M6PR-conjugated compounds and conjugates

Abstract

This disclosure provides a class of compounds comprising a ligand moiety that specifically binds to the cell surface mannose-6-phosphate receptor (M6PR). M6PR-binding compounds can trigger the receptor to move the bound compound into the cell. The ligand moieties of this disclosure can be conjugated to various target moieties without affecting their specific binding to and function of M6PR. Compounds that are conjugates of the ligand moiety conjugated to biomolecules such as antibodies are also provided, which can utilize cellular pathways to remove specific target proteins from the cell surface or extracellular environment. For example, the conjugates described herein can sequester and / or degrade target molecules of interest within cellular lysosomes. Methods for targeting proteins for sequester and / or lysosomal degradation using conjugates are also provided.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Application No. 63 / 439,806, filed on 18 January 2023 under 35 U.S. Code § 119(e), the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 1. Background Many therapeutic agents work by binding to functionally important sites on target proteins and modulating their activity, or by recruiting immune effectors to act on target proteins, as is the case with many monoclonal antibody drugs. However, there is an undeveloped repository of medically important human proteins, and these proteins are considered "undrug-unavailable" because they cannot be easily targeted by currently available therapeutic targeting approaches. Therefore, there is a need for therapies that can target a wider range of proteins.

[0003] Mannose-6-phosphate is a monosaccharide ligand that plays a crucial role in the intracellular retention and secretion of lysosomal hydrolytic enzymes to which it binds. When this sugar residue is incorporated into newly synthesized enzymes, it can induce the transport of those enzymes from the Golgi apparatus to lysosomes, where they are activated. Membrane-bound cell surface mannose-6-phosphate receptors (M6PRs) play a role in many biological processes, including the secretion and internal translocation of such lysosomal enzymes. Endocytosis by M6PRs enables the internal translocation of compounds containing mannose-6-phosphate (M6P) ligands into cells and their transport to lysosomes.

[0004] Alternative ligands that provide transport across the cell membrane following binding to cell surface M6PR are of great interest. [Overview of the project] [Means for solving the problem]

[0005] 2. Overview This disclosure provides a class of compounds comprising a ligand moiety that specifically binds to the cell surface mannose-6-phosphate receptor (M6PR). Cell surface M6PR-binding compounds can trigger the receptor, allowing the binding compound to be internally transported into the cell. The ligand moieties of this disclosure can be conjugated to various target moieties without affecting their specific binding to and function of cell surface M6PR. Compounds that are conjugates of the ligand moiety conjugated to biomolecules such as antibodies are also provided, which can utilize cellular pathways to remove specific proteins of interest from the cell surface or extracellular environment. For example, the conjugates described herein can sequester and / or degrade target molecules of interest within cellular lysosomes. Also provided herein are compositions comprising such conjugates, methods for targeting target polypeptides for sequesteration and / or lysosomal degradation using the conjugates, and methods for treating disorders or diseases using the conjugates. [Brief explanation of the drawing]

[0006] 3. Brief explanation of the drawing [Figure 1] Representative natural mass spectrometry (MS) analyses of matsuzumab-(compound A) conjugate versus deglycosylated matsuzumab, which are exemplary conjugates, are shown. [Figure 2] Representative natural mass spectrometry (MS) analyses of matsuzumab-(compound 520(I-7)) conjugate versus deglycosylated matsuzumab, which are exemplary conjugates, are shown. [Figure 3] This shows the time-dependent activity of cetuximab-(compound A) and cetuximab-(compound 520(I-7)) conjugates on surface EGFR levels in Hela parental cells and M6PR knockout (KO) cells, as measured by surface staining. [Figure 4]This shows the time-dependent activity of matsuzumab-(compound A) and matsuzumab-(compound 520(I-7)) conjugates on surface EGFR levels in Hela parental cells and M6PR KO cells, as measured by surface staining. [Figure 5] Intracellular Western blotting images showing the dose response of cetuximab-(compound A), cetuximab-(compound 520(I-7)), matsuzumab-(compound A), and matsuzumab-(compound 520(I-7)) conjugate to total EGFR levels in Hela parental cells and M6PR KO cells are shown. [Figure 6] This study demonstrates the time-dependent activity of cetuximab-(compound A), cetuximab-(compound 520(I-7)), matsuzumab-(compound A), and matsuzumab-(compound 520(I-7)) conjugates in relation to relative EGFR normalization levels in Hela parental cells and M6PR KO cells. [Figure 7A] The M6PR binding affinity curve of the unlabeled control to M6PR is shown. Binding to M6PR was measured by ELISA. RFU stands for relative fluorescence unit. [Figure 7B] This shows the M6PR binding affinity curves for compound 520(I-7), an exemplary conjugate of fluorescently labeled matsuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]) to M6PR. Binding to M6PR was measured by ELISA. The compound 520(I-7) (m or DAR=8) conjugate showed the highest binding affinity. d4 is DAR 4. d8 is DAR 8. RFU is relative fluorescence unit. [Figure 7C] This shows the M6PR binding affinity curves for compound 602(I-8), an exemplary conjugate of fluorescently labeled matsuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]) to M6PR. Binding to M6PR was measured by ELISA. d4 is DAR 4. RFU is the relative fluorescence unit. [Figure 7D]This shows the M6PR binding affinity curves for compound 603(I-9), an exemplary conjugate of fluorescently labeled matsuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]) to M6PR. Binding to M6PR was measured by ELISA. d4 is DAR 4. RFU is the relative fluorescence unit. [Figure 7E] This shows the M6PR binding affinity curves for compound 605(I-11), an exemplary conjugate of fluorescently labeled matsuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]) to M6PR. Binding to M6PR was measured by ELISA. The conjugate of compound 605(I-11) (m or DAR=4) showed the lowest binding affinity. d4 is DAR 4. RFU is relative fluorescence unit. [Figure 7F] The M6PR binding affinity curves for compound 716(I-12), an exemplary conjugate of fluorescently labeled matsuzumab (mtz) or human IgG isotype antibody (isotype) ([ab]) to M6PR, are shown. Binding to M6PR was measured by ELISA. d4 is DAR 4. RFU is relative fluorescence unit. [Figure 8A] This paper presents serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibodies in mice. Intracellular levels of compound 520(I-7) conjugates (DAR=8 at d8) and (DAR=4 at d4) in mouse serum were measured at 0.5, 1, 2, 6, and 24 hours after administration using ELISA. UNLB is the antibody control. [Figure 8B] This paper presents serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibodies in mice. Intracellular levels of compound 604(I-10) and compound 605(I-11) conjugates in mouse serum were measured at 0.5, 1, 2, 6, and 24 hours after administration using ELISA. UNLB is the antibody control. [Figure 8C]This paper presents serum pharmacokinetic (PK) analysis of exemplary conjugates of rIgG1 (anti-IgG2a) antibodies in mice. Intracellular levels of conjugates of compound 603(I-9) and compound 716(I-12) in mouse serum were measured at 0.5, 1, 2, 6, and 24 hours after administration using ELISA. UNLB is the antibody control. [Figure 9] This shows the time-course intracellular uptake of exemplary anti-IgG2a conjugates and their bound target proteins in Jurkat cells. The conjugates were detected by a fluorescent Alexa488-conjugate-targeted IgG2a antibody, and intracellular fluorescence levels (MFI) were measured using FACS at 1 hour and 24 hours. [Figure 10] The relative intracellular uptake of 10 nM exemplary anti-IgG2a conjugate and the conjugated target protein (Alexa488-conjugate-targeted IgG2a-antibody) into Jurkat cells after 24 hours is shown as a percentage of uptake of the reference compound 520(I-7) (d8 is DAR=8). [Figure 11] This graph shows the results of M6PR binding assays for various antibody conjugates of exemplary compounds with varying DAR loadings. [Figure 12] This graph shows cell fluorescence (MFI) versus antibody conjugate concentration ([Ab]) illustrating that an exemplary M6PR-conjugated antibody conjugate exhibited robust uptake of the target protein into Jurkat cells after 1 hour of incubation. [Figure 13] A graph of cell fluorescence (MFI) versus antibody conjugate concentration ([Ab]) is shown, illustrating that various antibody conjugates of exemplary M6PR or ASGPR-binding compounds showed comparable potent uptake into HepG2 cells after 1 hour of incubation. [Figure 14] This graph shows the CI-M6PR-dependent cellular uptake of exemplary antibody conjugates bound to Alexa488-labeled IgE targets in wild-type (WT) K562 cells versus CI-M6PR knockout (KO) cells. [Figure 15]The graph shows the cellular uptake of various conjugates of omalizumab (anti-IgE) with exemplary M6PR-binding compounds in Jurkat cells, where the conjugates bind to Alexa488-labeled target IgE. [Figure 16] Figure 15 shows a graph comparing the cellular uptake activity of specific exemplary conjugates. [Figure 17] Figure 15 shows a graph comparing the cellular uptake activity of specific exemplary conjugates. [Figure 18] This graph shows the cellular uptake of various conjugates of omalizumab (anti-IgE) bound to Alexa488-labeled target IgE and an exemplary M6PR ligand-linker in Jurkat cells. [Figure 19] Figure 18 shows a graph comparing the cellular uptake activity of specific exemplary conjugates. [Figure 20] Figure 18 shows a graph comparing the cellular uptake activity of specific exemplary conjugates. [Figure 21] Figure 18 shows a graph comparing the cellular uptake activity of specific exemplary conjugates. [Figure 22] Graphs of M6PR binding affinity data for various exemplary cetuximab (anti-EGFR) conjugates of this disclosure are shown. [Figure 23] A graph showing the cellular uptake activity of specific exemplary target-binding conjugates of this disclosure is shown. [Figure 24] A synthesis scheme for an M6PR binding moiety suitable for linking to a linker and / or the desired portion is shown. [Figure 25] A synthesis scheme for an M6PR binding moiety suitable for linking to a linker and / or the desired portion is shown. [Modes for carrying out the invention]

[0007] 4. Detailed explanation As summarized above, this disclosure provides a class of compounds comprising a specific ligand moiety X (also called an M6PR-binding moiety or M6PR ligand moiety) that specifically binds to the cell surface mannose-6-phosphate receptor (M6PR). The M6PR-binding moieties of this disclosure can be ligated to various desired moieties without affecting their specific binding to and function of cell surface M6PR. The inventors have demonstrated that the compounds of this disclosure can utilize the function of cell surface M6PR in biological systems, for example, internal translocation and / or sequestration into cellular lysosomes, and possibly lysosomal degradation of subsequent target molecules. The compounds of this disclosure can be used in a variety of applications. In some embodiments, the M6PR-binding moiety X provides intracellular delivery of the desired moiety. In some embodiments, the compound is a bifunctional compound comprising an M6PR-binding moiety X ligated to a target binding moiety for internal translocation and / or lysosomal degradation of the bound target molecule.

[0008] Therefore, this disclosure relates to compounds of formula (XI) comprising one or more M6PR-bonded moieties linked to the target moiety Y. [ka] or provide a salt thereof, in the formula, X is an M6PR-bonding portion (for example, as described herein), n is between 1 and 500 (for example, X is linked by monovalent or polyvalent linkers as described herein), m is between 1 and 500 (for example, 1 to 100, or 1 to 10), L is a linker, Y is the part of interest (for example, as described herein).

[0009] The compounds and conjugates of this disclosure, as well as the methods, are described in more detail below. A specific class of M6PR-binding compounds is described. In some embodiments, the compound is a biomolecular conjugate comprising one or more linked M6PR-binding moieties. The linker (L) and the target moiety (Y) used in the M6PR-binding compounds and biomolecular conjugates are also described. Methods in which the compounds and conjugates of this disclosure are used are also described.

[0010] 4.1.M6PR joint part As summarized above, the M6PR binding moieties (also called M6PR ligand moieties) of this disclosure can be linked to a variety of target moieties without affecting their specific binding to cell surface M6PR and its function. We have demonstrated that M6PR binding moieties having the specific structures described below provide high-affinity binding to cell surface M6PR, and when configured with a linker according to the bifunctional compounds of this disclosure, they can be utilized for the function of cell surface M6PR in biological systems, such as internalization and / or degradation of target molecules.

[0011] The terms "mannose-6-phosphate receptor" and "M6PR" refer to receptors of the mannose-6-phosphate receptor family. M6PR is an enzyme-targeting transmembrane glycoprotein receptor for intracellular lysosomes. M6PR endogenously transports proteins containing N-glycans capped with mannose-6-phosphate (M6P) residues to lysosomes, where they circulate between endosomes, the cell surface, and the Golgi complex. See, for example, 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 the insulin-like growth factor 2 receptor (IGF2R) and in humans, it is encoded by the IGF2R gene (see, for example, NCBI reference sequence: NM_000876.3 and NCBI gene ID: 3482). CI-M6PR is bound to insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P) tagged proteins. The compounds of this disclosure can specifically bind to cell surface M6PR, for example, to internally distributed CI-M6PR cell surface receptors. In certain embodiments, the surface CI-M6PR is human CI-M6PR. The terms M6PR and CI-M6PR are understood to be used interchangeably when referring to the M6PR binding moieties and binding properties of the compounds of this disclosure.

[0012] Compounds containing such an M6PR binding moiety (X) (e.g., as described herein) may also bind to other receptors, and may bind with lower affinity, for example, as determined by immunoassays or other assays known in the art. In certain embodiments, X, or a compound described herein containing such X, specifically binds to cell surface CI-M6PR with an affinity of at least 2-log, 2.5-log, 3-log, or 4-log than the affinity with which X or the compound binds to another cell surface receptor. In certain embodiments, X, or a compound described herein containing X, has an affinity of 20 mM or less (K d) binds specifically to CI-M6PR. In certain embodiments, such binding has an affinity (K d ) of 10 mM or less, 1 mM or less, 100 uM or less, 10 uM or less, 1 uM or less, 100 nM or less, 10 nM or less, or 1 nM or less. The terms "bind", "bind to", "bind specifically to", or "bind specifically to" are used interchangeably.

[0013] The M6PR binding compounds of the present disclosure include a moiety (X) (e.g., as described herein) that is a D-mannopyranose analog that binds specifically to the cell surface receptor M6PR. The M6PR binding compounds can be monovalent or multivalent (e.g., divalent or trivalent or higher valency), a monovalent compound includes a single M6PR ligand moiety, and a multivalent compound includes two or more such moieties.

[0014] 4.1.1. Alpha-linked pyranose ring The M6PR binding moiety of the compounds of the present disclosure can include a linked pyranose ring represented by formula (II),

Chemical formula

[0015] In some embodiments of formula (II), Z 2 is a linking moiety linked in an alpha configuration to the pyranose sugar ring at the anomeric position or the 1-position, as shown in formula (IIa) below. [ka]

[0016] 4.1.2. Beta-linked pyranose ring The inventors have demonstrated that while M6PR-binding compounds having an M6PR-binding moiety with the anomeric alpha configuration of formula (IIa) can provide good binding and internalization activity at the receptor, in some cases, it is possible to confer stronger binding and internalization activity at M6PR by constituting a pyranose sugar ring at the center of the M6PR-binding moiety having a beta configuration at the anomeric position. In some embodiments, such an M6PR-binding moiety can enhance the stability of the pyranose ring.

[0017] Therefore, in some embodiments of equation (II), Z 2 This is a linkage portion that is linked to the sugar ring in a beta configuration at the anomeric or 1-position, as shown in formula (IIb) below. [ka]

[0018] 4.2.M6PR binding compounds The portion of formula (II) can exhibit binding activity to M6PR, but the inventors believe that certain types of cyclic groups can bind to the linked portion Z. 2 We demonstrated that when linked adjacent to the pyranose ring of formula (II) in a specific configuration, an M6PR binding moiety with the desired binding activity can be generated.

[0019] Therefore, in some embodiments of formula (II), the M6PR coupling portion (X) is the one shown in formula (III), [ka] or its prodrug or salt thereof, in the formula, W is a hydrophilic head group, Z 1This is selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. Z 2 O, S, NR 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. A is an independently and arbitrarily substituted cyclic group, Z 3 It is an independent connecting part.

[0020] In some embodiments of formulas (II) to (III), W is a non-hydrolyzable hydrophilic head group.

[0021] In some embodiments of equations (II) to (III), Z 2 is optionally substituted ethylene. In some embodiments of formulas (II) to (III), Z 2 This is ethenylene with arbitrary substitution.

[0022] In some embodiments of equations (II) to (III), Z 2 is O. In some embodiments of equations (II) to (III), Z 2 is S. In some embodiments of equations (II) to (III), Z 2 -NR 21 - is the case. In some embodiments of equations (II) to (III), Z 2 -C(R 22 )2-, and in the formula, each R 22 is independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. In some embodiments of formulas (II)-(III), Z 2 It is -CH2-.

[0023] In some embodiments of formulas (II) to (III), A is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted cycloalkyl. In some embodiments of formulas (II) to (III), A is independently an optionally substituted aryl or heteroaryl linking moiety (e.g., an optionally substituted monocyclic or bicyclic aryl or heteroaryl).

[0024] Exemplary Z of equations (II) to (III) 3 The connecting parts are described herein.

[0025] Such an M6PR binding moiety of formula (III) can be bound to a target moiety or molecule to generate a bifunctional compound that undergoes effective M6PR-mediated intracellular translocation. The inventors have further demonstrated that, when the target moiety or molecule is a target protein binding moiety, the M6PR-binding compound also enables M6PR-mediated intracellular translocation and / or degradation of the bound target protein.

[0026] Therefore, in some embodiments of formula (XI), the M6PR-bound compound is the one of formula (XII), [ka] or its prodrug, or its salt, During the ceremony, W is a hydrophilic head group, Z 1 This is selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. Z 2 O, S, NR 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. A is an independently and arbitrarily substituted cyclic group, Z 3 It is an independent connecting part, n is between 1 and 500. L is a linker, Y is the target part, m is between 1 and 100.

[0027] In some embodiments of formulas (XI) to (XII), m is 1, and the cell surface M6PR binding compound is that of formula (XIII). [ka] or its prodrug, or its salt, During the ceremony, W is a hydrophilic head group, Z 1 This is selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. Z 2 O, S, NR 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. A is an independently and arbitrarily substituted cyclic group, Z 3 It is an independent connecting part, n is between 1 and 500. L is a linker, Y is the part of interest (for example, as described herein).

[0028] In some embodiments of formula (XIII), Y is a chemoselective ligation group. In some embodiments of formula (XIII), n is 1. In some embodiments of formula (XIII), Y is a chemoselective ligation group linked to n M6PR bond moieties (Xn-) by 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, for example, 20 to 80, or 20 to 50. In some embodiments of formula (XIII), when n is 5 or greater, L is a polypeptide-containing linker (for example, as described herein).

[0029] In some embodiments of formulas (XII) to (XIII), when n is 1 and A is phenyl, then i) L comprises a skeleton of at least 16 consecutive atoms (e.g., at least 18 consecutive atoms, or at least 20 consecutive atoms, and possibly up to about 200 consecutive atoms), ii) Y is a biomolecule, and / or ii) Z 3 This is an amide, sulfonamide, urea, or thiourea linking portion to linker L.

[0030] In some embodiments of equation (XII), Z 2 As shown in formula (IIa), this is a linkage portion connected to the sugar ring in an alpha configuration at the anomeric or 1-position, and as a result, the compound is of formula (XIIa). [ka]

[0031] In some embodiments of equation (XII), Z 2 As shown in formula (IIb), this is a linkage portion connected to the sugar ring in a beta configuration at the anomeric or 1-position, and as a result, the compound is of formula (XIIb).

