-bottom flask containing intermediate A-8 (1.00 equiv., 218 mg, 0.398 mmol), 4-nitrophenyl N-hex-5-ynylcarbamate (38A) (1.80 equiv., 188 mg, 0.717 mmol) and anhydrous DCM (4 mL) were added. Triethylamine (2.08 equiv., 0.11 mL, 0.826 mmol) was added to the reaction solution, and the solution was stirred at 40 °C for 16 h. The reaction mixture was then diluted with dichloromethane (30 mL) and washed with aqueous NaOH, water, and saturated brine. The organic layer was dried over anhydrous MgSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol / chloroform to give compound 38B. Yield: 154 mg, 58%; LCMS m / z 655.6 [M+1] + .

[0706] To a nitrogen-purged round-bottom flask containing compound 38B (1.00 equiv., 170 mg, 0.260 mmol) was added acetonitrile (4 mL). The solution was cooled to 0° C. under nitrogen, followed by the dropwise addition of TMSBr (5.00 equiv., 0.18 mL, 1.30 mmol). The cooling bath was removed, and the resulting mixture was stirred at room temperature under nitrogen. LCMS after 2 hours indicated no starting material remained, and the product was observed to have an M+H=599.6. The solvent was removed on a rotary evaporator, and the residue was dried under high vacuum. The resulting intermediate, 2-[(2R,3R,4S,5S,6R)-3,4,5-triacetoxy-6-[4-(hex-5-ynylcarbamoylamino)phenoxy]tetrahydropyran-2-yl]ethylphosphonic acid (155 mg, 0.259 mmol, 99.72% yield), was dissolved in methanol (3 mL). To the above solution under nitrogen and stirring was added 25 wt% NaOMe in MeOH (2.50 equiv., 0.14 mL, 0.649 mmol). The resulting mixture was stirred under nitrogen at room temperature for 50 minutes. LCMS revealed that most of the starting material remained. Another aliquot of 25 wt% NaOMe in MeOH (2.50 equiv., 0.14 mL, 0.649 mmol) was added and stirred at 20 °C for 1 hour more. Acetic acid (13.5 equiv, 0.20 mL, 3.50 mmol) was added and the solvent was removed on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC (0-35% acetonitrile / water with 0.1% TFA). The purified product fractions were combined and lyophilized to dryness to give compound 38C as a white solid. Yield: 45 mg, 37%; LCMS m / z 473.6 [M+1] + .

[0707] Synthesis of synthons 39B / 53A [ka]

[0708] Oct-7-ynoic acid (1.66 equiv., 82.6 mg, 0.589 mmol), DMF (3 mL), and HATU (1.50 equiv., 203 mg, 0.534 mmol) were added to a nitrogen-purged round-bottom flask. After stirring the reaction solution at 20 °C for 20 min, a solution of intermediate A-8 (1.00 equiv., 195 mg, 0.356 mmol) in DMF (1 mL) was added. The reaction solution was stirred at 20 °C for 24 h before analysis by LCMS. The reaction solution was diluted with EtOAc (30 mL) and washed with saturated aqueous NH4Cl (20 mL) followed by saturated aqueous NaCl (20 mL). The partitioned EtOAc phase was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel using a mobile phase ranging from 100% hexane to 75% EtOAc / hexane over 15 min to give compound 39A. Yield: 182 mg, 76%; LCMS m / z 653.6 [M+1] + .

[0709] To a nitrogen-purged round-bottom flask containing compound 39A (1.00 equiv., 182 mg, 0.278 mmol) and anhydrous acetonitrile (1 mL) under nitrogen at 0 °C, TMSBr (5.00 equiv., 0.18 mL, 1.39 mmol) was added. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 3.5 hours. LCMS analysis indicated no starting reagent remained. The volatiles were removed on a rotary evaporator, and the residue was briefly dried under high vacuum. The residue was dissolved in methanol (1 mL) with stirring under nitrogen, and 25 wt% sodium methoxide in MeOH (2.50 equiv., 0.15 mL, 0.696 mmol) was added. The resulting mixture was stirred under nitrogen at room temperature for 30 minutes. To this reaction mixture was added acetic acid (5.00 equiv., 0.080 mL, 1.39 mmol), and the volatiles were removed in vacuo. The residue was taken up in DMSO and purified by reverse-phase preparative HPLC (0-35% acetonitrile / water with 0.1% TFA) to give purified fractions. The combined fractions were lyophilized to dryness to give compound 39B as a white solid. Yield: 65 mg, 50%; LCMS m / z 472.3 [M+1] + .