[0032] [ka]

[0033] In some embodiments of formulas (XI) to (XIIb), multiple M6PR binding sites, such as those in formula (III), are linked by multiple linkers L to different ligation sites on the desired portion Y. In some embodiments, when Y is a biomolecule, the compounds of formulas (XI) to (XIIb) can be called conjugates.

[0034] 4.2.1. Hydrophilic head base and connecting portion In some embodiments of equations (II) to (XIII), the M6PR coupling portion (X) is the connecting portion (Z 1 The compound comprises an analog or precursor or prodrug of a D-mannopyranose ring having a hydrophilic head group linked at the 5th position of the sugar ring by a ) . The linking portion can be 1 to 6 atoms, 1 to 5, 1 to 4 or 1 to 3 atoms, for example, with a length of 1 or 2 atoms. It is understood that the length of the linking portion can be selected in combination with the hydrophilic head group.

[0035] The hydrophilic head group (W) can be any suitable negatively charged group or a salt thereof. In some embodiments, the hydrophilic head group is a neutral, polar, or hydrophilic group. Generally, the hydrophilic head group can hydrogen bond or interact electrostatically with M6PR under aqueous or physiological conditions, similar to the phosphate group of M6P. The hydrophilic head group can be a bioisoster (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., under physiological conditions, the Z of X to which the hydrophilic head group is bound 1 It is a functional group that is stable (e.g., chemically or enzymatically) against cleavage from the linking portion and / or the pyranose ring.

[0036] Hydrophilic head groups are generally small groups such as heteroatom-containing functional groups or single heterocyclic groups, and in some cases have a MW of less than 200, for example, less than 150 or less than 100.

[0037] In some embodiments, the hydrophilic head group is a phosphonate or its bioisoster, such as a carboxylate or malonic acid ester. In some embodiments, the hydrophilic head group is a thiophosphonate.

[0038] In some embodiments of formulas (II) to (XIII), the hydrophilic head group is not phosphate, thiophosphate, or dithiophosphate. This is because such groups have a phosphate ester bond to the compound, and this phosphate ester bond is unstable under physiological conditions and may be easily cleaved (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. This disclosure also provides alternative non-hydrolyzable head groups in addition to phosphonates that retain the binding and internalization activity of the resulting M6PR-bound compounds.

[0039] In any one of the embodiments of formulas (II) to (XIII), the 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 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 R2 COOH 、 -SO2R 3 -SOR 3 R 4 , -SO2NH 2、 -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] and [ka] , or selected from those salts, During the ceremony, R 1 and R 2 Independently, hydrogen, SR 3 , halo, or CN, R 3 and R 4 H and C are independent of each other. 1~6 Alkyl or substituted C 1~6 It is an alkyl group (e.g., -CF3 or -CH2CF3), A, B, and C are each independently CH or N. Each D is independently either O or S.

[0040] In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is a phosphate group or a thiophosphate group, for example, -OP=O(OH)2, -SP=O(OH)2, -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH)2, -OP=O(N(R3)2)(OH), or -OP=O(R3)(OH), or a salt thereof. In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is non-hydrolyzable, and thus is not selected from phosphoric acid or thiophosphoric acid, for example, -OP=O(OH)2, -SP=O(OH)2, -OP=O(SH)(OH), -SP=O(SH)(OH), -OP=S(OH) 3 )2)(OH), or -OP=O(R 3 )(OH), or a salt thereof.

[0041] In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is charged, for example, capable of forming a salt under aqueous or physiological conditions. In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is selected from -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<0{000095>COOH, and -NHC(O)CO2H.

[0042] In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is a phosphonate or thiophosphonate (e.g., -P=O(OH)2, -P=S(OH)2, -P=O(SH)(OH), or -P=S(SH)(OH), or salts thereof). In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is a phosphonate or a salt thereof. In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is -CO2H or a salt thereof. In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is a malonic ester (e.g., -CH(COOH)2 or a salt thereof).

[0043] In some embodiments of Formulas (II) to (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) to (XIII), the hydrophilic head group W is a sulfonate (e.g., -SO3H or a salt thereof).

[0044] In some embodiments, the hydrophilic head group W is neutrally hydrophilic. In some embodiments of Formulas (II) to (XIII), the hydrophilic head group W is -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, -SO2NHR3, -SO2NR 3 R 4 , -SO2NHCOR 3 , -NHCOR 3 , -NHSO2NHR 3 , -NHC(O)NHS(O)2R 3 , and -NHSO2R 3 selected from.

[0045] In some embodiments of formulas (II) to (XIII), the hydrophilic head group W is a heterocycle, for example, [ka] and [ka] , or including their salts, In the formula, A, B, and C are independently either CH or N, and D is independently either O or S.

[0046] In some embodiments of formulas (II) to (XIII), the hydrophilic head group W is a 5-membered heterocycle, for example, [ka] or [ka] , or including their salts.

[0047] In some embodiments of formulas (II) to (XIII), the hydrophilic head group W is selected from optionally substituted (C1 to C2) alkylenes and optionally substituted ethenylenes. 1 It is connected to the pyranose ring by Z. 1 Z can be selected in combination with W to provide a desired spacing between the 5th position of the ring and the charged or polar center of W. For example, if W is a malonate having a CH atom linking two carboxylic acid groups, then Z 1 This may be methylene, and together they provide the desired two-carbon spacer between the ring and the COOH group.

[0048] In some embodiments of equations (II) to (XIII), Z 1 is methylene or a substituted methylene. In some embodiments of formulas (II) to (XIII), Z 1 is ethyl or substituted ethyl. In some embodiments of formulas (II) to (XIII), Z1 is ethenylene or a substituted ethenylene. In some embodiments of formulas (II)-(XIII), Z 1 It is substituted with one or more halogens, such as fluorine.

[0049] In some embodiments of formula (III), the M6PR coupling portion (X) is represented by one of formulas (IV-1) to (IV-3), [ka] In the formula, R a , R b , R c and R d These are independently H or F.

[0050] In some embodiments of equations (IV-1) to (IV-3), Z 2 It is O.

[0051] In some embodiments of equations (IV-1) to (IV-3), Z 2 S is.

[0052] In some embodiments of equations (IV)-1 to (IV-3), Z 2 -NR 21 - is

[0053] In some embodiments of equations (IV-1) to (IV-3), Z 2 is -C(R 22 )2-, and in the formula, each R 22 Z is independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. In some embodiments of formulas (IV-1)-(IV-3), Z 2 It is -CH2-.

[0054] In some embodiments of equations (IV-1) to (IV-3), R a , R b , R c and R d These are H.

[0055] In some embodiments of formula (IV-1), R a H, R b is F. In some embodiments of equation (IV-1), R a and R b These are F.

[0056] In some embodiments of equation (IV-2), R c is H. In some embodiments of equation (IV-2), R c It is F.

[0057] In some embodiments of formula (IV-3), R d is H. In some embodiments of equation (IV-3), R d It is F.

[0058] In some embodiments of formulas (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 salts thereof. In some embodiments of formulas (IV-1) and (IV-3), W is -P=O(OH)2, or a salt thereof. In some embodiments of formulas (IV-1) and (IV-3), W is COOH, or a salt thereof.

[0059] In some embodiments of formula (IV-1), R a and R b is F, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-1), R a and R b is H, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-1), R a F is R b is H, and W is -P=O(OH)2 or a salt thereof.

[0060] In some embodiments of equations (IV-1) to (IV-3), Z 2It is linked to the anomeric position of the pyranose ring in an alpha configuration. In such cases, the M6PR bond portion (X) of (IV-1) to (IV-3) is represented by equations (IV-A1) to (IV-A3), respectively.

[0061] In some embodiments of equations (IV-A1) to (IV-A3), Z 2 is S. In some embodiments of equations (IV-A1) to (IV-A3), Z 2 is O. In some embodiments of equations (IV-A1) to (IV-A3), Z 2 is -CH2-. In some embodiments of equations (IV-A1) to (IV-A3), Z 2 It is -CF2-.

[0062] In some embodiments of formulas (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 salts thereof. In some embodiments of formulas (IV-A1) and (IV-A3), W is -P=O(OH)2, or a salt thereof. In some embodiments of formulas (IV-A1) and (IV-A3), W is COOH, or a salt thereof.

[0063] In some embodiments of formula (IV-A1), R a and R b is F, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-A1), R a and R b is H, and W is -P=O(OH)2 or a salt thereof. In some embodiments of formula (IV-A1), R a F is R b is H, and W is -P=O(OH)2 or a salt thereof.

[0064] In some embodiments of equations (IV-1) to (IV-3), Z 2It is linked to the anomeric position of the pyranose ring in a beta configuration. The inventors have demonstrated that compounds containing an M6PR binding moiety having a β-glycoside configuration may have at least equivalent binding activity and / or intracellular uptake activity compared to the corresponding conjugate having an α-glycoside configuration. In some embodiments, such an M6PR binding moiety having a β-glycoside configuration may have improved stability compared to a reference compound having a β-glycoside configuration. Therefore, in some embodiments of formula (IV), the M6PR binding moiety (X) is represented by one of formulas (IV-B1) to (IV-B3), [ka] In the formula, R a , R b , R c , and R d These are independently H or F.

[0065] In some embodiments of equations (IV-B1) to (IV-B3), Z 2 is S. In some embodiments of equations (IV-B1) to (IV-B3), Z 2 is O. In some embodiments of equations (IV-B1) to (IV-B3), Z 2 is -CH2-. In some embodiments of equations (IV-B1) to (IV-B3), Z 2 It is -CF2-.

[0066] In some embodiments of formulas (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 salts thereof.

[0067] In some embodiments of formulas (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 salts thereof. In some embodiments of formulas (IV-B1) and (IV-B3), W is -P=O(OH)2, or a salt thereof. In some embodiments of formulas (IV-B1) and (IV-B3), W is COOH, or a salt thereof.

[0068] In some embodiments of formula (IV-B1), R a and R b is F, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-B1), R a and R b is H, and W is -P=O(OH)2 or a salt thereof. In some embodiments of formula (IV-B1), R a F is R b is H, and W is -P=O(OH)2 or a salt thereof.

[0069] The inventors have demonstrated that a conjugate containing an M6PR binding moiety having a β-S-glycoside configuration may have at least equivalent or superior binding activity and / or intracellular uptake activity compared to the corresponding conjugate having an α-S-glycoside configuration or an α-O-glycoside configuration. See Figure 19.

[0070] Therefore, in some embodiments of equations (IV-B1) to (IV-B3), the M6PR bond portion (X) is represented by one of equations (IV-BS1) to (IV-BS3), [ka] In the formula, R a , R b , R c , and R d These are independently H or F.

[0071] In some embodiments of equations (IV-BS1) to (IV-BS3), R a , R b , R c and R d These are H.

[0072] In some embodiments of formula (IV-BS1), R a H, R b is F. In some embodiments of equation (IV-BS1), R a and R b These are F.

[0073] In some embodiments of formula (IV-BS2), R c is H. In some embodiments of equation (IV-B2), R c It is F.

[0074] In some embodiments of formula (IV-BS3), R d is H. In some embodiments of equation (IV-BS3), R d It is F.

[0075] In some embodiments of equations (IV-BS1) to (IV-BS3), Z 2 is S. In some embodiments of equations (IV-BS1) to (IV-BS3), Z 2 is O. In some embodiments of equations (IV-BS1) to (IV-BS3), Z 2 is -CH2-. In some embodiments of equations (IV-BS1) to (IV-BS3), Z 2 It is -CF2-.

[0076] In some embodiments of formulas (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 salts thereof. In some embodiments of formulas (IV-BS1) and (IV-BS3), W is -P=O(OH)2, or a salt thereof. In some embodiments of formulas (IV-BS1) and (IV-BS3), W is COOH, or a salt thereof.

[0077] In some embodiments of formula (IV-BS1), R a and R b is F, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-BS1), R a and R b is H, and W is -P=O(OH)2 or a salt thereof. In some embodiments of equation (IV-BS1), R a F is R b is H, and W is -P=O(OH)2 or a salt thereof.

[0078] In some embodiments, the mannose ring or analogue of the M6PR binding moiety is attached to the anomeric or 1-position of the sugar ring. 2 By attaching the connecting portion to the base, it can be incorporated into the compound of this disclosure.

[0079] In some embodiments, the M6PR bond is attached to the cyclic group A, Z 3 The base is incorporated into the compound of this disclosure by attaching a linker to it. In the compound of formula (III), Z 2 The cyclic group attached to it can be considered as part of the M6PR bond (X) and is thought to provide desirable bonding properties to M6PR.

[0080] 4.2.2. Cyclic Base A The A cyclic group in formulas (III) to (XIII) can be a monocyclic or bicyclic group. The desired bicyclic group can be a fused bicyclic group or a bicyclic group containing two monocyclic groups linked by a covalent bond. The A cyclic group in formulas (III) to (XIII) can be an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic (e.g., saturated heterocyclic), or optionally substituted cycloalkyl.

[0081] The cyclic group A in formulas (III) to (XIII) can be a monocyclic aryl group or a monocyclic heteroaryl group. In some embodiments of formulas (III) to (XIII), A is a five-membered monocyclic heteroaryl group. In some embodiments of formulas (III) to (XIII), A is a six-membered monocyclic aryl or heteroaryl group. In some embodiments of formulas (III) to (XIII), A can be a polycyclic aryl group or polycyclic heteroaryl group, such as a bicyclic aryl group or a bicyclic heteroaryl group. In some embodiments of formulas (III) to (XIII), A is a fused bicyclic group. In some embodiments of formulas (III) to (XIII), A is a bicyclic group containing two aryl and / or heteroaryl monocyclic rings linked by a covalent bond. In some embodiments of formulas (III) to (XIII), A is a bicyclic aryl or bicyclic heteroaryl group having two six-membered rings. In some embodiments of formulas (III)-(XIII), A is a bicyclic aryl or bicyclic heteroaryl group having one six-membered ring that is covalently linked or fused to a five-membered ring.

[0082] 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 phenylene-triazole.

[0083] In some embodiments of formulas (III)-(XIII), A is not phenyl (also called phenylene in the context of formula (III), e.g., 1,4-phenylene).

[0084] In some embodiments of formulas (III) to (XIII), A is substituted with at least one OH substituent. In some embodiments of formulas (III) to (XIII), A is substituted with one, two, or more OH groups. In some embodiments of formulas (III) to (XIII), A is substituted with at least one optionally substituted (C1 to C6) alkyl group.

[0085] In some embodiments of formulas (III) to (XIII), A is optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, or optionally substituted 2,5-pyridylene.

[0086] In some embodiments of equations (III) to (XIII), A is [ka] [ka] and [ka] Selected from, During the ceremony, R 11 ~R 14 These 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 Selected from, R 25 This is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0087] In some embodiments of formulas (III) to (XIII), A is an optionally substituted condensed bicyclic aryl or an optionally substituted condensed bicyclic heteroaryl.

[0088] In some embodiments of formulas (III) to (XIII), A is optionally substituted naphthalene or optionally substituted quinoline.

[0089] In some embodiments of equations (III) to (XIII), A is [ka] [ka] [ka] and [ka] Selected from, During the ceremony, R 11 and R 13 ~R 14 These 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 Selected from, s is between 0 and 3. Each R 25 This is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0090] In some embodiments of equations (III) to (XIII), A is [ka] [ka] and [ka] Selected from.

[0091] In some embodiments of formulas (III) to (XIII), A is a bicyclic aryl or bicyclic heteroaryl, which is optionally substituted for the following formulas. [ka] Or its salt, in the formula, Cy is independently a monocyclic aryl or monocyclic heteroaryl. R 11 ~R 15 These 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 Selected from, s is between 0 and 4. Each R 25 This is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0092] In some embodiments, if Cy is an optionally substituted phenyl, then A is an optionally substituted biphenyl in the following formula: [ka]

[0093] In some embodiments of equations (III) to (XIII), A is [ka] and [ka] Selected from.

[0094] In some embodiments, if Cy is a triazole, then A is [ka] and [ka] Selected from.

[0095] In some embodiments, R 11 ~R 15 At least one of them is an OH group (for example, at least two are OH groups).

[0096] In some embodiments, R 11 ~R 15 These are H, respectively.

[0097] 4.2.3.Connection part Z 3 Connecting part Z 3 This can be any convenient connecting part that connects the linker L to the annular ring A. In some embodiments of equations (III) to (XIII), Z 3 It has a skeleton of three or fewer atoms.

[0098] In some embodiments of equations (III) to (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(R23 )- Selected from, in the formula, X 1 and X 2 These are O, S and NR 23 Selected from, R 23 and R 24 H and C are independent of each other. (1~3) -alkyl (e.g., methyl) and substituted C (1~3) - Selected from alkyl groups.

[0099] In some embodiments of equations (III) to (XIII), Z 3 This is a covalent bond connecting A to L.

[0100] In some embodiments of equations (III) to (XIII), Z 3 is an optionally substituted amide, urea, or thiourea.

[0101] In some embodiments of equations (III) to (XIII), Z 3 The following applies: [ka] During the ceremony, X 1 is either O or S, t is either 0 or 1, Each R 23 H and C are independent of each other. (1~3) -Alkyl (e.g., methyl or ethyl) and substituted C (1~3) - Selected from alkyl groups. Z 3 In some embodiments of X 1 It is O. 3 In some embodiments of X 1 S is Z 3 In some embodiments, t is 0, X 1 is O, and as a result, Z 3 Z is an amide. 3 In some embodiments, t is 1, and thus Z 3 It is urea or thiourea.

[0102] In some embodiments of equations (III) to (XIII), Z 3 is -N(R 23 )SO2- or -SO2N(R 23 )-. In some embodiments of equations (III) to (XIII), Z 3 It is -NHSO2- or -SO2NH-.

[0103] In some embodiments of equations (III) to (XIII), Z 3 is -N(R 23 )CO- or -CON(R 23 )-. In some embodiments of equations (III) to (XIII), Z 3 It is -NHCO- or -CONH-.

[0104] In some embodiments of equations (III) to (XIII), Z 3 -NHC(=X 1 )NH-, and in the formula, X 1 is O or S. In some embodiments, X 1 is O (that is, Z 3 is -NHC(=O)NH-). In some embodiments, X 1 S is.

[0105] In some embodiments of equations (III)-(XIII), Z 3 This is a triazole with arbitrary substitutions. 3 If it is an optionally substituted triazole, it can be synthetically derived from click chemistry bonding between an azide-containing precursor and an alkyne-containing precursor of the compound.

[0106] In some embodiments, Z 3 This refers to the cyclic base A and / or the connecting portion Z. 1 Selected in combination with X to provide the desired M6PR coupling and internalization characteristics.

[0107] In some embodiments of equations (III) to (XIII), -AZ 3 -teeth, [ka] [ka] [ka] [ka] [ka] [ka] and [ka] Selected from.

[0108] In some embodiments of equations (III) to (XIII), -AZ 3 -teeth, [ka] and [ka] Selected from.

[0109] In some embodiments of equations (III) to (XIII), -AZ 3 -teeth, [ka] [ka] and [ka] Selected from.

[0110] In some embodiments of equations (II) to (XIb), -AZ 3 -teeth, [ka] and [ka] Selected from.

[0111] In some embodiments of equations (III) to (XIII), -AZ 3 -teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] Selected from.

[0112] In some embodiments of equations (III) to (XIII), Z 2 It is O.

[0113] In some embodiments of equations (III) to (XIII), Z 2 S is.

[0114] In some embodiments of equations (III)-(XIII), Z 2 -NR 21 - is

[0115] In some embodiments of equations (III) to (XIII), Z 2 -C(R 22 )2-, and in the formula, each R 22 This is independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. In some embodiments, Z 2 is -CH2-. In some embodiments, Z 2 is -CHF-. In some embodiments, Z 2 It is -CF2-.

[0116] In some embodiments of equations (III) to (XIII), Z 2 -AZ 3 - is as follows: [ka] During the ceremony, Z 21 is O, S, or -C(R 22 )2-, R 16 It is either OH or CH3, w is a value between 0 and 4 (for example, w is 0, 1, or 2).

[0117] In some embodiments, Z 21is S or O. In some embodiments, Z 21 is -CH2-. In some embodiments, Z 21 is -CHF-. In some embodiments, Z 21 is -CF2-. 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.

[0118] In some embodiments of equations (III) to (XIII), -Z 2 -AZ 3 -teeth, [ka] That is the case.

[0119] In some embodiments of equations (III) to (XII), -Z 2 -AZ 3 -teeth, [ka] That is the case.

[0120] In some embodiments of equations (III) to (XIII), -Z 2 -AZ 3 -teeth, [ka] That is the case.

[0121] In some embodiments of equations (III) to (XIII), -Z 2 -AZ 3 -teeth, [ka] That is the case.

[0122] In some embodiments of equations (III) to (XIII), -Z 2 -AZ3 -teeth, [ka] That is the case.

[0123] In some embodiments of equations (III) to (XIII), -Z 2 -AZ 3 -teeth, [ka] That is the case.

[0124] 4.2.4. Exemplary M6PR Ligands Exemplary M6PR binding moieties of formulas (I) to (XIII) that can be used in the preparation of the compounds and conjugates of this disclosure are shown in Table 1.

[0125] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0126] Table 2 shows exemplary synthons or synthetic precursors that can be used to incorporate the desired M6PR binding moiety in the preparation of the compounds of this disclosure. Depending on the selected M6PR binding moiety and linker, it will be understood that alternative synthons, including homologs and analogs of those shown in Table 2, are possible. The synthons in Table 2 are those with a binding moiety Z 3It is understood that the structural precursors may include structural elements that form part of the linker (L) in the compounds and conjugates of the present disclosure. Based on the exemplary synthetic precursors in Table 2, it is understood that the compounds of the present disclosure can be prepared using synthons corresponding to any of the M6PR binding moieties in Table 1.

[0127] [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]

[0128] Other M6PR binding moieties of interest and their synthones or synthetic precursors are shown in Table 3. X101-X103 represent compounds having a phosphate ester or thiophosphate ester head group. X109-X110 represent exemplary compounds of formula (V). In some embodiments, such M6PR binding moieties are used in reference compounds for evaluating compounds of formula (XII).

[0129] [Table 3-1] [Table 3-2] [Table 3-3]

[0130] 4.2.5. Disaccharide-containing M6PR binding moiety Aspects of the present disclosure include compounds and conjugates of formula (I) having an M6PR binding moiety comprising a specific dimannose structure having a first pyranose ring (e.g., of formula (II)) connected to a second 2,5-linked pyranose ring further connected to a linker.

[0131] Figure 20 shows the selected intracellular uptake activity, comparing compounds of formula (III) conjugate with compounds having a specific dimannose M6PR binding moiety. Conjugates of M6PR-binding compounds 660 or 659, each having a dimannose structure with a 2,5-linked pyranose ring bound to the linker, showed potent and equivalent activity to the conjugate of compound 520(I-7).

[0132] Therefore, aspects of this disclosure relate to cell surface M6PR-binding compounds of formula (XV), [ka] or a prodrug thereof, or a salt thereof, in the formula, W is a non-hydrolyzable hydrophilic head group, Z 1 This is selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. Z 4 is, -Z 14 -, -Z 14 -A-, -A-, and -CH2-Z 14 - Selected from, Z 14 O, S, NR21 and C(R 22 ) Selected from 2, in the formula, R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. A is an arbitrarily substituted cyclic group (e.g., an arbitrarily substituted aryl, an arbitrarily substituted heteroaryl, an arbitrarily substituted heterocyclic, or an arbitrarily substituted cycloalkyl), n is between 1 and 500. m is between 1 and 500. L is a linker, Y is the target part.

[0133] In some embodiments of equation (XV), Z 4 is -CH2-Z 14 - and Z 14 O, S, NR 21 , and C(R 22 ) Selected from 2.

[0134] In some embodiments of equation (XV), Z 4 It is -CH2-A-.

[0135] In some embodiments of equation (XV), Z 4 It is -A-.

[0136] In some embodiments of formula (XV), A is a cyclic group (for example, an optionally substituted aryl or optionally substituted heteroaryl, as described above for formula (III)).

[0137] In some embodiments of formula (XV), A is a triazole.

[0138] In some embodiments of equation (XV), Z 4 teeth, [ka] And "*" indicates a connection to linker L.

[0139] The M6PR bond of formula (XV) can be adapted for use in various compounds and conjugates described herein.

[0140] 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.

[0141] 4.2.6. Prodrugs Aspects of this disclosure include any prodrug of the M6PR binding moiety described herein, which is incorporated into the compounds and conjugates of this disclosure.

[0142] The term "prodrug" refers to a substance that is converted into a drug in vivo by some physiological or chemical process (for example, a prodrug is converted into a desired drug form when adjusted to a physiological pH).

[0143] Any prodrug form of the M6PR binding moiety described herein may be useful because it can provide certain therapeutic benefits, for example, as a result of extending the half-life of the resulting compound or conjugate in the body, or reducing the required active dose.

[0144] Prodrugs can be useful in certain situations because they may be easier to administer than their parent drugs. For example, they may be bioavailable through oral administration, while the parent drug is not. Prodrugs may also have improved solubility in pharmacological compositions compared to their parent drugs.

[0145] Prodrug derivatives of the M6PR bond generally contain a pro-molecular substituent, e.g., a hydroxyl group of the pyranose ring of formula (II), at a preferred unstable site of the compound. The pro-molecular refers to a group removed by enzymatic or chemical reaction when the prodrug is converted to a drug in vivo. For example, the pro-molecular can be an optionally substituted alkylacyl group bonded to the hydroxyl group of the compound by an ester bond. Exemplary alkylacyl pro-molecular groups include acetyl. In some embodiments, prodrug derivatives of one or more hydroxyl groups of the pyranose sugar ring can be incorporated into the compound. For example, an ester pro-molecular can be incorporated to one or more hydroxyl groups at positions 2, 3, and / or 4 of the sugar ring.

[0146] In some embodiments, a prodrug derivative of a hydrophilic head group (W) may be incorporated into the M6PR binding moiety and compound of the present disclosure. For example, the ester pro moiety may be incorporated into a phosphonate or thiophosphonate head group, or the ester pro moiety may be incorporated into a carboxylic acid or malonic acid head group.

[0147] 4.3. Linker The terms “linker,” “linking portion,” and “linking group” are used interchangeably and refer to a linking portion that covalently bonds two or more parts or compounds, such as an M6PR bond or other desired parts. In some cases, a linker is divalent and connects two parts. In certain cases, a linker is a trivalent or higher polyvalent branched linking group. In some cases, a linker connecting two or more parts has a linear or branched skeleton with a measured length between the two or more parts of 500 atoms or less (e.g., 400 atoms or less, 300 atoms or less, 200 atoms or less, 100 atoms or less, 80 atoms or less, 60 atoms or less, 50 atoms or less, 40 atoms or less, 30 atoms or less, or 20 atoms or less). The linking portion may be a covalent bond connecting two groups, or a linear or branched chain of 1 to 500 atoms in length, for example, a chain of about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 100, 150, 200, 300, 400, or 500 carbon atoms, and the linker may be linear, branched, cyclic, or single-atom. In certain cases, 1, 2, 3, 4, 5 or more, 10 or more, or even more carbon atoms in the linker skeleton may be optionally substituted with heteroatoms, such as sulfur, nitrogen, or oxygen heteroatoms. In certain cases, if the linker contains a PEG group, every other atom in that segment of the linker skeleton is substituted with oxygen. Bonds between skeleton atoms can be saturated or unsaturated, and typically there are no more than 1, 2, or 3 unsaturated bonds in the linker skeleton. The linker may contain one or more substituents, such as alkyl groups, aryl groups, or alkenyl groups. The linker may contain, but is not limited to, one or more oligos (ethylene glycol), ethers, thioethers, disulfides, amides, carbonates, carbamates, tertiary amines, or linear or branched alkyl groups (e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl)). The linker skeleton may contain a cyclic group, such as an aryl, heterocyclic, cycloalkyl, or heterogroup, with two or more atoms of the cyclic group, for example, 2, 3, or 4 atoms, included in the skeleton.

[0148] In some embodiments, the “linker” or linking portion is derived from a molecule having two reactive ends, one of which is for binding to a desired portion (Y), such as a biomolecule (e.g., an antibody), and the other is for binding to a portion (denoted as X) that binds to the cell surface M6PR. When Y is a polypeptide, the polypeptide-binding reactive end of the linker is a site that can optionally bind to the polypeptide by a cysteine ​​thiol or lysineamine group on the polypeptide, and is therefore a thiol-reactive group such as maleimide or dibromomaleimide or a thiol-reactive group as defined herein, or an amine-reactive group such as an active ester (e.g., pentafluorophenyl ester, tetrafluorophenyl ester, or NHS ester) or an amine-reactive group as defined herein.

[0149] In certain embodiments of the formulas described herein, the linker L comprises one or more linear or branched carbon moieties and / or polyether (e.g., ethylene glycol) moieties (e.g., repeating units of -CH2CH2O-), as well as combinations thereof. In certain embodiments, these linkers optionally have amide bonds, urea or thiourea bonds, carbamate bonds, ester bonds, amino bonds, ether bonds, thioether bonds, sulfhydryl bonds, 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.

[0150] In certain embodiments, the length of L is approximately 10 Å to approximately 20 Å. In certain embodiments, the length of L is approximately 15 Å to approximately 20 Å. In certain embodiments, the length of L is approximately 15 Å. In certain embodiments, the length of L is approximately 16 Å. In certain embodiments, the length of L is approximately 17 Å.

[0151] 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, comprising an optionally substituted arylene linked to a cell surface M6PR binding site (X), an optionally substituted heteroarylene bound to X, an optionally substituted heterocyclene bound to X, or an optionally substituted cycloalkylene bound to X. In certain embodiments, L is a linker of about 10 Å to about 500 Å, comprising an optionally substituted arylene bound to X, an optionally substituted heteroarylene bound to X, an optionally substituted heterocyclene bound to X, or an optionally substituted cycloalkylene bound to X. In certain embodiments, L is a linker of about 10 Å to about 400 Å, comprising an optionally substituted arylene bound to X, an optionally substituted heteroarylene bound to X, an optionally substituted heterocyclene bound to X, or an optionally substituted cycloalkylene bound to X. In certain embodiments, L is a linker of about 10 Å to about 200 Å, comprising an optionally substituted arylene, an optionally substituted heteroarylene, an optionally substituted heterocyclene, or an optionally substituted cycloalkylene bound to X.

[0152] In certain embodiments, L separates the cell surface M6PR binding site (Y) and Y (or Z) by a skeleton containing at least 10 consecutive atoms. In certain cases, the skeleton is at least 12 consecutive atoms. In certain cases, the skeleton is at least 14 consecutive atoms. In certain cases, the skeleton is at least 16 consecutive atoms. In certain cases, the skeleton is at least 18 consecutive atoms. In certain cases, the skeleton is at least 20 consecutive atoms. In certain cases, the skeleton is at least 22 consecutive atoms. In certain cases, the skeleton is at least 24 consecutive atoms. In certain cases, the skeleton is at least 26 consecutive atoms. In certain cases, the skeleton is at least 28 consecutive atoms. In certain cases, the skeleton is at least 30 consecutive atoms. In certain cases, the skeleton is at least 32 consecutive atoms. In certain cases, the skeleton is at least 34 consecutive atoms. In certain cases, the skeleton is at least 36 consecutive atoms. In certain cases, the skeleton consists of at least 38 consecutive atoms. In certain cases, the skeleton consists of at least 40 consecutive atoms. In certain cases, the skeleton consists of up to 50 consecutive atoms. In certain cases, the skeleton consists of up to 60 consecutive atoms. In certain cases, the skeleton consists of up to 70 consecutive atoms. In certain cases, the skeleton consists of up to 80 consecutive atoms. In certain cases, the skeleton consists of up to 90 consecutive atoms. In certain cases, the skeleton consists of up to 100 consecutive atoms.

[0153] In certain embodiments, linker L separates the cell surface M6PR binding site (X) and Y (or Z) by a chain of 4 to 500 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 4 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 6 to 50 consecutive atoms, a chain of 11 to 50 consecutive atoms, a chain of 16 to 50 consecutive atoms, a chain of 21 to 50 consecutive atoms, a chain of 26 to 50 consecutive atoms, a chain of 31 to 50 consecutive atoms, a chain of 36 to 50 consecutive atoms, a chain of 41 to 50 consecutive atoms, or a chain of 46 to 50 consecutive atoms. In certain embodiments, linker L separates X and Y (or Z) by a chain of 6 to 50 consecutive 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 a particular embodiment, the linker L separates X and Y (or Z) by a chain of 46 to 50 consecutive atoms.

[0154] In certain embodiments, the linker L separates X and Y (or Z) by chains of four or five consecutive atoms, six to ten consecutive atoms, eleven to fifteen consecutive atoms, sixteen to twenty consecutive atoms, twenty-one to twenty-five consecutive atoms, twenty-six to thirty consecutive atoms, thirty-one to thirty consecutive atoms, thirty-one to thirty consecutive atoms, thirty-six to forty consecutive atoms, forty-one to forty consecutive atoms, or forty-six to fifty consecutive atoms.

[0155] In certain embodiments, the linker L separates X and Y (or Z) by a chain of 50 or 55 consecutive atoms, a chain of 56-60 consecutive atoms, a chain of 61-65 consecutive atoms, a chain of 66-70 consecutive atoms, a chain of 71-75 consecutive atoms, a chain of 76-80 consecutive atoms, a chain of 81-85 consecutive atoms, a chain of 86-90 consecutive atoms, a chain of 91-95 consecutive atoms, or a chain of 96-100 consecutive atoms.

[0156] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylenes linked to X, optionally substituted heteroarylenes linked to X, optionally substituted heterocyclenes linked to X, or optionally substituted cycloalkylenes linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylenes linked to X, optionally substituted heteroarylenes linked to X, optionally substituted heterocyclenes linked to X, or optionally substituted cycloalkylenes linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylenes linked to X, optionally substituted heteroarylenes linked to X, optionally substituted heterocyclenes linked to X, or optionally substituted cycloalkylenes linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylenes linked to X, optionally substituted heteroarylenes linked to X, optionally substituted heterocyclenes linked to X, or optionally substituted cycloalkylenes linked to X.

[0157] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylene or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylene or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylene or optionally substituted heteroarylene linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylene or optionally substituted heteroarylene linked to X.

[0158] In certain embodiments, linker L is a chain of 5 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted phenylene linked to X. In certain embodiments, linker L is a chain of 7 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted phenylene linked to X. In certain embodiments, linker L is a chain of 10 to 500 consecutive atoms separating X and Y (or Z), and includes optionally substituted phenylene linked to X. In certain embodiments, linker L is a chain of 15 to 400 consecutive atoms separating X and Y (or Z), and includes optionally substituted phenylene linked to X.

[0159] In some embodiments, the linker L is a chain of 16 to 400 consecutive atoms separating X and Y (or Z), and includes optionally substituted arylenes linked to X, optionally substituted heteroarylenes linked to X, optionally substituted heterocyclenes linked to X, or optionally substituted cycloalkylenes linked to X.

[0160] The linker is located at the Z of the M6PR joint (X).3 or Z 4 It is understood that it can be considered to be directly linked to the base (for example, as described herein). In some embodiments of formula (III) or (V), the linker is Z 3 or Z 4 It could be considered to connect directly to the base. Alternatively, a linker-type -Z 3 -L 1 -Base or -Z 4 -L 1 -(For example, as described herein) is Z 3 or Z 4 It can be considered as part of the linking portion that connects to Y. This disclosure is intended to include all such arrangements of the M6PR linking portion (X) and linker (L).

[0161] In some embodiments of equations (XI) to (XIII), L is the linker of equation (VII), [ka] During the ceremony, L 1 and L 3 It is independently a linker, and L 2 This is the branching connection section, L 1 ~L 3 They come together to form a linear or branched linker between X and Y. a, b, and c are independently either 0 or 1. ** is Z 1 L of X via 1 Represents the connection point to, *** represents the connection point 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.

[0162] In some specific embodiments of the linker of formula (VII), L 1 ~L 3 These are, independently, -C 1~20 -Alkilen-, -NHCO-C 1~6-Alkilen-, -CONH-C 1~6 -Alkilen-, -NHC 1~6 -Alkilen-, -NHCONH-C 1~6 -Alkilen-, -NHCSNH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-NHCO-,-C 1~6 -Alkilen-CONH-, -C 1~6 -alkylene-NH-,-C 1~6 -Alkilen-NHCONH-,-C 1~6 -Alkylene-NHCSNH-,-O(CH2) p ,-(OCH2CH2) p The formula comprises one or more binding moieties independently selected from -, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3-linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (natural or unnatural amino acid residue), -NH-, and -NMe-, where each p is independently 1 to 50.

[0163] In a particular embodiment of the linker of formula (VII), L 1 ~L 3 One of these contains a repeating ethylene glycol moiety (e.g., -CH2CH2O- or -OCH2CH2-). In certain cases, the linker of formula (VII) 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) contains three or more ethylene glycol moieties, e.g., five or more, seven or more, ten or more, fifteen or more, twenty or more, or even more ethylene glycol moieties.

[0164] In a particular embodiment of the linker of formula (VII), L 1 ~L 3Each of these includes one or more triazole linkages. In some cases, the linker includes one or more 1,2,3-triazole linkages. In certain cases, one or more 1,2,3-triazole linkages are selected from one of the following structures: [ka] In the formula, w1, u1, and q1 are independently between 1 and 25 (for example, 1 to 12, for example, 1 to 6).

[0165] In a particular embodiment of the linker of formula (VII), n is 1, and as a result b is 0, and the linker is of formula (VIIa), [ka] During the ceremony, L 1 and L 3 It is independently a linker (as described herein, for example), L 1 ~L 3 Together they provide a linear linker between X and Y. a is 1, c is either 0 or 1. ** is Z 1 L of X via 1 Represents the connection point to, *** represents a connection point to Y.