[0710] Synthesis of synthon 49B [ka]

[0711] A solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethan-1-amine (49A) (1.40 equiv., 30.7 mg, 0.164 mmol) in NMP (0.6 mL) was added to Intermediate A (1.00 equiv., 45.8 mg, 0.117 mmol) in a 1-dram vial equipped with a stir bar. The resulting mixture was stoppered and stirred at room temperature for 18 h. The solid gradually dis...

Claims

Claim 1: A cell surface M6PR-binding compound, wherein (a) the compound has the formula (XIIa): 【Chemical 308】 (wherein W is a non-hydrolyzable hydrophilic head group, Z １ is selected from optionally substituted (C １ -C ３ ) alkylene and optionally substituted ethenylene, Z ２ is selected from O, S, NR ２１ , and C(R ２２ ), ２ with the proviso that each R ２１ is independently selected from H and optionally substituted (C １ -C ６ )alkyl, and each R ２２ is independently selected from H, halogen (e.g., F), and optionally substituted (C １ -C ６ )alkyl. each A is independently an optionally substituted aryl or heteroaryl linking moiety (e.g., an optionally substituted monocyclic or bicyclic aryl or heteroaryl), Each Z ３ is an independent connection part, n is from 1 to 500, m is from 1 to 100, L is a linker, Y is a moiety of interest, When A is phenyl and Z ２ is O, then i) W is -P(O)(OH) ２ or ii) the linker L contains a backbone of at least 16 consecutive atoms and Y is a target-binding moiety)), or a prodrug thereof, or a salt thereof; or (b) the compound has the formula (XIIb): 【Chemical 309】 (wherein W is a non-hydrolyzable hydrophilic head group, Z1 is selected from optionally substituted (C1-C3) alkylene and optionally substituted ethenylene, Z2 is selected from O, S, NR21, and C(R22)2, provided that R21 is independently selected from H and optionally substituted (C1-C6) alkyl, and each R22 is independently selected from H, halogen (e.g., F), and optionally substituted (C1-C6) alkyl, A is an optionally substituted cyclic group (e.g., an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, or an optionally substituted cycloalkyl), each Z3 is independently a linking moiety, n is from 1 to 500, m is from 1 to 100, L is a linker, Y is a moiety of interest)), or a prodrug thereof, or a salt thereof, a cell surface M6PR-binding compound. Claim 2 Z ２ is S, and W is optionally a phosphonic acid, a thiophosphonic acid, a carboxylic acid or malonic acid, or a salt thereof, the compound according to claim 1, or a prodrug thereof, or a salt thereof. Claim 3: (a) the compound is a compound of formula (XIIb) and contains one M6PR-binding moiety (X) of the formula: 【Chemical 310】 (wherein R ａ , R ｂ , R ｃ , and R ｄ are each independently H or F) ; or (b) the compound is a compound of formula (XIIa) and contains one M6PR-binding moiety (X) of the formula: 【Chemical 311】 (wherein Ra, Rb, Rc, and Rd are independently H or F), the compound according to Claim 1, or a prodrug thereof, or a salt thereof. Claim 4 A is optionally substituted aryl or optionally substituted heteroaryl, preferably A is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted triazole, and optionally substituted phenyltriazole, optionally A is independently selected from optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, optionally substituted 2,5-pyridylene, and triazole, optionally A is 【Chemical 312】 wherein R11 to R14 are independently selected from H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, -CONHR25, and -NHCOR25, R25 is independently selected from H and optionally substituted (C1-C6) alkyl) selected from; or A is optionally substituted condensed bicyclic aryl or optionally substituted condensed bicyclic heteroaryl, optionally A is optionally substituted naphthalene or optionally substituted quinoline, optionally A is 【Chemical 313】 wherein R11 and R13 to R14 are independently selected from H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, -CONHR25, and -NHCOR25, s is 0 to 3, each R25 is independently selected from H and optionally substituted (C1-C6) alkyl) selected from, optionally A is 【Chemical 314】 selected from; or A is the following formula: 【Chemical 315】 wherein Cy is independently monocyclic aryl or monocyclic heteroaryl, R11 to R15 are each independently selected from H, halogen, OH, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, -CONHR25, and -NHCOR25, s is from 0 to 4, each R25 is independently selected from H and optionally substituted (C1-C6) alkyl), of an optionally substituted bicyclic aryl or an optionally substituted bicyclic heteroaryl, or a salt thereof, optionally Cy is phenyl optionally substituted, and A is of the formula: 【Chemical 316】 of an optionally substituted biphenyl, optionally A is 【Chemical 317】 selected from or optionally Cy is triazole and A is 【Chemical 318】 selected from; in all of the above, A is substituted with at least one OH substituent; and / or at least one of R11 to R15 is OH (for example, at least two are OH) or R11 to R15 are each H, the compound according to claim 1, or a prodrug thereof, or a salt thereof.