[0166] In certain embodiments of the linker of formula (VIIa), the linear linker is a skeleton of 25 or more consecutive atoms, or 30 or more consecutive atoms, and possibly up to 100 consecutive atoms, such as Z 1 It has a framework of 20 or more consecutive atoms that covalently bond X and Y. In a particular embodiment of formula (VIIa), the linear linker has a chain of 20 to 50 consecutive atoms that covalently bond X and Y (or Z). 1) separates X and Y (or Z). In a particular embodiment, the linear linker L separates X and Y (or Z) by a chain of 21-50 consecutive atoms, a chain of 22-50 consecutive atoms, a chain of 23-50 consecutive atoms, a chain of 24-50 consecutive atoms, a chain of 25-50 consecutive atoms, a chain of 26-50 consecutive atoms, a chain of 27-50 consecutive atoms, a chain of 28-50 consecutive atoms, or a chain of 29-50 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 30 to 60 consecutive atoms. In a particular embodiment of formula (VIIa), the linear linker separates X and Y (or Z) by a chain of 30 to 60 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 31 to 60 consecutive atoms. In a particular embodiment, the linear linker separates X and Y (or Z) by a chain of 31 to 60 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 32 to 60 consecutive atoms. In a particular embodiment, the linear linker separates X and Y (or Z) by a chain of 32 to 60 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 33 to 60 consecutive atoms. In a particular embodiment, the linear linker separates X and Y (or Z) by a chain of 33 to 60 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 34 to 60 consecutive atoms. In a particular embodiment, the linear linker separates X and Y (or Z) by a chain of 34 to 60 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 35-50 consecutive atoms. In a particular embodiment, the linear linker L separates X and Y (or Z) by a chain of 35-50 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 36 to 50 consecutive atoms. In a particular embodiment, the linear linker L separates X and Y (or Z) by a chain of 36 to 50 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 41-50 consecutive atoms. In a particular embodiment, the linear linker L separates X and Y (or Z) by a chain of 41-50 consecutive atoms. 1 ) separates X and Y (or Z) by a chain of 46-50 consecutive atoms. In a particular embodiment, the linear linker L separates X and Y (or Z) by a chain of 46-50 consecutive atoms. 1 ) and separate them.

[0167] In certain other embodiments of formula (VII), n is 2 or greater, and L 1 ~L 3 Together, they provide a branch linker between X and Y.

[0168] In a particular embodiment of formula (VII), n is 2, and L 2 The following can be selected: [ka] and [ka] In the equation, each x and y is independently between 1 and 10.

[0169] In a particular embodiment of formula (VII), L 1 ~L 2 This includes a skeleton of 14 or more consecutive atoms between X and the branched atom, for example, a skeleton of 14-50, 14-40, 14-35, or 14-30 consecutive atoms between X and the branched atom.

[0170] In certain embodiments of formula (VII) or (VIIa), L 3 This includes a skeleton of 10 to 80 consecutive atoms, such as consecutive atoms of 12 to 70, 12 to 60, or 12 to 50.

[0171] In a particular embodiment of formula (VII) or (VIIa), L 3 is, (C 10 ~C 20 -Alkylene (for example, C 12 -Alkylene), or -(OCH2CH2) p -Includes a connected part selected from, where p is 1-25, e.g., 3-25, 5-24, 7-25, 10-25, 15-25 or 20-24.

[0172] In certain embodiments, L is from formula (VIIb), [ka] In the formula, L 1 ~L 5 Each of these is an independent connecting part, and when they come together, Z 1 A linear or branched linker is formed between and Y. a, b, c, d, and e are each independently 0, 1, or 2. ** is Z 1 L of X via 1 Represents the connection point to, *** represents the connection point to Y, If n is 1, then a is 1 and c is 0. If n > 1, then a is 1 and c is 1.

[0173] In a particular embodiment of the linker of formula (VIIb), L 1 ~L 5 These are, independently, -C 1~20 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -NHC 1~6 -Alkilen-, -NHCONH-C 1~6 -Alkilen-, -NHCSNH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-NHCO-,-C 1~6 -Alkilen-CONH-, -C 1~6 -alkylene-NH-,-C 1~6 -Alkilen-NHCONH-,-C 1~6 -Alkylene-NHCSNH-,-O(CH2) p -,-(OCH2CH2) p -, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3-linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (natural or unnatural amino acid residue), -NH-, and -NMe-, comprising one or more linking moieties independently selected from -, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3-linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (natural or unnatural amino acid residue), -NH-, and -NMe-, where each p is independently 1 to 50.

[0174] In a particular embodiment of formula (VIIb), -(L 1 ) a- contains optionally substituted alkyl or ethylene glycol linkages. In certain cases, L 1 This is an arbitrarily substituted -C 1~6 -Contains alkylenes. In certain cases, L 1 This includes an ethylene glycol bonded portion.

[0175] In a particular embodiment of formula (VIIb), L 1 Independently, -C 1~6 -Alkylene-, -(CH2CH2O) t -, --C 1~6 -Alkilen-NR 4 CO-, -C 1~6 -Selected from alkylene CONH- or OCH2, where t is 1 to 20, R 4 The elements are independently selected from H and optionally substituted (C1-C6) alkyl groups. In certain cases, L 1 is -C 1~6 -Alkilen-, for example--C 1~3 -Alkilen-. In certain cases, L 1 is -(CH2CH2O) t - and in the formula, t is 1 to 20, for example, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 4. In a certain case, L 1 is, --C 1~6 -Alkilen-NR 4 It is CO-. In certain cases, L 1 is -C 1~6 -Alkilen CONH-. In certain cases, L 1 This is OCH2.

[0176] In some embodiments of formula (VIIb), one or more L 1 These are independently -CH2O- and -(CH2CH2O) t -, -NR 4 CO-, -C 1~6 -Alkilen-, [ka] And, In the formula, R 13 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 Selected from, Each r is independently between 0 and 20, and L 1 Some of the parts have been optionally replaced.

[0177] In a particular embodiment of formula (VIIb), L 2 Independently, -NR 4 CO-C 1~6 -Alkilen-, -CONR 4 -C 1~6 -Alkilen, [ka] , -OCH2-, and -(OCH2CH2) q - is selected from, where q is 1 to 10, u is 0 to 10, and w is 1 to 10, R 4 The elements are independently selected from H and optionally substituted (C1-C6) alkyl groups. In certain cases, L 2 -NR 4 CO-C 1~6 -Alkilen-. In certain cases, L 2 -CONR 4 -C 1~6 -It is alkylene.

[0178] In certain cases, L 2 teeth, [ka] In the equation, w is 1 and u is either 0 or 1.

[0179] In certain cases, L 2 teeth, [ka] In the equation, w is 1 and u is either 0 or 1.

[0180] In certain cases, L 2 teeth, [ka] In the equation, w is 1, u is 0 or 1, and q is 1.

[0181] In certain cases, L 2 teeth, [ka] And in the formula, u is either 0 or 1.

[0182] In certain cases, L 2 teeth, [ka] That is the case.

[0183] In a particular embodiment, L 2 is -OCH2-. In some other specific embodiments, L 2 (OCH2CH2) q - and q is 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. In certain cases, q is 2-8, for example 2-6, 4-6, or 2-4.

[0184] In a particular embodiment of formula (VIIb), L 4 It does not exist, or independently, -C 1~6 -Alkylene-, -(CH2CH2O) t -, --C 1~6 -Alkilen-NHCO-,-C 1~6 -Selected from alkylene CONH- or OCH2. In certain cases, L 4It does not exist. In certain cases, L 4 is -C 1~6 -It is an alkylene. In certain cases, L 4 is -(CH2CH2O) t - and in the formula, t is 1 to 20, for example, 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 is, --C 1~6 -Alkylene-NHCO-. In certain cases, L 4 is -C 1~6 -Alkilen CONH-. In certain cases, L 4 This is OCH2.

[0185] In some embodiments of the target compound, n is 1, and L in formula (VIIb) 3 It does not exist.

[0186] In certain embodiments of the target compound, n is 2 or greater, and L in formula (VIIb) 3 This is the branching and connecting section.

[0187] Therefore, in some embodiments of equation (VIIb), L 3 This is a branched connection part, for example, a trivalent connection part. For example, L 3 The connecting part is one of the following general formulas: [ka]

[0188] In some embodiments of formula (VIIb), the branched connection portion has a higher valence, [ka] It can be expressed using one of the following formulas: In the formula, any two L 3 The bases may be directly linked or connected by any linear linking sections (as described herein, for example).

[0189] In some embodiments of formula (VIIb), the branched connection portion consists of one, two, or more L, each of which is a trivalent portion. 3 It can include linked parts, and when they are linked together, it provides multiple branching points for the covalent bonding of ligands, which can be described by one of the following general formulas: [ka] In the formula, t is between 0 and 500, for example, between 0 and 100, 0 and 20, or 0 and 10.

[0190] In some embodiments, the branching connection portion (for example, L 3 ) contains one or more amino acid residues (e.g., Asp, Lys, Orn, Glu, Ser), N-substituted amides (-N(-)C(=O)-), tertiary amino acids, polyols (e.g., O-substituted glycerol), etc.

[0191] In some embodiments of formula (VIIb), one or more L 3 teeth, [ka] and [ka] This is the branching part selected from,

[0192] In the equation, each x and y is independently between 1 and 10, for example, 1 to 6, and 1 to 3, for example, 1 or 2. In some cases, each x is 1, 2, or 3, for example, 2.

[0193] In some embodiments of formula (VIIb), one or more L 5 These are independently -CH2O- and -(CH2CH2O) t -, -NR 4 CO-, -C 1~6 -Alkilen-, [ka] And, In the formula, R 13 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 Selected from, Each r is independently between 0 and 20, and L 5 Some of the parts have been optionally replaced.

[0194] In certain cases, L 5 It is -CH2O-. In certain cases, L 5 is -(CH2CH2O) t - and in the formula, t is 1 to 20, for example 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4. In a particular case, L 5 -NR 4 CO-, and in the formula, R 4 is H, or an optionally substituted (C1-C6) alkyl group. In certain cases, L 5 is -C 1~6 -It is alkylene-.

[0195] In certain cases, L 5 teeth, [ka] In the formula, r is between 0 and 20, for example, between 0 and 15, 0 and 10, 0 and 8, and 0 and 5.

[0196] In certain cases, L 5 teeth, [ka] In the formula, each r is independently between 0 and 20, for example, 0 to 15, 0 to 10, 0 to 8, or 0 to 5, and R 13is H, or optionally substituted (C1-C6) alkyl.

[0197] In certain cases, L 5 teeth, [ka] In the formula, r is 0 to 20, for example 0 to 15, 0 to 10, 0 to 8, or 0 to 5, and R 13 is H, or an optionally substituted (C1-C6) alkyl group.

[0198] In certain cases, L 5 teeth, [ka] In the formula, r is 0 to 20, for example 0 to 15, 0 to 10, 0 to 8, or 0 to 5, and R 13 is H, or an optionally substituted (C1-C6) alkyl group.

[0199] In certain cases, L 5 teeth, [ka] In the formula, r is 0 to 20, for example 0 to 15, 0 to 10, 0 to 8, or 0 to 5, and R 13 is H, or an optionally substituted (C1-C6) alkyl group.

[0200] In certain cases, L 5 teeth, [ka] In the equation, each r is independently 0-20, 0-15, 0-10, 0-8, and 0-5.

[0201] In certain cases, L 5 teeth, [ka] In the equation, each r is independently 0-20, 0-15, 0-10, 0-8, and 0-5.

[0202] In certain cases, L 5 teeth, [ka] In the equation, each r is independently 0-20, 0-15, 0-10, 0-8, and 0-5.

[0203] In certain cases, L 5 teeth, [ka] In the equation, each r is independently 0-20, 0-15, 0-10, 0-8, and 0-5.

[0204] In certain cases, L 5 teeth, [ka] In the formula, r is between 0 and 20, for example, between 0 and 15, 0 and 10, 0 and 8, and 0 and 5.

[0205] 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.

[0206] In some embodiments of formula (VIIb), L 5This 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, and polyols (e.g., O-substituted glycerol). Examples of amino acid analogs include, but are not limited to, unnatural amino acids and other modifications well known in the art. The amino acids may include L-amino acids, D-amino acids, or both, and may contain any of the various amino acid modifications or analogs known in the art.

[0207] In some embodiments of formula (VIIb), L 1 ~L 5 It includes one or more of the following units: [ka] In the formula, R a R is a (C1-C6) alkyl or substituted (C1-C6) alkyl, for example, an amine, a tertiary amine, an optionally substituted alkoxy, an optionally substituted carboxyl, an optionally substituted aryl, or an optionally substituted heteroaryl (C1-C6) alkyl. a It is understood that it can be connected to the M6PR coupling portion.

[0208] 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.

[0209] In certain embodiments of formula (VII), (VIIa), or (VIIb), the linker contains 20 to 100 consecutive atoms, such as 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, or 20 to 30 consecutive atoms. In certain cases, the linker contains 25 to 100 consecutive atoms, such as 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive atoms.

[0210] In certain embodiments of formula (VII), (VIIa), or (VIIb), the linker contains 25 or more consecutive atoms, such as 26 or more consecutive atoms, 27 or more consecutive atoms, 28 or more consecutive atoms, 29 or more consecutive atoms, or 30 or more consecutive atoms. In certain embodiments of formula (VII), (VIIa), or (VIIb), the linker contains 30 or more consecutive atoms, such as 31 or more consecutive atoms, 32 or more consecutive atoms, 33 or more consecutive atoms, 34 or more consecutive atoms, 35 or more consecutive atoms, 36 or more consecutive atoms, 37 or more consecutive atoms, 38 or more consecutive atoms, 39 or more consecutive atoms, or 40 or more consecutive atoms.

[0211] In a particular embodiment where the linker of formula (VII) or (VIIb) is a branched linker, each branch of the linker is such that each X portion is connected to the branch point of the linker. 1 To be covalently linked, it contains a linear linker of 14 or more consecutive atoms. In certain cases, each branch of the linker contains a linear linker of 15 or more consecutive atoms up to the branching point. In certain cases, each branch of the linker contains a linear linker of 16 or more consecutive atoms up to the branching point. In certain cases, each branch of the linker contains a linear linker of 18 or more consecutive atoms up to the branching point. In certain cases, each branch of the linker contains a linear linker of 20 or more consecutive atoms up to the branching point. In certain cases, each branch of the linker contains a linear linker of 22 or more consecutive atoms up to the branching point.

[0212] In certain embodiments of formula (VII) or (VIIb), the linker connects each X portion to the branch point of the linker Z 1 This includes branched linkers containing branches covalently linked by Y, and linear linkers covalently linked to Y at the branch point. In certain cases, the linear linker covalently linked to Y at the branch point consists of 12 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 15 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 20 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 25 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 30 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 40 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 50 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branch point consists of 60 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branching point consists of 70 or more consecutive atoms. In certain cases, the linear linker covalently linked to Y at the branching point consists of 80 or more consecutive atoms.

[0213] In some embodiments, the linker comprises a polypeptide scaffold in which some or all of the side chain groups of amino acid residues are modified to bind an M6PR binding moiety (e.g., as described herein). It is understood that the M6PR binding moiety (e.g., as described herein) can be conjugated by convenient conjugation chemistry to amino acid residues such as Asp, Lys, Orn, Glu, and Ser of the polypeptide-containing linker. In some embodiments, the linker contains a polylysine polypeptide. In some embodiments, the linker contains a polyornithine polypeptide. In some embodiments, the linker contains a polyserine polypeptide. In some embodiments, the linker contains a polyaspartate polypeptide. The polypeptide may be a randomly polymerized polymer having an average length, or a polymer of a specified length prepared, for example, in a controlled stepwise manner. In some cases, the polypeptide linker segment has a length of 10 to 100 amino acid residues, e.g., 20 to 90, or 20 to 50 amino acid residues. In some embodiments, the N-terminus or C-terminus of the polypeptide linker segment is modified to include linking units for further M6PR binding (as described herein, for example). In some embodiments, the N-terminus or C-terminus of the polypeptide linker segment is modified to include one or more linking units suitable for attachment to the desired Y-molecule (as described herein, for example).

[0214] In some embodiments, the linker includes a scaffold of formula (VIIIa) or (VIIIb), [ka] During the ceremony, L 0 This is a linking portion (e.g., one or more amino acid residues), a linked M6PR linking portion, an optionally substituted alkyl, or an optionally substituted aryl or heteroaryl. R aThis is a (C1-C6) alkyl or substituted (C1-C6) alkyl, for example, an amine, a tertiary amine, an optionally substituted alkoxy, an optionally substituted carboxyl, an optionally substituted aryl, or an optionally substituted heteroaryl, an optionally substituted (C1-C6) alkyl, a derivative of an amino acid side chain group (e.g., lysine, serine, aspartic acid, glutamic acid, ornithine, etc.), or a linked M6PR bond moiety. r is between 1 and 10 (for example, r is between 1 and 5), t is between 1 and 11 (for example, w is between 1 and 5), u is between 0 and 5 (for example, u is 0, 1, or 2), s is between 1 and 50 (for example, s can be between 1 and 20, 1 and 10, or 1 and 5).

[0215] It is understood that the C-terminal carboxylic acid group of formulas (VIIIa) to (VIIIb) can provide a further linking moiety (e.g., one or more amino acid residues) and / or a linkage to the moiety of interest (Y) (e.g., as described herein) (e.g., via a chemoselective ligation group).

[0216] In some embodiments of (VIIIa) or (VIIIb), r is 1 to 3. In some embodiments of (VIIIa) or (VIIIb), t is 3 to 11, e.g., 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, e.g., 2 to 5, e.g., 2 or 3.

[0217] 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 (e.g., 2 or 3).

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 4.3.1. Exemplary linkers and connecting parts Tables 4-6 show exemplary linkers and linking parts that can be used to prepare the compounds of this disclosure (for example, linking the M6PR bond (X) to the desired part (Y) in formulas (XI) to (XV)).

[0228] In certain embodiments, the linker includes a linear linker or linking portion as shown in Table 4. In certain embodiments, the linker includes a linear linker or linking portion as shown in Table 5. In certain embodiments, the linker includes a linear linker or linking portion as shown in Table 6. It is understood that various end modifications to the exemplary linking portions can be incorporated based on the synthetic procedure and / or conjugated chemistry used in the preparation of the compound.

[0229] Table 4 shows various exemplary linkers or linking parts used in the compounds described herein. In some embodiments of formulas (XI) to (XV), the compound comprises one of the linkers or linking parts listed in Table 4.

[0230] [Table 4-1] [Table 4-2] [Table 4-3]

[0231] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0232] Table 6 shows exemplary synthetic precursors of linker components used, for example, to prepare the compounds of this disclosure by conjugated chemistry. Various homologs of the structures shown in Table 6 are also included in this disclosure and are understood to provide linkers of various lengths. It is understood that alternative chemoselective ligation groups and other chemical functional groups may also be incorporated as needed to prepare the desired linkers.

[0233] [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]

[0234] 4.4. Chemoselective ligation groups In certain embodiments of formulas (XI) to (XV), Y is a chemoselective ligation group or its precursor. A chemoselective ligation group is a group having a reactive functional group or functional group that can be conjugated with the compatible group of the second part. For example, a chemoselective ligation group (or its precursor) may be one of a pair of groups associated with conjugation chemistry such as azido-alkyne click chemistry, copper-free click chemistry, Staudinger ligation, tetrazine ligation, hydrazine-iso-picte-Spengler (HIPS) ligation, cysteine-reactive ligation chemistry (e.g., thiol-maleimide, thiol-haloacetamide, or alkyne hydrothiolation), amine-active ester coupling, tyrosine-specific conjugation chemistry (e.g., eY-CLICK), methionine-specific conjugation chemistry (e.g., oxaziridine-based or ReACT chemistry), reductive amination, and dialkyl squalate chemistry.

[0235] Table 6 shows exemplary synthetic precursors of linker components having various chemoselective ligation groups, which were used to prepare the compounds of this disclosure. Various other chemical functional groups may also be incorporated as needed to prepare the desired linker.

[0236] Chemoselective ligation groups that can be used to link two parts include, but are not limited to, aminos (e.g., the N-terminal amino group or lysine side chain group of a polypeptide), azides, aryl azides, alkynyls (e.g., ethinyl or cyclooctin or derivatives), active esters (e.g., N-hydroxysuccinimide (NHS) esters, sulfo-NHS esters, or PFP esters or thioesters), haloacetamides (e.g., iodoacetamide or bromoacetamide), chloroacetyl, bromoacetyl, hydrazides, maleimides, vinyl sulfones, 2-sulfonylpyridine, cyano-alkynes, thiols (e.g., cysteine ​​residues), disulfides or protected thiols, isocyanates, isothiocyanates, aldehydes, ketones, alkoxyamines, hydrazides, aminooxy, phosphines, HIPS hydrazinyl-indolyl groups, or aza-HIPS hydrazinyl-pyrrolo-pyridinyl groups, tetrazines, cyclooctene, and squalates.

[0237] In some situations, chemoselective ligation groups can spontaneously conjugate to a compatible chemical group when the two groups come into contact under appropriate conditions (such as copper-free click chemistry conditions). In other situations, chemoselective ligation groups can conjugate to a compatible chemical group when the two groups come into contact in the presence of a catalyst or other reagent (e.g., copper-catalyzed click chemistry conditions).

[0238] In some embodiments, the chemoselective ligation group is a photoactive ligation group. For example, upon irradiation with ultraviolet light, the diazirine group may form a reactive carbene, which can be inserted into the CH, NH, and OH bonds of the second portion.

[0239] In some situations, Y is a precursor of a reactive functional group or functional group that can be conjugated with the compatible group of the second part. For example, carboxylic acids are precursors of active ester chemoselective ligation groups.

[0240] In certain embodiments, Y is a reactive moiety capable of forming a covalent bond with a polypeptide (for example, with an amino acid side chain of a polypeptide having a compatible reactive group). The reactive moiety can be called a chemoselective ligation group.

[0241] Exemplary chemoselective ligation groups that may be adapted for use in the compounds of this disclosure, and their synthetic precursors, are shown in Table 6B.

[0242] [Table 6B-1] [Table 6B-2] [Table 6B-3]

[0243] Table 6B shows, [ka] This can represent the connection point between Y and the connected X portion (for example, the M6PR connection).

[0244] 4.5. Conjugate Aspects of the present disclosure include conjugates of compounds described herein, for example, of formula (XIII), where Y is a chemoselective ligation group, with another part of interest. When such conjugates are prepared, one or more M6PR ligand-linker compounds can be attached to or conjugated to another part of interest. For example, if the part of interest is a biomolecule, the chemoselective ligation group of the M6PR ligand-linker compound can be conjugated at one or more sites of the biomolecule. It is understood that such biomolecular conjugates of the present disclosure may be encompassed by formulas (XI), (XII), and (II)-(III), as well as the formulas described below.

[0245] In some embodiments, the conjugate of the present disclosure is represented by formula (XII), [ka] or its prodrug, or its salt (e.g., a pharmaceutically acceptable salt), in the formula, W is a non-hydrolyzable hydrophilic head group, Z 1 This is selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. Z 2 O, S, NR 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. Each A is independently a cyclic group (e.g., an optionally substituted aryl or heteroaryl linkage), each Z 3 It is an independent connecting part, n is between 1 and 500. m is between 1 and 100. L is a linker, Y is a biomolecule.

[0246] In some embodiments of formula (XII), A is phenyl, and Z 2 If O, (i) W is either -P(O)(OH)2 or (ii) The linker L contains a backbone of at least 16 consecutive atoms, and Y is the target bonding site.

[0247] In some embodiments of formula (XII), the cell surface mannose-6-phosphate receptor (M6PR) binding conjugate is that of formula (XIIa). [ka]

[0248] In some embodiments of formula (XII), the cell surface mannose-6-phosphate receptor (M6PR) binding conjugate is that of formula (XIIa). [ka]

[0249] In some embodiments, the target portion to which the M6PR binding site is linked is a biomolecule. In some embodiments, the target portion is a biomolecule. In some embodiments, the biomolecule is selected from polypeptides (e.g., peptides or proteins), polynucleotides, polysaccharides, glycans, glycoproteins, lipids, enzymes, antibodies, and antibody fragments.

[0250] In some embodiments, the target portion Y is selected from small molecules, small molecule drugs, chemotherapeutic agents, cytotoxic agents, diagnostic agents, dyes, fluorophores, etc. In some embodiments, m is 1, and one M6PR binding portion is linked to Y.

[0251] In some embodiments, one Y biomolecule is coupled to a single moiety (X) that specifically binds to cell surface M6PR by linker L. In some embodiments, one Y biomolecule is coupled to a single moiety (X) n -L)- Conjugate to the base, and when n=1, (X n -L)- groups are called monovalent, and when n>1, (X n The -L)- group is called polyvalent (e.g., divalent, trivalent, etc.). In some embodiments of the formulas described herein, if Y is a biomolecule, Y is two or more (X n -L)- can be conjugated, each (X n It is understood that the -L)- group itself may be monovalent or polyvalent (e.g., divalent, trivalent, etc.). In such cases, linked (X n The ratio of the -L)- group to the biomolecule can be said to be 2 or greater.

[0252] In some embodiments of formula (XII), the conjugate is generated from the conjugation of a compound of formula (XIII), where Y is a chemoselective ligation group, with a biomolecule, and the conjugate is of formula (XXI), [ka] or its prodrug, or a pharmaceutically acceptable salt thereof, in the formula, n is between 1 and 3. m is a load of 1 to 20. L is a linker, P is a biomolecule that specifically binds to target proteins. Z 5 This is a residual linkage portion formed by covalent linkage between a chemoselective ligation group located at the end of the linker of formula (XIII) and a compatible group of P. In some embodiments of formula (XXI), Z 2 It is bonded to the anomeric position of the pyranose ring having a beta configuration. Depending on the chemoselective ligation group used and the conjugation chemistry, m can be the average load (also known herein as DAR), or m can be a specific load (e.g., m is 1 or 2).

[0253] In some embodiments of formula (XXI), the conjugate is that of formula (XXIa). [ka]

[0254] In some embodiments of formula (XXI), the conjugate is that of formula (XXIa). [ka] In some embodiments of equations (XXI) to (XXIb), n is 1.

[0255] In some embodiments of equations (XXI) to (XXIb), n is 2.

[0256] In some embodiments of equations (XXI) to (XXIb), n is 3.

[0257] In some embodiments of equations (XXI) to (XXIb), n is 4.

[0258] In some embodiments of formulas (XXI) to (XXIb), n is 5 or greater, for example, 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, for example, 10 to 50, 10 to 20, or 20 to 50. In some embodiments of formulas (XXI) to (XXIb), L comprises a polypeptide, for example, polylysine or a polyserine derivative. In some embodiments of formulas (XXI) to (XXIb), L is a polypeptide-containing linker, where one M6PR binding moiety (X) binds to L per amino acid residue of the polypeptide.

[0259] In some embodiments of equations (XXI) to (XXIb), m is the average loading of the M6PR binding site (X) on the biomolecule P. For example, if lysine-conjugated chemistry is used to link X to P and P contains multiple lysine residues, it is understood that m can refer to the average loading.

[0260] In some embodiments of formulas (XXI) to (XXIb), m is 1 to 10, for example, 1 to 8, 1 to 7, or 1 to 6. In some embodiments of formulas (XXI) to (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) to (XXIb), m is at least 3. In some embodiments of formulas (XXI) to (XXIb), m is at least 4.

[0261] In some embodiments of equations (XXI) to (XXIb), m is about 8, about 7, about 6, about 5, about 4, about 3, or about 2.

[0262] In some embodiments of equations (XXI) to (XXIb), n is 1 and m is 1 to 10. In some embodiments of equations (XXI) to (XXIb), m is 2 to 8 (e.g., 2 to 6 or 3 to 5). In some embodiments of equations (XXI) to (XXIb), m is approximately 4.

[0263] In some embodiments of formulas (XXI) to (XXIb), m is a specific loading of the M6PR binding site (X) on the biomolecule P. For example, when X is linked to P by a linker using site-directed conjugation chemistry, it is understood that m can refer to a specific loading. In some embodiments of formulas (XXI) to (XXIb), m is 1. In some embodiments, the biomolecule P is a polypeptide having a single site for conjugation. In some embodiments of formulas (XXI) to (XXIb), m is 2. In some embodiments, the biomolecule P is an antibody. In some embodiments, the biomolecule P is an antibody fragment.

[0264] In some embodiments of equations (XXI) to (XXIb), n is 2 and m is 1 to 6 (e.g., 2 to 6 or 3 to 5). In some embodiments of equations (XXI) to (XXIb), m is approximately 4.

[0265] In some embodiments of equations (XXI) to (XXIb), n is 3 and m is 1 to 6 (e.g., 2 to 6 or 3 to 5).

[0266] In some embodiments of equations (XXI) to (XXIb), Z 5 This refers to one or more cysteine ​​residues of P in a thiol-reactive chemoselective ligation group (e.g., maleimide), for example, [ka] This is the residual portion resulting from the shared connection to, in the formula, [ka] This represents the connection point to linker L, [ka] This represents the connection point to P.

[0267] In some embodiments of equations (XXI) to (XXIb), Z 5 This is the residual portion of an amine-reactive chemoselective ligation group (e.g., PFP ester, TFP ester, or NHS ester) that is covalently linked to one or more lysine residues of P, i.e., to the amide bond-CONH-.

[0268] Further residual portion Z 5 The chemoselective ligation groups derived therefrom are described herein.

[0269] In some embodiments of equations (XXI) to (XXIb), L is Z 3It is a linear linker having a framework of 16 or more consecutive atoms covalently linked to P (e.g., a framework of 16-100, 18-100, or 20-100 consecutive atoms). In some embodiments of formulas (XI)-(XXIb), L is Z 3 This is a branched linker having a framework of 14 or more consecutive atoms (for example, 14-50 or 14-30 atoms) between the branched atoms of the linker and the linker.

[0270] 4.5.1.Target binding moiety In preferred embodiments, the portion of interest is a molecule that specifically binds to a target of interest, i.e., a target-binding portion. Thus, the compounds of the present disclosure may be referred to as target protein degradation compounds or conjugates. In such cases, the conjugates of the present disclosure provide intracellular uptake of the target, followed by lysosomal degradation, after the target has non-covalently bound to the conjugate. The inventors have demonstrated that a conjugate of the present disclosure having a specific M6PR-binding portion of a desired affinity, with a linker of a desired titer and length, can simultaneously and specifically bind to both M6PR and the target with high affinity. Thus, the conjugates of the present disclosure can provide intracellular translocation and sequestration of the bound target protein into cellular lysosomes, as well as subsequent degradation of the target protein.

[0271] The target-binding moiety can be any portion having an affinity for the target of less than 1 μM, for example, 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 by an in vitro binding assay. In some embodiments, the target-binding moiety has an affinity of 10 nM or less, for example, 1 nM or less, for the target protein.

[0272] In some embodiments, the target binding site is a biomolecule. In some embodiments, the target binding site is a biomolecule that specifically binds to a target protein. In some embodiments, the biomolecule is selected from polypeptides (e.g., peptides or proteins), polynucleotides, polysaccharides, glycans, antibodies, antibody fragments, and glycoproteins. The term polypeptide is understood to encompass antibodies, antibody fragments, and glycoproteins.

[0273] In some embodiments, the target-binding moiety is a polynucleotide that specifically binds to a target molecule, such as a target protein or 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.

[0274] In some embodiments, the target-binding moiety is a glycan. In some embodiments, the target-binding moiety includes a glycan epitope against an autoantibody.

[0275] 4.5.1.1. 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 polypeptide, 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 the bifunctional compound of the 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, comprising a receptor ligand that binds to a target cell surface receptor, or a receptor-binding moiety or fragment of a receptor ligand.

[0276] Depending on the source, the target-binding polypeptide may contain L-amino acids, D-amino acids, or both, and may contain a variety of naturally occurring amino acids, non-naturally occurring amino acids, and / or amino acid modifications or analogs known in the art. Useful modifications include, for example, N-terminal acetylation, amidation, and methylation.

[0277] In certain embodiments, the conjugate polypeptide (P) 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 the ligand-binding portion of the cell surface receptor or its bioisoster, for example, the extracellular domain of the cell surface receptor, for example, 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 the receptor-binding portion of the ligand or its bioisoster.

[0278] In some embodiments, the polypeptide (P) of the conjugate of the present disclosure is a synthetic D-protein conjugate for the target protein of interest, e.g., a VEGF-A-binding or PD1-binding D-protein described in WO2020198074 and WO2020198075.

[0279] Polypeptide conjugates (i.e., Y is P), such as conjugates of an antibody (Ab) and a compound (Xn-LY, where Y is a chemoselective ligation group), can be produced using various bifunctional protein coupling agents such as BMAP, 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). This disclosure further intends that the conjugates described herein can be prepared using any suitable method disclosed in the Art (see, for example, Bioconjugate Techniques (Hermanson ed., 2d ed. 2008)).

[0280] In certain embodiments of the conjugate described herein, L is bound to a lysine residue of P by an amide bond. In certain embodiments of the conjugate described herein, L is bound to a cysteine ​​residue of P by a thioether bond.

[0281] 4.5.1.2. Antibodies For example, in some embodiments of formula (XXI), the target binding portion is an antibody or antibody fragment that specifically binds to a target portion, such as a target protein.

[0282] Therefore, in this specification, the conjugate of the following formula (XXII) [ka] A prodrug thereof, or a pharmaceutically acceptable salt thereof, is provided, in the formula, n is between 1 and 20. m is the average load from 1 to 80. Each X is a portion that binds to the cell surface M6PR (for example, X is of formula (III) as described herein), Each L is a linker, each Z 5 This is a residual portion resulting from covalent bonding between a chemoselective ligation group and a compatible group of Ab. Ab is an antibody or antibody fragment that specifically binds to a target protein.

[0283] In some embodiments of formula (XXII), L is a linker (for example, as described herein). In some embodiments of formula (XXII), Xn-LZ 5 - is derived from a compound of formula (XIII) (for example, as described herein), where Y is a chemoselective ligation group.

[0284] In some embodiments of equation (XXII), L is a linker in the following equation: [ka] In the formula, L 1 , L 2 , L 3 , L 4 , L 5 a, b, c, d, e, and n are defined herein.

[0285] In certain embodiments of formula (XXII), L is selected from the linkers in Tables 4-5.

[0286] In equation (XXII), Z 5The compatible reactive group of the antibody (Ab) can be any convenient residual portion obtained by covalent linking or conjugation of a chemoselective ligation group (Y) to the compatible reactive group of the antibody (Ab). In some cases, the compatible reactive group of the antibody (Ab) is a group that can exist naturally on the biomolecule. In some cases, the compatible reactive group of the antibody (Ab) is introduced or incorporated into the biomolecule before conjugation. In such cases, the antibody (Ab) can be a modified version of the biomolecule. For example, a compatible chemoselective ligation group can be introduced by modifying a functional group of the biomolecule (e.g., an amino group, a carboxylic acid group, or a thiol group) (e.g., using a chemical reagent such as a 2-haloacetyl reagent or 2-iminothiolane, or by coupling a linker group containing a chemoselective ligation group such as an azide or alkyne).

[0287] In some embodiments of formula (XXII), Z 5 teeth, [ka] and [ka] Selected from, During the ceremony, [ka] This represents the connection point to linker L, During the ceremony, [ka] This represents the connection point to Ab, W is CH2, N, O, or S. Ab is an antibody.

[0288] In a particular embodiment of formula (XXII), Z 5 teeth, [ka] and [ka] Selected from, During the ceremony, [ka] This represents the connection point to L, During the ceremony, [ka] This represents the connection point to Ab, Ab is an antibody.

[0289] In a particular embodiment of formula (XXII), Z 5 teeth, [ka] Selected from, During the ceremony, [ka] represents the connection point to L, and in the formula, [ka] This represents the connection point to Ab.

[0290] In certain embodiments of equations (XXI) to (XXII), Z 5 This is derived from the chemoselective ligation groups disclosed herein.

[0291] In certain embodiments of equations (XXI) to (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.

[0292] The M6PR binding moiety can be site-specifically covalently bound to an antibody or antibody fragment by any binding moiety. The M6PR binding moiety can be covalently bound to an antibody or antibody fragment (e.g., L443C) by site-specific cysteine ​​modifications and thiol-reactive chemoselective ligation groups. The M6PR binding moiety can also be covalently bound to an antibody or antibody fragment by one or more lysine residues in the antibody or antibody fragment and amine-reactive chemoselective ligation groups.

[0293] The M6PR binding portion can be linked to a target-binding antibody or antibody fragment via chimeric protein fusion or by any spacer sequence.

[0294] In some embodiments, the conjugate of the present disclosure comprises an antibody (Ab). In some embodiments, Ab is a monoclonal antibody. In some embodiments, Ab is a human antibody. In some embodiments, Ab is a humanized antibody. In some embodiments, Ab is a chimeric antibody. In some embodiments, Ab is a full-length antibody comprising two heavy chains and two light chains. In some embodiments, Ab is an IgG antibody, e.g., IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, Ab is a single-chain antibody. In some embodiments, the target binding portion is an antigen-binding fragment of the antibody, e.g., a Fab fragment.

[0295] In some embodiments, the antibody or antibody fragment is specifically bound to the cancer antigen.

[0296] In some embodiments, the antibody or antibody fragment is specifically bound to the hepatocyte antigen.

[0297] In some embodiments, the antibody or antibody fragment is specifically bound to the antigen presented on the macrophage.

[0298] In some embodiments, the antibody or antibody fragment is specifically bound to the complete complement or a fragment thereof. In some embodiments, the antibody or antibody fragment is specifically bound to one or more immunodominant epitopes within the complete complement or a fragment thereof.

[0299] In some embodiments, the antibody or antibody fragment is specifically bound to a cell surface receptor. In some embodiments, the antibody or antibody fragment is specifically bound to a cell surface receptor ligand.

[0300] In some embodiments, the antibody or antibody fragment is specifically bound to epidermal growth factor (EGF) protein, such as human EGF. In some embodiments, the antibody or antibody fragment is specifically bound to one or more immunodominant epitopes within the EGF protein.

[0301] In some embodiments, the antibody or antibody fragment specifically binds to the epidermal growth factor receptor (EGFR) protein, for example, 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 contains a CDR present in cetuximab. In some embodiments, the antibody or antibody fragment contains 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 contains a CDR present in matsuzumab. In some embodiments, the antibody or antibody fragment contains a variable light chain and a variable heavy chain present in matsuzumab. In some embodiments, the antibody is matsuzumab.

[0302] In some embodiments, the antibody or antibody fragment is specifically bound to a vascular endothelial growth factor (VEGF) protein, such as human VEGF protein. In some embodiments, the antibody or antibody fragment is specifically bound to one or more immunodominant epitopes within the VEGF protein.

[0303] In some embodiments, the antibody or antibody fragment specifically binds to vascular endothelial growth factor receptor (VEGFR) protein, such as human VEGFR protein. In some embodiments, the antibody or antibody fragment specifically binds to vascular endothelial growth factor receptor 2 (VEGFR2) protein, such as human VEGFR2 protein. In some embodiments, the antibody or antibody fragment specifically binds to vascular endothelial growth factor receptor 3 (VEGFR3) protein, such as human VEGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the VEGFR protein, VEGFR2 protein, or VEGFR3 protein.

[0304] In some embodiments, the antibody or antibody fragment is specifically bound to fibroblast growth factor (FGF), such as human FGF. In some embodiments, the antibody or antibody fragment is specifically bound to one or more immunodominant epitopes within the FGF protein.