5. Z ３ is selected from a covalent bond, -O-, -NR ２３ -, -NR ２３ CO-, -CONR ２３ -, -NR ２３ CO ２ -, -OCONR ２３ , -NR ２３ C(=X １ )NR ２３ -, -CR ２４ =N-, -CR ２４ =N-X ２ , -N(R ２３ )SO ２ -, and -SO ２ N(R ２３ ), and is selected from -SO X １ and X ２ are selected from O, S, and NR ２３ and R ２３ and R ２４ are each independently selected from H, C （１～３） -alkyl (e.g., methyl), and substituted C （１～３） -alkyl, optionally Z3 is 【Chemical 319】 (wherein, X1 is O or S, t is 0 or 1, each R23 is independently selected from H, C(1-3)-alkyl (for example, methyl) and substituted C(1-3)-alkyl)), and optionally Z3 is -NHC(=O)NH-; and -A-Z3- is optionally 【Chemical 320】 【Chemical 321】 【Chemical 322】 selected from, the compound according to claim 1, or a prodrug thereof, or a salt thereof. **Claim 6**: The compound is a compound of formula (XIIa), and Z ２ is O, -NR₂₁-, -C(R₂₂)₂-, each R₂₂ is independently selected from H, halogen (for example, F), and optionally substituted (C₁-C₆) alkyl, and optionally Z₂ is -CH₂- or -CF₂- optionally -Z2-Ar-Z3- is 【Chemical 323】 (wherein, X is O, S, -CH2-, or -CF2, R16 is OH, w is from 0 to 4 (for example, w is 0, 1, or 2)), and optionally -Z2-Ar-Z3- is 【Chemical 324】 and, the compound according to claim 1, or a prodrug thereof, or a salt thereof.

7. Formula (XV): 【Chemical 325】 (wherein, W is a non-hydrolyzable hydrophilic head group, Z １ is selected from optionally substituted (C １ -C ３ ) alkylene and optionally substituted ethenylene, Z ４ is -Z １４ -, -Z １４ -A-, -A-, and -CH ２ -Z １４ - and is selected from, optionally Z4 is -CH2-Z14-, Z14 is selected from O, S, NR21, and C(R22)2, or Z4 is -CH2-A- or -A-, optionally A is optionally substituted aryl, or optionally substituted heteroaryl, preferably triazole, or Z4 is 【Chemical 326】 and, "*" indicates a bond to the linker L, Z １４ is selected from O, S, NR ２１ , and C(R ２２ ), ２ provided that R ２１ is independently selected from H and optionally substituted (C １ -C ６ ) alkyl, each R ２２ is independently selected from H, halogen (e.g., F), and optionally substituted (C １ -C ６ ) alkyl, A is an optionally substituted cyclic group (e.g., optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted cycloalkyl), n is from 1 to 500, m is from 1 to 100, L is a linker, Y is the moiety of interest), a cell surface M6PR-binding compound, or a prodrug thereof, or a salt thereof. **Claim 8** The non-hydrolyzable hydrophilic head group W is -OH, -CR ２ R ２ OH, -NR ３ P=O(OH) ２ , -P=O(OH) ２ , -P=S(OH) ２ , -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R １ OH, -PH(=O)OH, -CR １ R ２ -P=O(OH) ２ , -SO ２ OH (i.e., -SO ３ H), -S(O)OH, -COOH, -CN, -CONH ２ , -CONHR ３ , -CONR ３ R ４ , -CONH(OH), -CONH(OR ３ ), -CONHS O ２ R ３ , -CONHS O ２ NR ３ R ４ , -CH(COOH) ２ , -CR １ R ２ COOH, -SO ２ R ３ , -SOR ３ R ４ , -SO ２ NH ２ , -SO ２ NHR ３ , -SO ２ NR ３ R ４ , -SO ２ NHCOR ３ , -NHCOR ３ , -NH C(O)CO ２ H, -NHSO ２ NHR ３ , -NH C(O)NH S(O) ２ R ３ , -NHSO ２ R ３ , -NHSO ３ , 【Chemical 327】 selected from wherein R １ and R ２ are each independently hydrogen, SR ３ , halo, or CN, and R ３ and R ４ are each independently H, C １～６ alkyl, or substituted C １～６ alkyl (e.g., -CF ３ or -CH ２ CF ３ ), and A, B, and C are each independently CH or N, D is each independently O or S, optionally W is selected from -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), -COOH, and -CH(COOH)₂, and / or Z₁ is -(C(R₂₂)₂)j-, provided that each R₂₂ is independently selected from H, halogen (e.g., F), and optionally substituted (C₁-C₆)alkyl, j is from 1 to 3, Z₁ is preferably -(CH₂)₂-, -CH₂-CF₂- or -CH₂-CHF-, W is optionally selected from -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or Z₁ is -CH₂- or -CF₂-, W is optionally -CH(COOH)₂, or Z₁ is -CH=CH-, W is optionally selected from -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, the compound according to claim 1, or a prodrug thereof, or a salt thereof. **Claim 9** n is from 1 to 20 (e.g., from 1 to 10, from 1 to 6, or from 1 to 3), optionally n is 1, 2 or 3, optionally when n is 1, L comprises a linear linker having a backbone of 16 or more consecutive atoms that covalently attaches Z₃ to Y (e.g., a backbone of 16 to 100, or 20 to 100 consecutive atoms), and / or L is of formula (II): 【Chemical 328】 wherein L₁ and L₃ are independently linkers, L₂ is a branched linking moiety, and L₁ to L₃ together provide a linear or branched linker between X and Y, a, b, and c are independently 0 or 1, ** represents the junction point of X to L1 via Z1, *** represents the junction point to Y, when n is 1, a is 1 and b is 0, when n > 1, a is 1 and b is 1) is L of optionally, L1 to L3 are each independently, -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH-C1-6-alkylene-, -NHC1-6-alkylene-, -NHCONH-C1-6-alkylene-, -NHCSNH-C1-6-alkylene-, -C1-6-alkylene-NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCOCONH-, -C1-6-alkylene-NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, pyrrolidine-2,5-dione, 1,2,3-triazole, -NH-, and -NMe- (where each p is independently 1 to 50), and includes one or more linking moieties independently selected from optionally, L contains repeats of ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-), preferably 1 to 25 ethylene glycol moieties (e.g., 3, 7, or 24 ethylene glycol moieties), optionally, L contains one or more 1,2,3-triazole linking moieties, preferably L has the following structure: 【Chemical 329】 (wherein w1, u1, and q1 are independently 1 to 25 (e.g., 1 to 12, e.g., 1 to 6)) and includes one or more linking moieties selected from optionally, n is 1 or n is 2 or more, and L2 is optionally 【Chemical 330】 (where each x and y are independently 1 to 10) selected from Optionally, L1 to L2 contain a main chain of 14 or more consecutive atoms (e.g., 14 to 50 atoms, or 14 to 30 atoms, etc.) between Z2 or Z4 and the branching atom, and / or L3 contains a main chain of 10 to 80 consecutive atoms (e.g., 12 to 50 atoms, etc.), and L3 preferably contains a linking moiety selected from (C10 - C20)-alkylene (e.g., C12-alkylene), or -(OCH2CH2)p- (where p is 1 to 25 (e.g., 3, 7, or 24)). The compound according to claim 1, or a prodrug thereof, or a salt thereof, wherein optionally the linker of formula (II) contains 20 to 100 consecutive atoms, preferably 25 or more consecutive atoms, preferably 30 or more consecutive atoms. [