[0305] In some embodiments, the antibody or antibody fragment specifically binds to fibroblast growth factor receptor (FGFR), for example, human FGFR. In some embodiments, the antibody or antibody fragment specifically binds to fibroblast growth factor receptor 2 (FGFR2) protein, for example, human FGFR2 protein, for example, FGFR2b protein. In some embodiments, the antibody or antibody fragment specifically binds to fibroblast growth factor receptor 3 (FGFR3) protein, for example, human FGFR3 protein. In some embodiments, the antibody or antibody fragment specifically binds to one or more immunodominant epitopes within the FGFR protein, FGFR2 protein, or FGFR3 protein.

[0306] 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 epitopes within the receptor tyrosine kinase cMET protein.

[0307] In some embodiments, the antibody specifically binds to the CD47 protein, for example, human CD47 protein. In some embodiments, the antibody specifically binds to one or more immunodominant epitopes within the CD47 protein.

[0308] In some embodiments, the antibody is specifically bound to an immune checkpoint inhibitor. In some embodiments, the antibody is bound to one or more immunodominant epitopes within the immune checkpoint inhibitor. In some embodiments, the antibody is specifically bound to a programmed cell death protein, such as human PD-1. In some embodiments, the antibody is specifically bound to one or more immunodominant epitopes within the PD-1 protein.

[0309] In some embodiments, the antibody specifically binds to programmed death ligand-1 (PD-L1) protein, such as human PD-L1. In some embodiments, the antibody specifically binds to one or more immunodominant epitopes within the PD-L1 protein.

[0310] In some embodiments, the antibody is bound to TIM3. In some embodiments, the antibody is bound to one or more immunodominant epitopes within TIM3.

[0311] In some embodiments, the antibody is specifically bound to the lectin. In some embodiments, the antibody is specifically bound to one or more immunodominant epitopes within the lectin. In some embodiments, the antibody is bound to SIGLEC. In some embodiments, the antibody is bound to one or more immunodominant epitopes within SIGLEC. In some embodiments, the antibody is bound to the cytokine receptor. In some embodiments, the antibody is bound to one or more immunodominant epitopes within the cytokine receptor. In some embodiments, the antibody is bound to sIL6R. In some embodiments, the antibody is bound to one or more immunodominant epitopes within sIL6R. In some embodiments, the antibody is bound to the cytokine. In some embodiments, the antibody is bound to one or more immunodominant epitopes within the cytokine. In some embodiments, the antibody is bound to MCP-1, TNF (e.g., TNF-alpha), IL1a, IL1b, IL4, IL5, IL6, IL12 / IL23, IL13, IL17, or p40. In some embodiments, the antibody is bound to one or more immunodominant epitopes within MCP-1, TNF (e.g., TNF-alpha), IL1a, IL1b, IL4, IL5, IL6, IL12 / IL23, IL13, IL17, or p40.

[0312] In some embodiments, the antibody is bound to a major histocompatibility protein (e.g., an MHC class I or class II molecule). In some embodiments, the antibody is bound to one or more immunodominant epitopes within a major histocompatibility protein (e.g., an MHC class I or class II molecule). In some embodiments, the antibody is bound to beta-2 microglobulin. In some embodiments, the antibody is bound to one or more immunodominant epitopes within beta-2 microglobulin.

[0313] In some embodiments, the target binding site is a biological agent that is a TNF protein antagonist (e.g., TNF-alpha). Many biological agents (e.g., monoclonal antibody drugs) have been developed to inhibit TNF binding to TNF receptors and have been shown to be clinically effective in many autoinflammatory diseases.

[0314] In certain embodiments of the conjugate described herein, L is bound to a lysine residue of P by an amide bond. In certain embodiments of the conjugate described herein, L is bound to a cysteine ​​residue of P by a thioether bond. In certain embodiments of the conjugate described herein, L is bound to a lysine residue of Ab by an amide bond, as described above. In certain embodiments of the conjugate described herein, L is bound to a cysteine ​​residue of Ab by a thioether bond, as described above. In certain embodiments of the conjugate described herein, L is bound to two cysteine ​​residues of Ab by two thioether bonds, which are derived from an open cysteine-cysteine ​​disulfide bond in Ab. In certain embodiments, the open cysteine-cysteine ​​disulfide bond is an interchain disulfide bond.

[0315] In certain embodiments of the conjugate described herein, when L is bound to a lysine residue of P by an amide bond, m is an integer from 1 to 80. In certain embodiments of the conjugate described herein, when L is bound to a cysteine ​​residue of P by a thioether bond, m is an integer from 1 to 8.

[0316] In certain embodiments, the conjugation to polypeptide P or antibody Ab may be carried out by site-specific conjugation. For example, site-specific conjugation may result in a uniform load and minimize conjugate subpopulations that may alter antigen binding or pharmacokinetics. In certain embodiments, for example, the conjugation may involve engineering cysteine ​​substitutions at positions on the polypeptide or antibody that provide reactive thiol groups, for example, on the heavy and / or light chains of the antibody, without interfering with the folding and assembly of the polypeptide or antibody, and without altering polypeptide or antigen binding (see, e.g., Junutula et al., J.Immunol.Meth.2008;332:41-52, and Junutula et al., Nature Biotechnol.2008;26:925-32, and also see WO2006 / 034488 (which is incorporated herein by reference in its entirety)). Another non-restrictive approach involves selenocysteine ​​being co-translationally inserted into polypeptide or antibody sequences by re-coding the stop codon UGA from termination to selenocysteine ​​insertion, enabling site-specific covalent bonding at the nucleophilic selenol group of selenocysteine ​​in the presence of other native 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). Further non-limiting techniques that enable site-specific binding to polypeptides or antibodies include the manipulation of non-natural amino acids at specific binding sites, such as p-acetylphenylalanine (p-acetyl-Phe), p-azidomethyl-N-phenylalanine (p-azidomethyl-Phe), and azidrisine (azido-Lys), as well as the manipulation of intrinsic functional tags for enzyme-mediated binding, such as LPXTG, LLQGA, sialic acid, and GlcNAc.See Jackson, Org. Process Res. Dev. 2016;20:852-866, and Tsuchikama and An, Protein Cell 2018;9(1):33-46, the entire contents of each thereof are incorporated by reference. Also see US2019 / 0060481A1 and US2016 / 0060354A1, the entire contents of each thereof are incorporated by reference. All such methods are intended to be used in connection with the preparation of the conjugates described herein.

[0317] The loading of compounds of formulas (I) and (III) to (IIIb) onto polypeptides (e.g., antibodies) described herein is represented by "m" in various formulas, which is the average number of "Xn-L-" or "Xn-" units per conjugate molecule. As used herein, the term "DAR" refers to the average value of "m" or the loading of the conjugate. The number of "X" parts (e.g., M6P parts) per "Xn-L-" or "Xn-" unit is represented by "n" in the formula. The terms "valence" or "multiple valences" refer to the number of "X" parts ("n") per unit. It will be understood that the loading, i.e., DAR, is not necessarily the same as the number of "X" parts per conjugate molecule. For example, if there is one "X" part per unit (n=1, with a valence of "1") and one "Xn-L-" unit per conjugate (m=1), then there are 1 x 1 = 1 "X" parts per conjugate. However, if there are two "X" parts per unit (n=2, bond valency "2") and four "Xn-L-" units per conjugate (m=4), then there will be 2 x 4 = 8 "X" parts per conjugate. Therefore, for the conjugates described herein, the total number of "X" parts per conjugate molecule is n x m. As used herein, the term "total bond valency" refers to the total number of "X" parts per conjugate molecule (n x m, total bond valency).

[0318] The DAR (load) may range from 1 to 80 units per conjugate. The conjugates provided herein may include, for example, a collection of polypeptides, antibodies, or antigen-binding fragments conjugated in units ranging from 1 to 80. The average number of units per polypeptide or antibody in the conjugate preparation obtained from the conjugation reaction can be characterized by conventional means such as mass spectrometry. The quantitative distribution of the DAR (load) in terms of m can also be measured. In some cases, the separation, purification, and characterization of homogeneous conjugates where m is a specific value can be achieved by means such as electrophoresis.

[0319] In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 80. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 70. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 60. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 50. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 40. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 35. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 30. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 25. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 20. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 18. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 15. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 12. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 10. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 9. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 8. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 7. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 6. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 5. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 4. In certain embodiments, the range of DAR for the conjugate provided herein is 1 to 3.In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 12. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 10. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 9. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 8. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 7. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 6. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 5. In certain embodiments, the range of DAR for the conjugate provided herein is 2 to 4. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 12. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 10. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 9. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 8. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 7. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 6. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 5. In certain embodiments, the range of DAR for the conjugate provided herein is 3 to 4.

[0320] In a particular embodiment, the range of DARs for the conjugate provided herein is 1 to about 8, about 2 to about 6, about 3 to about 5, about 3 to about 4, about 3.1 to about 3.9, about 3.2 to about 3.8, about 3.2 to about 3.7, about 3.2 to about 3.6, about 3.3 to about 3.8, or about 3.3 to about 3.7.

[0321] In certain embodiments, the DAR for the conjugate provided herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or more. In some embodiments, the DAR for the conjugate provided herein is about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, or about 3.9.

[0322] In some embodiments, the DAR for the conjugates provided herein is in the range of 2-20, 2-19, 2-18, 2-17, 2-16, 2-15, 2-14, or 2-13. In some embodiments, the range of DAR for the conjugates provided herein is 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, or 3-13. In some embodiments, the DAR for the conjugates provided herein is about 1. In some embodiments, the DAR for the conjugates provided herein is about 2. In some embodiments, the DAR for the conjugates provided herein is about 3. In some embodiments, the DAR for the conjugates provided herein is about 4. In some embodiments, the DAR for the conjugates provided herein is about 3.8. In some embodiments, the DAR for the conjugates provided herein is about 5. In some embodiments, the DAR for the conjugates provided herein is about 6. In some embodiments, the DAR for the conjugate provided herein is about 7. In some embodiments, the DAR for the conjugate provided herein is about 8. In some embodiments, the DAR for the conjugate provided herein is about 9. In some embodiments, the DAR for the conjugate provided herein is about 10. In some embodiments, the DAR for the conjugate provided herein is about 11. In some embodiments, the DAR for the conjugate provided herein is about 12. In some embodiments, the DAR for the conjugate provided herein is about 13. In some embodiments, the DAR for the conjugate provided herein is about 14. In some embodiments, the DAR for the conjugate provided herein is about 15. In some embodiments, the DAR for the conjugate provided herein is about 16. In some embodiments, the DAR for the conjugate provided herein is about 17.In some embodiments, the DAR for the conjugate provided herein is about 18. In some embodiments, the DAR for the conjugate provided herein is about 19. In some embodiments, the DAR for the conjugate provided herein is about 20.

[0323] In some embodiments, the DAR for the conjugate provided herein is about 25. In some embodiments, the DAR for the conjugate provided herein is about 30. In some embodiments, the DAR for the conjugate provided herein is about 35. In some embodiments, the DAR for the conjugate provided herein is about 40. In some embodiments, the DAR for the conjugate provided herein is about 50. In some embodiments, the DAR for the conjugate provided herein is about 60. In some embodiments, the DAR for the conjugate provided herein is about 70. In some embodiments, the DAR for the conjugate provided herein is about 80.

[0324] In certain embodiments, during the conjugation reaction, fewer units than the theoretical maximum number of units are conjugated to the polypeptide, such as an antibody. The polypeptide may contain, for example, lysine residues that do not react with the compound or linker reagent. Generally, for example, an antibody contains few free reactive cysteinethiol groups that can be linked to a drug unit; in fact, most cysteinethiol residues in an antibody exist as disulfide bonds. In certain embodiments, the antibody may be reduced under partially or completely reducing conditions with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) to generate reactive cysteinethiol groups. In certain embodiments, the antibody is subjected to denaturing conditions to expose reactive nucleophiles such as lysine or cysteine. In some embodiments, the compound is conjugated by lysine residues on the antibody. In some embodiments, the linker unit or drug unit is conjugated by cysteine ​​residues on the antibody.

[0325] In certain embodiments, the amino acids attached to the unit are located in the heavy chain of the antibody. In certain embodiments, the amino acids attached to the unit are located in the light chain of the antibody. In certain embodiments, the amino acids attached to the unit are located in the hinge region of the antibody. In certain embodiments, the amino acids attached to the unit are located in the Fc region of the antibody. In certain embodiments, the amino acids attached to the unit are located 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 another embodiment, the amino acids attached to the unit or drug unit are located in the VH framework region of the antibody. In yet another embodiment, the amino acids attached to the unit are located in the VL framework region of the antibody.

[0326] The DAR (loading) of the conjugate can be controlled in various ways, such as (i) limiting the molar excess of the compound or conjugating reagent relative to the polypeptide, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limited reducing conditions for cysteine ​​thiol modification, or (iv) modifying the amino acid sequence of the polypeptide by recombinant techniques to change the number and position of cysteine ​​residues and thereby control the number and / or position of linker-drug attachments (e.g., in the case of thiomab prepared as disclosed in WO2006 / 034488 (which is incorporated herein by reference in its entirety)).

[0327] It should be understood that the preparation of conjugates described herein may yield a mixture of multiple conjugates having a distribution of one or more units attached to a polypeptide, such as an antibody. Individual conjugate molecules in the mixture can be identified by mass spectrometry and separated by HPLC, such as hydrophobic interaction chromatography, including methods known in the art. In certain embodiments, homogeneous conjugates with a single DAR (load) value can be separated from the conjugation mixture by electrophoresis or chromatography.

[0328] 4.5.1.3.Small molecules In some embodiments, the target binding moiety of the bifunctional compound of this disclosure is a small molecule that specifically binds to a target molecule, such as a target protein. In some embodiments, the bifunctional compound comprises a small molecule inhibitor or ligand of the target protein. The small molecule target binding moiety can be covalently linked to one or more M6PR binding moieties by a linker. The linker can be attached to the small molecule by substitution at any suitable site on the small molecule such that binding to the target protein is substantially maintained.

[0329] In some embodiments, the target-binding moiety is a small molecule inhibitor or antagonist of the target protein (as described herein, for example). Any convenient small molecule known to bind to the target of interest can be adapted for use in the compound and conjugate of the subject.

[0330] 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.

[0331] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of EGFR protein, VEGFR protein, FGFR2 protein, or FGFR3 protein.

[0332] In some embodiments, the target binding moiety is a small molecule inhibitor or antagonist of the TNF protein (e.g., TNF-alpha). TNF-alpha (TNFα) is a soluble cytokine produced by monocytes and macrophages as part of immune and inflammatory processes, and is involved in a diverse range of cellular responses, including differentiation, proliferation, inflammation, and cell death. TNFα is a type II transmembrane protein that can be cleaved and secreted as a soluble form. Both the transmembrane and soluble biologically active forms of TNFα are homotrimeric complexes that can be signaled by TNF receptors 1 and 2 (TNF-R1 and TNF-R2). TNFα is directly involved in systemic inflammation by regulating intracellular NF-κB, JNK, and p38-MAPK signaling pathways.

[0333] The TNFα-binding moiety can be a TNFα inhibitor, such as a competitive inhibitor of TNF receptor binding or an allosteric inhibitor of TNF signaling. The compounds of this disclosure may include potent TNFα inhibitors, for example, inhibitors having submicromolar inhibitory activity. In some embodiments, the TNFα inhibitor is an allosteric inhibitor. In some embodiments, the TNFα-binding moiety is an allosterically asymmetric TNFα inhibitor. An allosterically asymmetric TNFα inhibitor is a compound that binds to an allosteric site in TNFα and stabilizes the trimer unit in an asymmetric structure that allows the TNFα trimer to recruit only two of the three copies of the TNF receptor (TNFR, e.g., TNFR1), resulting in a dysfunctional TNFα-TNFR signaling complex.

[0334] For example, see Xiao et al. in Journal of Medicinal Chemistry 2020 63(23),15050-15071 and McMillan et al. in Nature Communications (2021)12:582, which disclose the analysis of X-ray cocrystal structures of exemplary inhibitors bound to TNFα. Allosteric asymmetric TNFα inhibitors can act by specific mechanisms of action to provide potent inhibitory activity. For example, (a) the TNFα inhibitor binding site is a cavity within the TNFα trimer generated by the movement of monomer A; (b) the inhibitor stabilizes the TNFα trimer in an inactive structure by forming key π-π and hydrogen bond interactions; (c) the allosteric asymmetric TNFα inhibitor binds to the TNFα trimer, resulting in a large disruption of one TNFR binding site and a small disruption of a second site, while the third site remains unchanged; and (d) the allosteric asymmetric TNFα inhibitor modulates TNF-R activity by an allosteric mechanism rather than by direct competition with TNFR. Therefore, binding of an allosteric asymmetric TNFα inhibitor to a symmetric TNFα trimer can result in the formation of an asymmetric trimer that prevents the recruitment of the three TNF receptor molecules necessary for signal transduction.

[0335] 4.5.2.Target As summarized above, the bifunctional compounds of this disclosure may include a target moiety (Y) specifically bound to a target molecule. The target molecule may be a cell surface molecule or an extracellular molecule.

[0336] In some embodiments of the compounds and methods of this disclosure, the target molecule is a cell surface molecule. “Cell surface molecule” means a target molecule associated with the cell membrane, for example, having 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 by the endosomal / lysosomal pathway is desired. In some embodiments, the cell surface molecule is a cell surface receptor.

[0337] The target cell surface receptors 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 re-transfecting (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 embodiments, 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.

[0338] In some embodiments, the target portion (Y) specifically binds to a cell surface molecule, and its effect is mediated not through specific molecular interactions (and therefore less likely to be inhibited), but through bulk biophysical or aggregation effects. A non-limiting example of such a cell surface molecule is mucin. Examples of mucins include, but are not limited to, MUC1, MUC16, MUC2, MUC5AC, MUC4, CD43, CD45, GPIb, etc.

[0339] In some embodiments, if the part of interest specifically binds to a cell surface molecule, that cell surface molecule is present on cancer cells. "Cancer cell" means a cell exhibiting a neoplastic cellular phenotype that can be characterized by one or more appropriate indicators of cell transformation, such as abnormal cell growth, abnormal cell proliferation, loss of density-dependent growth inhibition, anchorage-independent growth ability, ability to promote tumor growth and / or development in non-human animal models of immunodeficiency, and / or cell transformation. Herein, "cancer cell" is used interchangeably with "tumor cell," "malignant cell," or "cancerous cell" and includes cancer cells such as solid tumors, semi-solid tumors, hematopoietic malignancies (e.g., leukemia cells, lymphoma cells, myeloma cells, etc.), primary tumors, and metastatic tumors. In some embodiments, the cell surface molecule present on cancer cells is a tumor-associated antigen or tumor-specific antigen. In certain embodiments, if the part of interest (Y) specifically binds to a cell surface molecule, that cell surface molecule is present on immune cells. In some embodiments, the cell surface molecules are present on immune cells selected from T cells, B cells, natural killer (NK) cells, macrophages, monocytes, neutrophils, dendritic cells, mast cells, basophils, and eosinophils. In certain embodiments, the cell surface molecules present on immune cells are inhibitory immune receptors. As used herein, “inhibitory immune receptor” is a receptor present on immune cells that negatively regulates the immune response. Examples of inhibitory immune receptors that can be inhibited according to the methods of this disclosure include, but are not limited to, inhibitory immune receptors of the Ig superfamily, including CD200R, CD300a (IRp60, mouse MAIR-I), CD300f (IREM-1), CEACAM1 (CD66a), FcyRIIb, ILT-2 (LIR-1, LILRB1, CD85j), ILT-3 (LIR-5, CD85k, LILRB4), ILT-4 (LIR-2, LILRB2), ILT-5 (LIR-3, LILRB3, mouse PIR-B), LAIR-1, PECAM-1 (CD31), PILR-a (FDF03), SIRL-1, and SIRP-a. Further examples of inhibitory immune receptors that can be inhibited according to the methods of this disclosure include, for example, sialic acid-binding Ig-like lectin (Sigrec) receptors, such as Sigrec 7 and Sigrec 9.Further examples of inhibitory immune receptors that can be inhibited according to the methods of this disclosure include, but are not limited to, C-type lectins including CLEC4A(DCIR), Ly49Q, and MICL. Further details regarding inhibitory immune receptors are described, for example, in Steevels et al. (2011) Eur.J.Immunol. 41(3):575-587. In some embodiments, cell surface molecules present on immune cells are ligands for inhibitory immune receptors. In certain embodiments, the cell surface molecules present on immune cells are immune checkpoint molecules. Non-limiting examples of immune checkpoint molecules to which the part of interest (Y) can specifically bind include PD-1, PD-L1, CTLA4, TIM3, LAG3, TIGIT, and members of the B7 family.