10. ] The compound according to claim 1, or a prodrug thereof, or a salt thereof, wherein m is 1, or m is at least 2, optionally 2 to 20 (e.g., m is 2 to 10), or m is 20 to 500 (e.g., 20 to 400, 20 to 300, or 20 to 200, or 50 to 500, or 100 to 500), and L is an α-amino acid polymer (e.g., poly-L-lysine), and a number of -Ar-Z3-groups are covalently bonded to the main chain of the polymer via side chain groups (e.g., via conjugation with the side chain amino group of a lysine residue). [

11. ] Y is selected from a small molecule, a dye, a fluorophore, a monosaccharide, a disaccharide, a trisaccharide, and a chemoselective linking group or a precursor thereof; or Y is a biomolecule, and the biomolecule is optionally selected from a peptide, a protein, a polynucleotide, a polysaccharide, a glycoprotein, a lipid, an enzyme, an antibody, and an antibody fragment; and / or Y is a moiety that specifically binds to a target protein, and the target protein is optionally a membrane-bound protein or a soluble extracellular protein; and / or The compound according to claim 1, or a prodrug thereof, or a salt thereof, wherein Y is selected from an antibody, an antibody fragment (e.g., an antigen-binding fragment of an antibody), a chimeric fusion protein, a modified protein domain, a D-protein binder of a target protein, an aptamer, a peptide, and a small molecule inhibitor or ligand. **Claim 12**: The non-hydrolyzable hydrophilic head group W is selected from -OH, -CR₂R₂OH, -NR₃P=O(OH)₂, -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), P(=O)R₁OH, -PH(=O)OH, -CR₁R₂-P=O(OH)₂, -SO₂OH (i.e., -SO₃H), -S(O)OH, -COOH, -CN, -CONH₂, -CONHR₃, -CONR₃R₄, -CONH(OH), -CONH(OR₃), -CONHSO₂R₃, -CONHSO₂NR₃R₄, -CH(COOH)₂, -CR₁R₂COOH, -SO₂R₃, -SOR₃R₄, -SO₂NH₂, -SO₂NHR₃, -SO₂NR₃R₄, -SO₂NHCOR₃, -NHCOR₃, -NHC(O)CO₂H, -NHSO₂NHR₃, -NHC(O)NHSO₂R₃, -NHSO₂R₃, -NHSO₃H, 【Chemical 327】 selected from wherein R₁ and R₂ are independently hydrogen, SR₃, halo, or CN; R₃ and R₄ are independently H, C₁₋₆ alkyl, or substituted C₁₋₆ alkyl (e.g., -CF₃ or -CH₂CF₃); A, B, and C are each independently CH or N; D is each independently O or S; optionally W is selected from -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), -COOH, and -CH(COOH)₂, and / or Z₁ is -(C(R₂₂)₂)j-, provided that each R₂₂ is independently selected from H, halogen (e.g., F), and optionally substituted (C₁ - C₆) alkyl, j is from 1 to 3, Z₁ is preferably -(CH₂)₂-, -CH₂ - CF₂ - or -CH₂ - CHF-, and W is optionally selected from -P=O(OH)₂, -P=S(OH)₂, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or Z1 is -CH2- or -CF2-, and W is optionally -CH(COOH)2, or Z1 is -CH=CH-, W is optionally selected from -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, the compound according to claim 7, or a prodrug thereof, or a salt thereof.