[0340] In some embodiments of the compounds and methods of this disclosure, the target molecule is an extracellular molecule. “Extracellular molecule” means a soluble molecule located outside the cell membrane of any cell near a soluble molecule. The extracellular molecule may be any extracellular molecule for which targeted degradation by the endosomal / lysosomal pathway is desired.

[0341] 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), cholesterol carrier (e.g., ApoB), infectious toxin (e.g., AB toxin, ESAT-6), infectious particle (e.g., whole virus, whole bacterium, etc.), coagulation factor (e.g., factor IX), target of an FDA-approved antibody that binds to the extracellular molecule (e.g., TNF-alpha), chemokine or cytokine (e.g., a sepsis or chronic inflammation mediator such as IL-1), protein hormone (e.g., insulin, ACTH, etc.), protein mediator of mood disorders, protein mediator of energy homeostasis (e.g., leptin, ghrelin, etc.), protein allergen present in the bloodstream or antibodies against such allergens (e.g., in the case of peanut allergy, etc.), protein toxin (e.g., snake venom hyaluronidase, etc.), autoantibodies, etc.

[0342] In some embodiments, the target molecule is an extracellular molecule that is an antibody, for example, an antibody specifically bound to a cell surface molecule or a different extracellular molecule. In some embodiments, the antibody is an autoantibody. In some embodiments, the target is human immunoglobulin A (IgA). In some embodiments, IgA is a specific antibody that plays a crucial role in mucosal immune function. In the blood, IgA interacts with an Fc receptor called CD89 expressed on immune effector cells, initiating an inflammatory response. Abnormal IgA expression is thought to be associated with many autoimmune and immune-mediated diseases. In some embodiments, the target is human immunoglobulin G (IgG). The Fc region of IgG contains an N-glycosylation site conserved at asparagine 297 in the constant region of the heavy chain. Various N-glycans can be attached to this site. N-glycan IgG composition is associated with several autoimmune diseases, infections, and metabolic diseases. Furthermore, overexpression of IgG4 has been associated with IG4-related diseases. In some embodiments, the target is human immunoglobulin E (IgE). IgE is a type of immunoglobulin that plays an important role in type I hypersensitivity, which can cause various allergic diseases and conditions.

[0343] In some embodiments, the extracellular molecule is a ligand for a cell surface receptor. The cell surface receptor ligand of interest includes, but is not limited to, growth factors (e.g., epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), etc.), cytokines (e.g., interleukins, interferons, tumor necrosis factor (TNF), transforming growth factor β (TGF-β), and any specific subtype of such cytokines), hormones, etc. In a particular embodiment, the part of interest (Y) specifically binds to apolipoprotein E4 (ApoE4).

[0344] 4.5.3. Target portion for intracellular delivery In some embodiments, the part of interest is a molecule that does not bind to an extracellular target and is rather a molecule that is desirable to be delivered intracellularly. In some embodiments, the part of interest is selected from enzymes (e.g., lysosomal enzymes), nanoparticles, viral compositions (e.g., viral particles), therapeutic proteins, and therapeutic antibodies.

[0345] In some embodiments, the target portion Y is selected from small molecules, small molecule drugs, chemotherapeutic agents, cytotoxic agents, diagnostic agents, dyes, fluorophores, and the like.

[0346] In some embodiments, the target portion Y is a nanoparticle suitable for the delivery of one or more drugs or cargo within the nanoparticle.

[0347] 4.5.3.1. Conjugates for Enzyme Replacement Therapy In some embodiments, the object of interest is a lysosomal enzyme for delivery to cells for use in enzyme replacement therapy, such as acid alpha-glucosidase (GAA). The lysosomal enzymes of interest that may be adapted for use in the conjugate of this disclosure include acid alpha-glucosidase, acid beta-galactosidase-1, acid sphingomyelinase, alpha-D-mannosidase, alpha-fucosidase, alpha-galactosidase A, alpha-glucosaminidoacetyltransferase, alpha-glucosidase, alpha-L-idulonidase, alpha-N-acetylgalactosaminidase, alpha-acetylglucosaminidase, alpha-D-neuraminidase, allylsulfatase A, allylsulfatase B, beta-galactosidase, beta-glucuronidase, beta-mannosidase, cathepsin D, cathepsin K, ceramidase, cystinosine, and cancer. This includes, but is not limited to, glioside activator GM2, galactocerebrosidase, glucocerebrosidase, heparanthulfatase, hexosaminidase A, hexosaminidase B, hyaluronidase, iduronic acid-2-sulfatase, LAMP2, lysosomal acid lipase, N-acetylglucosamine-1-phosphotransferase, N-acetylgalactosamine-6-sulfatase, N-acetylglucosamine-1-phosphotransferase, N-acetylglucosamine-6-sulfate sulfatase, N-aspartyl-beta-glucosaminidase, palmitoylthioesterase-1, acid phosphatase, protective protein / cathepsin A (PPCA), sialin, and tripeptidyl peptidase 1.

[0348] Conjugation to enzymes can be achieved using the methods described herein for preparing polypeptide and antibody conjugates.

[0349] 4.5.3.2. Modified viral 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 containing 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 with a viral composition produces a modified viral composition that provides enhanced viral transduction compared to an unlabeled viral composition.

[0350] In certain embodiments, the Specified Information provides 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) conjugated (e.g., directly or indirectly, e.g., by 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 optionally containing a transgene, e.g., a transgene useful for therapeutic applications.

[0351] The modified viral compositions presented herein, for example, viral conjugates, may comprise any viral composition described herein, for example, any viral particle, capsid, or viral protein described herein, for example, a capsid protein or an envelope protein, or fragments thereof.

[0352] In certain embodiments, the viral compositions described herein may include viral particles. The terms “viral particle,” “viral vector,” or “viral vector” are used interchangeably herein. “Viral particle” means a viral capsid and polynucleotides (DNA or RNA) which may include a viral genome, a portion of a viral genome, or polynucleotides (e.g., one or more ITRs) derived from a viral genome, the polynucleotides optionally including a transgene. In certain examples, the viral particle further includes an envelope (generally including a lipid portion and envelope proteins) surrounding or partially surrounding the capsid.

[0353] Viral particles may also be called “recombinant viral particles,” and as used herein, these terms refer to genetically modified viral particles, for example, by deletion or other mutation of endogenous viral genes, and / or by addition or insertion of heterologous nucleic acid constructs into the polynucleotides of the viral particle. Thus, recombinant viral particles generally refer to viral particles that contain a capsid coat or shell (and any outer envelope) that packages a polynucleotide sequence (i.e., a polynucleotide heterologous to the virus) containing both viral and non-viral sequences. This polynucleotide sequence is typically the sequence of interest for genetic modification of cells.

[0354] In certain embodiments, the viral compositions described herein, when referred to herein in the context of viruses, may include “viral capsid,” “empty viral particle,” “empty viral particle,” or “capsid,” and as used herein, these terms refer to a three-dimensional shell or coat comprising a viral capsid protein that is 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, for example, a viral capsid protein or fragment thereof, or an envelope protein or fragment thereof.

[0355] In some embodiments, the viruses used in the modified viral compositions provided herein are adenoviruses (AV), adeno-associated viruses (AAV), retroviruses (e.g., lentiviruses (LV), rhabdoviruses, murine leukemia viruses), herpes simplex viruses, coronaviruses, reoviruses, and the like. In some embodiments, the viral vectors, viral particles, or viral proteins used in this disclosure are derived from unenveloped viruses, such as adeno-associated viruses (AAV).

[0356] In some embodiments, lentiviral vectors can be used, for example, in CAR-T gene delivery, vaccines, or research tools to introduce genes into mature T cells to generate immunity against cancer by delivery of chimeric antigen receptors (CARs) or cloned T cell receptors.

[0357] Naturally occurring AAV forms a viral particle containing 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.

[0358] The modified AAV compositions presented herein, for example, AAV conjugates or fusions, may include any AAV composition described herein, for example, any AAV particles, capsids or capsid proteins, or fragments thereof. The terms “AAV capsid protein” or “AAV cap protein” refer to a protein encoded by the AAV capsid (cap) gene (e.g., VP1, VP2, and VP3) or its variants or fragments. This term includes capsid proteins expressed by or derived from AAV, such as recombinant AAV, including chimeric AAV. For example, this term includes, but is not limited to, capsid proteins derived from any AAV serotype, such as AAV1, AAV2, AAV2i8, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV rh10, AAV11, AAV12, AAV13, AAV-DJ, AAV3b, AAV LK03, AAV rh74, AAV Anc81, Anc82, Anc83, Anc84, Anc110, Anc113, Anc126, or Anc127, AAV_go.1, AAV hu.37, or AAVrh.8, or their variants.

[0359] 4.5.3.3. Crosslinking portion for binding the virus composition In some embodiments, Y is a crosslinking moiety that specifically binds to the above-mentioned viral composition, such as a viral particle, viral capsid, viral envelope, or viral protein (e.g., viral capsid protein or envelope protein), and the binding is not via covalent linkage. Such a conjugate can be useful in enhancing intracellular delivery and viral transduction of the target viral composition.

[0360] Any suitable portion that binds to a viral particle, viral capsid, viral envelope, or viral protein (e.g., viral capsid protein or envelope protein) can be adapted for use in the cross-linked portion conjugate of this disclosure.

[0361] In certain embodiments, the crosslinking portion is a polypeptide that specifically binds to a viral composition. In some embodiments, the crosslinking portion is a polypeptide that binds to a viral composition, such as a viral particle, viral capsid, viral envelope, or viral protein, such as a viral capsid protein or viral envelope protein. In certain embodiments, the crosslinking composition binds to a viral capsid protein or viral envelope protein if the viral protein is part of a viral particle.

[0362] In certain embodiments, the crosslinked portion 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, the crosslinked portion that binds to the viral protein may also bind to the viral particle, for example, by binding to the viral protein incorporated into the viral particle. Similarly, in certain embodiments, the crosslinked portion that binds to the 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 virus particle. The viral protein may be an AAV capsid protein.

[0363] In some embodiments, the crosslinked portions of the disclosed herein specifically bind to AAV compositions, such as AAV particles, AAV capsids, or AAV viral proteins (e.g., AAV capsid proteins, e.g., VP1, VP2, or VP3 proteins).

[0364] In connection with the modified viral compositions provided herein, for example, antibodies or antigen-binding fragments that may be used in connection with the crosslinked compositions and crosslinked portions presented herein include, but are not limited to, monoclonal antibodies, antibody compositions having polyepitope specificity or monoepitope specificity, polyclonal antibodies or monovalent antibodies, multivalent antibodies, and multispecific antibodies (e.g., bispecific antibodies insofar as they exhibit the desired biological activity), formed from at least two complete antibodies (intact antibodies), single-chain antibodies and fragments thereof (e.g., domain antibodies).

[0365] 4.6. Exemplary Conjugates Exemplary monomer compounds of this disclosure, including chemoselective ligation groups, are shown in Table 7 and can be used to prepare conjugates of the desired portion.

[0366] [Table 7]

[0367] Exemplary dimeric (n=2) compounds of the present disclosure that contain chemoselective ligation groups and can be used to prepare conjugates of the desired portion are shown in Table 8.

[0368] [Table 8]

[0369] The structures of exemplary monomer (n=1) compounds of this disclosure, which contain a structurally selective ligation group and can be used to prepare a conjugate of the desired portion, are shown in Table 9.

[0370] [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 9-15 Table 9-16

[0371] 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]

[0372] [Table 11]

[0373] The structures of exemplary polyvalent (n>1) compounds of this disclosure that can be used to prepare the conjugate of the desired portion are shown in Table 12.

[0374] [Table 12-1] [Table 12-2] [Table 12-3] Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 12-16 Table 12-17 Table 12-18

[0375] The structures of exemplary polyvalent (n>1) compounds of this disclosure that can be used to prepare the conjugate of the desired portion are shown in Table 12B.

[0376] [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]

[0377] [Table 12B-15] [Table 12B-16] [Table 12B-17]

[0378] 4.7. Additional Experimental Observations Without being constrained by any particular mechanism or theory, within a certain desired range, the binding affinity of an M6PR ligand may be inversely correlated with a longer half-life of the resulting compound and conjugate, and the selection of a desired binding affinity may be useful for tuning (e.g., modifying) the pharmacokinetic properties of the conjugate described herein. In certain embodiments, a compound or conjugate having the structure described herein may be selected to have a binding affinity to cell surface M6PR that provides a combination of desired pharmacokinetic properties (e.g., a sufficient half-life) while providing sufficiently robust uptake and / or degradation of the target.

[0379] 4.8. Pharmaceutical Compositions In another embodiment, this specification provides a pharmaceutical composition comprising one or more conjugates disclosed herein and a pharmaceutically acceptable carrier.

[0380] In certain embodiments, the pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more conjugates provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. The pharmaceutical compositions may be useful for the prevention, treatment, management, or improvement of one or more of the diseases or disorders or symptoms described herein.

[0381] Pharmaceutical carriers suitable for administering the conjugates provided herein include any carrier known to those skilled in the art to be suitable for a particular method of administration.

[0382] The conjugates described herein can be formulated as the sole pharmaceutically active ingredient in a composition, or they can be combined with other active ingredients.

[0383] In certain embodiments, the conjugate is formulated into one or more suitable pharmaceutical formulations, such as a solution in a sterile solution or suspension for parenteral administration, a suspension, a powder, a sustained-release formulation or elixir, or a transdermal patch formulation and a dry powder inhalant.

[0384] In the compositions provided herein, the conjugates described herein may be mixed with a suitable pharmaceutical carrier. The concentration of the conjugate in the composition may be effective, for example, at the time of administration, to deliver an amount that treats, prevents, or improves the disease or disorder or its symptoms described herein.

[0385] In certain embodiments, the pharmaceutical compositions provided herein are formulated for single-dose administration. To formulate the composition, a weight fraction of the conjugate is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration such that the symptoms to be treated are alleviated, prevented, or one or more symptoms are improved.

[0386] The concentration of the conjugate in the pharmaceutical compositions provided herein depends, for example, on the physicochemical properties of the conjugate, the administration schedule, the dosage, and other factors known to those skilled in the art.

[0387] The pharmaceutical compositions described herein are provided for administration to subjects, e.g., humans or animals (e.g., mammals), in unit dosage forms such as sterile parenteral (e.g., intravenous) solutions or suspensions containing an appropriate amount of the compound or a pharmaceutically acceptable derivative thereof. The pharmaceutical compositions are also provided for administration to humans and animals in unit dosage forms containing oral or nasal solutions or suspensions, and oil-water emulsions, containing an appropriate amount of the conjugate or a pharmaceutically acceptable derivative thereof. In certain embodiments, the conjugate is formulated and administered in unit dosage forms or multi-dose dosage forms. As used herein, unit dosage forms refer to physically separate units, individually packaged as known in the art, suitable for human or animal (e.g., mammalian) subjects. Each unit dose contains a predetermined amount of conjugate sufficient to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules, syringes, and individually packaged capsules. Unit dosage forms can be administered in divided doses or in multiple doses. A multi-dose dosage form is a dosage form in which multiple identical unit dosage forms are packaged in a single container and administered in separate unit dosage forms. Examples of multi-dose dosage forms include vials, capsule bottles, or bottles. Therefore, in certain embodiments, a multi-dose dosage form is a multiple of unit dosage forms that are not separated in the packaging.

[0388] In certain embodiments, the conjugates of this specification are in the form of liquid pharmaceutical formulations. Liquid pharmaceutical formulations can be prepared, for example, by dissolving, dispersing, or mixing the conjugate and optional pharmaceutical adjuvants in a carrier such as water, saline, aqueous dextrose, glycerol, or glycol to form a solution or suspension. In certain embodiments, the pharmaceutical composition provided herein to be administered may also contain small amounts of non-toxic adjuvants such as wetting agents, emulsifiers, solubilizers, and pH buffers.

[0389] Practical methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy (2012) 22nd ed., Pharmaceutical Press, Philadelphia, PA. Dosage forms or compositions can be prepared containing antibody in an amount ranging from 0.005% to 100%, with the remainder consisting of a non-toxic carrier.

[0390] In certain embodiments, parenteral administration is characterized by subcutaneous, intramuscular, or intravenous injection, but parenteral administration is also considered herein. Injectable preparations can be prepared in liquid solution or suspension, solid form suitable for dissolving or suspending in liquid before injection, or conventional forms such as emulsions. Injectable preparations, solutions, and emulsions also contain one or more excipients. Suitable excipients include, for example, water, saline, glucose, glycerol, or ethanol. Other routes of administration may include intraenteral, intracerebral, nasal, intra-arterial, intracardiac, intraosseous, intrathecal, and intraperitoneal administration.

[0391] Preparations for parenteral administration include sterile solutions for injection, sterile dried soluble products such as lyophilized powders to be combined with a solvent immediately before use (including subcutaneous tablets), sterile suspensions for injection, sterile dried insoluble products to be combined with a vehicle immediately before use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[0392] For intravenous administration, suitable carriers include physiological saline or phosphate-buffered saline (PBS), and solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, as well as mixtures thereof.

[0393] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspensions and dispersants, emulsifiers, metal ion sequestering agents or chelating agents, and other pharmaceutically acceptable substances.

[0394] The pharmaceutical carrier also includes ethyl alcohol, polyethylene glycol, propylene glycol as a water-miscible vehicle, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0395] In certain embodiments, intravenous or intra-arterial infusion of a sterile aqueous solution containing the conjugate described herein is an effective method of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the conjugate described herein, which is infused as needed to produce the desired pharmacological effect.

[0396] In certain embodiments, the pharmaceutical formulation is a lyophilized powder that can be reconstituted as a solution, emulsion, or other mixture for administration. It can also be reconstituted and formulated as a solid or gel.

[0397] Lyophilized powders are prepared by dissolving the conjugates described herein in a suitable solvent. In some embodiments, the lyophilized powders are sterilized. Suitable solvents may contain excipients or other pharmacological components that improve the stability of the powder or the reconstituted solution prepared from the powder. Suitable excipients include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. Suitable solvents may also include buffers such as citrate, sodium phosphate, potassium phosphate, or other buffers known to those skilled in the art (in certain embodiments, at a nearly neutral pH). An example of a formulation is then obtained by sterile filtering the solution and subsequently lyophilizing it under standard conditions well known to those skilled in the art. In certain embodiments, the obtained solution is divided into vials for lyophilization. Lyophilized powders can be stored under suitable conditions, such as from about 4°C to room temperature.

[0398] By redissolving this lyophilized powder in sterile water for injection, a formulation for parenteral administration can be obtained. For redissolution, the lyophilized powder is added to sterile water or another suitable carrier.