13. n is 1 to 20 (for example, 1 to 10, 1 to 6, or 1 to 3), optionally n is 1, 2 or 3, when n is optionally 1, L includes a linear linker having a main chain of 16 or more consecutive atoms (for example, a main chain of 16 to 100 atoms, or 20 to 100 atoms) that covalently bonds Z3 to Y, and / or L is of formula (II): 【Chemical 328】 (wherein L1 and L3 are each independently a linker, L2 is a branched chain linking moiety, and L1 to L3 together provide a linear or branched chain linker between X and Y, a, b, and c are each independently 0 or 1, ** represents the bonding point of X to L1 via Z1, *** represents the bonding point to Y, when n is 1, a is 1 and b is 0, when n>1, a is 1 and b is 1) is L of optionally L1 to L3 are each independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH-C1-6-alkylene-, -NHC1-6-alkylene-, -NHCONH-C1-6-alkylene-, -NHCSNH-C1-6-alkylene-, -C1-6-alkylene-NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene-NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, pyrrolidine-2,5-dione, 1,2,3-triazole, -NH-, and -NMe- (where each p is independently 1 to 50) and includes one or more linking moieties independently selected from Optionally, L is a repeat of ethylene glycol moieties (e.g., —CH2CH2O— or —OCH2CH2—), preferably containing 1 to 25 ethylene glycol moieties (e.g., 3, 7, or 24 ethylene glycol moieties), Optionally, L contains one or more 1,2,3-triazole linking moieties, preferably L has the following structure: 【Chemical 329】 (wherein w1, u1, and q1 are independently 1 to 25 (e.g., 1 to 12, e.g., 1 to 6)) and contains one or more linking moieties selected from: Optionally, n is 1, or n is 2 or more, and L2 is optionally 【Chemical 330】 (wherein each x and y is independently 1 to 10) selected from: Optionally, L1 to L2 contain a main chain of 14 or more consecutive atoms (e.g., 14 to 50, or 14 to 30 atoms, etc.) between Z2 or Z4 and the branching atom, and / or L3 contains a main chain of 10 to 80 consecutive atoms (e.g., 12 to 50 atoms, etc.), and L3 preferably contains a linking moiety selected from (C10 - C20)-alkylene (e.g., C12-alkylene), or —(OCH2CH2)p— (where p is 1 to 25 (e.g., 3, 7, or 24)); Optionally, the linker of formula (II) contains 20 to 100 consecutive atoms, preferably 25 or more consecutive atoms, preferably 30 or more consecutive atoms, the compound according to claim 7, or a prodrug thereof, or a salt thereof.

14. The compound according to claim 7, or a prodrug thereof, or a salt thereof, wherein m is 1, or m is at least 2, optionally 2 to 20 (e.g., m is 2 to 10), or m is 20 to 500 (e.g., 20 to 400, 20 to 300, or 20 to 200, or 50 to 500, or 100 to 500), and L is an α-amino acid polymer (e.g., poly-L-lysine), and a number of —Ar—Z3— groups are covalently bonded to the main chain of the polymer via side chain groups (e.g., via conjugation with the side chain amino group of lysine residues).

15. Y is selected from small molecules, dyes, fluorophores, monosaccharides, disaccharides, trisaccharides, and chemoselective linking groups or precursors thereof; or Y is a biomolecule, and the biomolecule is optionally selected from peptides, proteins, polynucleotides, polysaccharides, glycoproteins, lipids, enzymes, antibodies, and antibody fragments; and / or Y is a moiety that specifically binds to a target protein, and the target protein is optionally a membrane-bound protein or a soluble extracellular protein; and / or Y is selected from an antibody, an antibody fragment (e.g., an antigen-binding fragment of an antibody), a chimeric fusion protein, a modified protein domain, a D-protein binder of a target protein, an aptamer, a peptide, and a small molecule inhibitor or ligand, the compound according to claim 7, or a prodrug thereof, or a salt thereof.

16. Formula (XXI): 【Chemical 331】 a target protein-degrading conjugate, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein In the formula,[[]] n is 1 to 3,[[]] m is an average loading number of 1 to 10,[[]] L is a linker,[[]] P is a biomolecule that specifically binds to the target protein,[[]] Z ５ is a bonding moiety remaining from covalently bonding a chemoselective linking group of linker L to a compatible group of P, W is a non-hydrolyzable hydrophilic head group,[[]] Z １ is selected from optionally substituted (C １ -C ３ ) alkylene and optionally substituted ethenylene, Z ２ is selected from O, S, NR ２１ , and C(R ２２ ) ２ , provided that R ２１ is independently selected from H and optionally substituted (C １ -C ６ ) alkyl, and each R ２２ is independently selected from H, halogen (e.g., F), and optionally substituted (C １ -C ６ ) alkyl. A is an optionally substituted cyclic group,[[]] Z ３ is a connecting part, the conjugate is optionally a conjugate of formula (XXIb): 【Chemical 332】 wherein W, Z1, Z2, A, Z3, n and / or L are each independently, preferably as defined in any one of claims 2 to 6, 8 and 9, and / or the conjugate preferably contains an M6PR-binding moiety as defined in any one of claims 3 to 6, 8 and 9,[[]] Y is optionally an antibody or an antibody fragment that specifically binds to the target protein,[[]] m is optionally 1 to 8 (e.g., 1 to 7, or 1 to 6), preferably about 8, about 6, about 5, about 4, about 3, or about 2,[[]] optionally n is 1, m is 1 to 10, preferably 2 to 8 (e.g., 2 to 6, or 3 to 5), preferably about 4, or n is 2, m is 1 to 6 (e.g., 2 to 6, or 3 to 5), preferably about 4,[[]] ​ Optionally, Z5 is a moiety remaining from covalently linking a thiol-reactive chemoselective linker (e.g., maleimide) to one or more cysteine residues of P, or Z5 is a moiety remaining from covalently linking an amine-reactive chemoselective linker (e.g., PFP ester or TFP ester) to one or more cysteine residues of P, Optionally, L is a linear linker having a backbone of 16 or more consecutive atoms (e.g., a backbone of 16 to 100, or 20 to 100 consecutive atoms) that covalently links Z3 to P, or L is a branched linker having a backbone of 14 or more consecutive atoms (e.g., 14 to 50, or 14 to 30 atoms, etc.) between Z2 and the branching atom of the branched linker, Optionally, the linker L is selected from any one of the structures in Tables 4-5, Optionally, the conjugate is derived from the conjugation of a compound of any one of the structures in Tables 7-9, 12, and 13 with a biomolecule P, where P is preferably an antibody or antibody fragment, the antibody or antibody fragment is preferably an IgG antibody and / or a humanized antibody, and / or the conjugate, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, that specifically binds to a secreted protein or soluble protein or specifically binds to a cell surface receptor.

17. A composition for use in a method of internalizing a target protein into cells containing cell surface M6PR, the composition comprising a compound according to any one of claims 1 to 15, or a prodrug thereof, or a salt thereof, the method comprising contacting a cell sample containing the cells and the target protein with the compound, the prodrug, or the salt, The compound, the prodrug, or the salt specifically binds to the target protein and specifically binds to the cell surface receptor to promote cellular uptake of the target protein, the target protein being optionally a membrane-bound protein or an extracellular protein, and / or the compound, the prodrug, or the salt comprises an antibody or antibody fragment (Ab) that specifically binds to the target protein, the composition.

18. A composition for use in a method for reducing the level of a target protein in a biological system, said composition comprising the compound according to any one of claims 1 to 15, or a prodrug thereof, or a salt thereof, said method comprising contacting said biological system with said compound, said prodrug, or said salt, wherein said compound, said prodrug, or said salt specifically binds to said target protein and specifically binds to the cell surface M6PR of cells in said biological system to promote cellular uptake and degradation of said target protein, said biological system being optionally a human subject or an in vitro cell sample, and / or said target protein being a membrane-bound protein or an extracellular protein, said method.

19. A composition for treating a disease or disorder associated with a target protein in a subject in need of treatment for a disease or disorder associated with a target protein, said composition comprising the compound according to any one of claims 1 to 15, or a prodrug thereof, or a salt thereof, wherein said compound, said prodrug, or said salt specifically binds to said target protein, and said disease or disorder is optionally selected from the group consisting of inflammatory diseases, autoimmune diseases, or cancers, said composition.

20. A composition for use in a method for internalizing a target protein into cells containing cell surface M6PR, said composition comprising the conjugate according to claim 16, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, said method comprising contacting a cell sample containing said cells and said target protein with said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof, wherein said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof specifically binds to said target protein and specifically binds to said cell surface receptor to promote cellular uptake of said target protein, said target protein being optionally a membrane-bound protein or an extracellular protein, and / or said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof comprising an antibody or antibody fragment (Ab) that specifically binds to said target protein, said composition. A composition for use in a method of reducing the level of a target protein in a biological system, said composition comprising the conjugate according to claim 16, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, said method comprising contacting said biological system with said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof, wherein said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof specifically binds to said target protein and specifically binds to the cell surface M6PR of a cell in said biological system to promote cellular uptake and degradation of said target protein, said biological system being optionally a human subject or an in vitro cell sample, and / or said target protein being a membrane-bound protein or an extracellular protein, said method. A composition for treating a disease or disorder associated with a target protein in a subject in need thereof, said composition comprising the conjugate according to claim 16, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein said conjugate, or said prodrug, or said pharmaceutically acceptable salt thereof specifically binds to said target protein, and said disease or disorder is optionally selected from the group consisting of inflammatory diseases, autoimmune diseases or cancers, said composition.

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