[0399] In certain embodiments, the conjugates provided herein can be formulated for topical administration or application, for example, in the form of gels, creams, and lotions, for topical application to the skin and mucous membranes such as the eyes, and for application to the eyes, or for application into capsules or the spinal cord. Topical administration is considered for transdermal delivery, for administration to the eyes or mucous membranes, or for inhalation therapy. Nasal drops of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0400] 4.9.How to use In one embodiment, this specification provides a method for removing a target polypeptide (target protein) from the cell surface using a conjugate described herein. In another embodiment, this specification provides a method for removing a target polypeptide (target protein) from the extracellular environment using a conjugate described herein. For example, in one embodiment, this specification provides a method for removing a target polypeptide (target protein) from the cell surface by sequestering the target protein in the cell's lysosomes using a conjugate described herein. In another embodiment, this specification provides a method for removing a target polypeptide (target protein) from the extracellular space (extracellular environment) of a cell by sequestering the target protein in the cell's lysosomes using a conjugate described herein. In yet another embodiment, this specification provides a method for removing a target polypeptide (target protein) from the cell surface by sequestering the target protein in the cell's lysosomes using a conjugate described herein and degrading the target protein. In yet another embodiment, this specification provides a method for removing a target polypeptide (target protein) from the extracellular space (extracellular environment) of a cell by sequestering the target protein in the cell's lysosomes using a conjugate described herein and degrading the target protein.

[0401] The removal of a target protein can refer to a reduction or depletion of the target protein from the cell surface, extracellular space, or extracellular environment, i.e., a reduction or depletion of the amount of the target protein on the cell surface or in the extracellular environment. In some embodiments, this method is a method for reducing the amount or level of a target protein in a biological system or cell sample.

[0402] In one embodiment, a method for sequestering a target polypeptide (target protein) within the lysosomes of a cell using a conjugate described herein is provided. In one embodiment, a method for sequestering a target polypeptide (target protein) within the lysosomes of a cell using a conjugate described herein and for degrading the target polypeptide is provided.

[0403] In one embodiment, this specification provides a method for degrading a target polypeptide (target protein) using a conjugate described herein.

[0404] In one embodiment, this specification provides a method for depleting a target polypeptide (target protein) described herein by degradation via the lysosomal pathway of a cell.

[0405] In another embodiment, this specification provides a method for depleting a target polypeptide (target protein) described herein by administering a conjugate or pharmaceutically acceptable salt, or an effective amount of a pharmaceutical composition described herein, to a subject in need of treatment. In certain embodiments, the subject is a mammal (e.g., human).

[0406] In certain embodiments, the target protein is a membrane-bound protein. In certain embodiments, the target protein is a cell surface receptor. In certain embodiments, the target protein is an extracellular protein.

[0407] In certain embodiments, the target protein is a VEGF protein, an EGFR protein, a VEGFR protein, a PD-L1 protein, a FGFR2 protein, or a FGFR3 protein.

[0408] In another embodiment, this specification provides a method for treating a disease or disorder by administering an effective amount of the conjugate or pharmaceutically acceptable salt described herein, or the pharmaceutical composition described herein, to an object in need, such as a human being.

[0409] The terms “administer,” “dosage,” or “to administer” 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) by mucosal delivery, local delivery, intradermal delivery, parenteral delivery, intravenous delivery, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. In certain embodiments, administration is carried out by intravenous infusion.

[0410] The terms “effective dose” or “therapeutic effective dose” refer to an amount of 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, a given condition, disorder, or disease, and / or symptoms associated therewith. These terms also encompass amounts necessary to reduce, delay, or improve the progression or progression of a given disease, reduce, delay, or improve the recurrence, progression, or onset of a given disease, and / or improve or enhance the preventive or therapeutic effect(s) of another treatment, or to serve as a bridge to another treatment. In some embodiments, “effective dose” as used herein also refers to an amount of the conjugate described herein to achieve a particular result.

[0411] In certain embodiments, if the disorder or disease is cancer, “effective dose” or “therapeutic dose” means the amount of the conjugate or pharmaceutical composition provided herein that, when administered to a person having cancer, is sufficient to provide effective treatment for cancer. “To treat” or “to cure” cancer means, (1) To limit / inhibit the growth of cancer, for example, to limit its development. (2) To reduce / prevent the spread of cancer, for example, to reduce / prevent metastasis. (3) To reduce cancer, for example, to induce cancer regression, (4) To reduce / prevent cancer recurrence, (5) Relieving the symptoms of cancer, including one or more of the above.

[0412] The terms “subject” and “patient” are used interchangeably. The subject may be a mammal, such as a non-primate (e.g., cattle, 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 diagnosed with the disease or disorder provided herein, e.g., a human. In other embodiments, the subject is a mammal at risk of developing the disease or disorder provided herein, e.g., a human. In specific embodiments, the subject is a human.

[0413] The terms “multiple therapies” and “therapy” may refer to any protocol(s), methods(s), compositions, formulations, and / or agents(s) that can be used in the prevention, treatment, management, or improvement of a disease or disorder or its symptoms (for example, one or more symptoms or conditions related thereto provided herein). In certain embodiments, the terms “multiple therapies” and “therapy” may refer to pharmacotherapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, and / or other therapies useful in the treatment, management, prevention, or improvement of a disease or disorder or its symptoms. In certain embodiments, the term “therapy” may refer to therapies other than the conjugates or their pharmaceutical compositions described herein.

[0414] In certain embodiments, a disease or disorder is treated by depletion of a target protein through degradation via the lysosomal pathway.

[0415] In certain embodiments, a disease or disorder is treated by depletion of a specific protein, e.g., soluble protein, e.g., secretory protein, cell surface protein (e.g., cell surface receptor protein, e.g., tyrosine kinase receptor, soluble cytokine receptor, and immune checkpoint receptor, e.g., EGFR, VEGFR, FGFR, and PD-L1), lectin, complement, lipoprotein, transport protein, MHC class I and class II molecules, cytokine, chemokine, and / or receptor, or any of the aforementioned fragments or subunits.

[0416] In certain embodiments, the disease or disorder is cancer.

[0417] In certain embodiments, cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, bile duct cancer, endometrial cancer, hepatocellular carcinoma, kidney cancer, melanoma, myeloneoma, non-small cell lung cancer (NSCLC), Ewing's sarcoma, and Hodgkin lymphoma.

[0418] In certain embodiments, cancer is a solid tumor.

[0419] In certain embodiments, the disease or disorder is an inflammatory disease or an autoimmune disease.

[0420] In a particular embodiment, the disease or disorder is an inflammatory disease.

[0421] In certain embodiments, the disease or disorder is an autoimmune disease.

[0422] 4.10.Definition This disclosure is not limited to the specific embodiments described and is naturally subject to change. It should also be understood that the terminology used herein is solely for the purpose of describing specific embodiments and is not intended to limit them, as the scope of this disclosure is limited only by the appended claims.

[0423] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of embodiments of this disclosure.

[0424] It should be noted that the singular forms “a,” “and,” and “the” used herein and in the appended claims include multiple referents unless the context clearly indicates otherwise. For example, the expression “compound” includes not only a single compound but also combinations of two or more compounds, and the expression “substituent” includes not only a single substituent but also two or more substituents, and so on.

[0425] In describing and claiming the present invention, certain terms will be used in accordance with the definitions set forth below. It will be understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical terms may fall under the definitions of multiple terms.

[0426] Where used herein, the words “for example,” “for instance,” “etc.,” or “including” are intended to introduce examples that further clarify the more general subject matter. These examples are provided solely as an aid to understanding the disclosure and are not limiting in any way.

[0427] The publications discussed herein are provided only for disclosures prior to the filing date of this application. Nothing in this specification should be construed as admitting that the present invention does not have prior rights to such publications by prior invention. Furthermore, the dates of the publications provided may differ from the actual publication dates and may need to be verified individually.

[0428] The terms “protein” and “polypeptide” are used interchangeably. Proteins may contain portions other than amino acids (e.g., glycoproteins) and / or may be processed or modified in other ways. Those skilled in the art will understand that a “protein” may be a complete protein chain (with or without a signal sequence) produced by a cell, or a portion thereof. Those skilled in the art will understand that a protein may sometimes contain multiple protein chains linked, for example, non-covalently or covalently, by one or more disulfide bonds, or otherwise associated. In certain embodiments, polypeptides may exist as a single chain or as two or more associated chains, and may exist as polymers such as dimers, trimers, etc. These terms also include amino acid polymers that are modified naturally or by intervention (e.g., by the formation of disulfide bonds, glycosylation, lipidization, acetylation, phosphorylation, or other operations or modifications). The definition also includes polypeptides containing one or more amino acid analogs, including, but not limited to, non-natural amino acids, as well as other modifiers known in the art. Polypeptides may comprise L-amino acids, D-amino acids, or both, and may contain any of the various amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, proteins may comprise native amino acids, non-native amino acids, synthetic amino acids, and combinations thereof. In some embodiments, proteins may comprise antibodies, antibody fragments, their biologically active portions, and / or characteristic portions thereof.

[0429] The terms “antibody” and “immunoglobulin” are technical terms and may be used interchangeably in this specification in their broadest sense, including certain types of immunoglobulin molecules that contain one or more antigen-binding domains that specifically bind to an antigen or epitope.

[0430] In certain embodiments, the isolated antibody described herein (e.g., a monoclonal antibody) or its antigen-binding fragment specifically binds to a protein of interest, such as EGFR, and is conjugated to one or more lysosomal targeting moieties, for example, by a linker.

[0431] An "antigen" is a portion or molecule containing an epitope to which an antibody can specifically bind. Therefore, the antigen is also specifically bound by the antibody. In certain embodiments, the antigen to which the antibody described herein binds is the protein of interest, for example, EGFR (e.g., human EGFR), or a fragment thereof, or for example, the extracellular domain of EGFR (e.g., human EGFR).

[0432] "Epitope" is a known term in this technology and refers to a local region of an antigen to which an antibody can specifically bind. An epitope may be a linear epitope of consecutive amino acids, or it may contain amino acids from two or more discontinuous regions of the antigen.

[0433] In the context of antibody binding, the terms “binding,” “binding,” “specifically binding,” or “specifically binding to” refer to an antibody that binds to an antigen (e.g., an epitope) as such binding is understood by those skilled in the art. For example, a molecule that specifically binds to an antigen may also bind to other polypeptides, in which case the affinity determined by immunoassays, Biacore®, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art is generally lower. In certain embodiments, a molecule that specifically binds to an antigen may have a K when that molecule binds to another antigen. d Affinity (K) that is at least 2 logs, 2.5 logs, 3 logs, or 4 logs lower (higher affinity) than d ) binds to the antigen. In another specific embodiment, the molecule that specifically binds to the antigen does not cross-react with other proteins. In another specific embodiment, if EGFR is the protein of interest, the molecule that specifically binds to the antigen does not cross-react with other non-EGFR proteins.

[0434] Antibodies include full-length antibodies (e.g., complete immunoglobulins), antibody fragments, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies containing two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain / antibody heavy chain pairs, and antibodies having two light chain / heavy chain pairs (e.g., identical pairs). This includes, but is not limited to, bodies, intrabodies, heterozygous antibodies, single-domain antibodies, monovalent antibodies, bivalent antibodies (including monospecific or bispecific bivalent antibodies), single-chain antibodies, or single-chain Fv(scFv), camelized antibodies, aphibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, disulfide-bound Fv(sdFv), anti-idiotype (anti-Id) antibodies (e.g., anti-anti-Id antibodies), and any of the epitope-binding fragments described above.

[0435] The antibody may be any type of immunoglobulin molecule (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). In certain embodiments, the antibody described herein is an IgG antibody (e.g., human IgG), or a class thereof (e.g., human IgG1, IgG2, IgG3, or IgG4) or a subclass thereof.

[0436] In certain embodiments, the antibody is a four-chain antibody unit containing two heavy chain (H) / light chain (L) pairs, where the amino acid sequences of the H chains and L chains are identical. In certain embodiments, the H chains and L chains include a constant region, e.g., a human constant region. In even more specific embodiments, the L chain constant region of such an antibody is a κ or λ light chain constant region, e.g., a human κ or λ light chain constant region. In yet another specific embodiment, the H chain constant region of such an antibody includes a γ heavy chain constant region, e.g., a human γ heavy chain constant region. In certain embodiments, such an antibody includes an IgG constant region, e.g., a human IgG constant region.

[0437] The term "constant region" or "constant domain" is a well-known antibody term (sometimes called "Fc") and refers to the carboxyl-terminal portion of the light and / or heavy chain of an antibody, which does not directly participate in antibody-antigen binding but can exert various effector functions, such as interaction with Fc receptors. These terms refer to portions of an immunoglobulin molecule that generally have more conserved amino acid sequences compared to immunoglobulin variable domains.

[0438] The term "heavy chain" as used in relation to antibodies can refer to any different type based on the amino acid sequence of the constant domain, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), which give rise to antibodies of the IgA, IgD, IgE, IgG, and IgM classes, respectively, and also include subclasses of IgG, such as IgG1, IgG2, IgG3, and IgG4.

[0439] The term "light chain" as used in relation to antibodies can refer to any different type based on the amino acid sequence of the constant domain, such as lambda (λ) and kappa (κ). Light chain amino acid sequences are well known in the art. In certain embodiments, the light chain is a human light chain.

[0440] The term “monoclonal antibody” is a well-known technical term referring to an antibody obtained from a homogeneous or substantially homogeneous population of antibodies. The term “monoclonal” is not limited to a specific method for producing the antibody. Generally, a population of monoclonal antibodies can be produced by cells, cell populations, or cell lines. In certain embodiments, the “monoclonal antibody” as used herein is an antibody produced by a single cell (e.g., a hybridoma or host cell producing a recombinant antibody) and the antibody is specifically bound to an epitope as determined, for example, by ELISA or other antigen-binding assays or competitive binding assays known in the art or shown in the examples described herein. In certain embodiments, the monoclonal antibody may be a chimeric antibody or a humanized antibody. In certain embodiments, the monoclonal antibody may be a monovalent or polyvalent (e.g., bivalent) antibody. In certain embodiments, the monoclonal antibody may be a monospecific antibody or a multispecific antibody (e.g., bispecific antibody).

[0441] The term “variable region” or “variable domain” refers to a portion of an antibody, typically the light chain or heavy chain, usually the approximately 110–120 amino acids at the amino terminus of the mature heavy chain and approximately 90–100 amino acids of the mature light chain. The variable region includes a complementation-determining region (CDR) flanked by a framework region (FR). Generally, the spatial positioning of the CDR and FR is as follows, from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. While we do not wish to be bound by a specific mechanism or theory, the CDRs of the light and heavy chains are thought to be primarily responsible for antibody-antigen interaction and antibody specificity to an epitope. In certain embodiments, the amino acid position numbering of the antibody described herein follows the EU Index described in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242. In a particular embodiment, the variable region is a human variable region.

[0442] In certain embodiments, the CDR of an antibody may be (i) numbered using 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, USD Department of Health and Human Services, NIH Publication No. 91-3242); or (ii) numbered using the Chothia numbering scheme (hereinafter referred to as "Chothia CDR") (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. See (iii) for example, the ImMunoGeneTics (IMGT) numbering system described in Lefranc, 1990, The Immunologist, 7:132-136 and Lefranc et al., 1999, Nucleic Acids Res., 27:209-212 ("IMGT CDR"); or (iv) for example, MacCallum et al. The AbM numbering system (referred to herein as "AbM CDR") is described in al., 1996, J.Mol.Biol., 262:732-745.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) it can be determined according to the Contact numbering system referred to herein as “Contact CDRs” (the definition of Contact is based on the analysis of available complex crystal structures (bioinf.org.uk / abs) (see, for example, MacCallum et al., 1996, J.Mol.Biol., 262:732-745)).

[0443] In this specification, the terms “full-length antibody,” “complete antibody,” and “whole antibody” are used interchangeably to refer to an antibody in substantially complete form, and not to an antibody fragment as defined below. These terms specifically refer to antibodies having a heavy chain containing an Fc region.

[0444] An "antibody fragment" comprises only a portion of a complete antibody, which retains at least one, two, three, and as many as possible, or all of the functions typically associated with that portion when present in a complete antibody. In one embodiment, the antibody fragment contains the antigen-binding site of a complete antibody and therefore retains the ability to bind to an antigen. In another embodiment, an antibody fragment, for example, an antibody fragment containing an Fc region, retains at least one of the biological functions typically associated with the Fc region when present in a complete antibody. Such functions may include FcRn binding, regulation of antibody half-life, conjugate function, and complement binding. In another embodiment, the antibody fragment is a monovalent antibody whose half-life in vivo is substantially similar to that of a complete antibody. For example, such an antibody fragment may include an antigen-binding arm linked to an Fc sequence that can confer in vivo stability to the fragment. Suitable antibody fragments for use in the compounds of this disclosure include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv(sFv) fragments, and scFv-Fc fragments.

[0445] In this specification, the terms “polynucleotide” or “nucleic acid,” used interchangeably, refer to polymeric forms of nucleotides of any length, which are either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides can have any three-dimensional structure and can perform any known or unknown function. 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, regulatory regions, isolated RNA of any sequence, nucleic acid probes, and primers. Nucleic acid molecules may be linear or circular. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrates that can be incorporated into polymers by DNA or RNA polymerase or by synthetic reactions. Polynucleotides may include modified nucleotides such as methylated nucleotides and their analogs. Nucleic acid molecules may be aptamers.

[0446] The term "purification" refers to the separation of a substance (compound, polynucleotide, protein, polypeptide, polypeptide composition) such that the substance of interest constitutes the majority of the sample. Typically, substantially purified components in a sample make up 50%, 80-85%, and 90-99% of the sample, such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%. 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 density precipitation.

[0447] Terms such as “treatment” and “to treat” refer to obtaining a desired pharmacological and / or physiological effect, such as a reduction in tumor burden. This effect may be prophylactic in the sense of completely or partially preventing the disease or its symptoms, and / or partially or completely curing the disease and / or adverse effects resulting from the disease. As used herein, “treatment” encompasses any treatment of a disease in a mammal, in particular a human, and includes (a) preventing the development of the disease or its symptoms in a subject that may be disease-predisposed but has not yet been diagnosed with the disease (including, for example, diseases associated with or potentially caused by a primary disease, such as hepatic fibrosis which may occur in the context of chronic HCV infection), (b) inhibiting the disease, i.e., stopping its progression, and (c) reducing the disease, i.e., causing disease regression (e.g., a reduction in tumor burden).

[0448] In this specification, the terms “individual,” “host,” “subject,” and “patient” are used interchangeably and refer to animals including, but not limited to, humans and non-human primates (including monkeys and humans), rodents (including rats and mice), cattle, horses, sheep, cats, dogs, etc. “Mammal” means any member(s) or member(s) of any mammalian species, including, for example, Canidae, Felidae, Equidae, Bovidae, Aquifidae, rodents, etc., as well as primates (including non-human primates) and humans. Non-human animal models, such as mammals, such as non-human primates, mice, and rabbits, may be used in experimental studies.

[0449] The "therapeutic dose" or "effective dose" refers to the amount of a compound sufficient to produce a therapeutic effect on a disease, condition, or disorder when administered to a mammal or other subject for the treatment of that disease, condition, or disorder. The "therapeutic dose" varies depending on the compound, the disease and its severity, the age and weight of the patient being treated, and other factors.

[0450] Unless otherwise specified, if a compound may exist in alternative tautomers, positional isomers, and / or stereoisomers, all alternative isomers are intended to be included within the scope of the claimed subject matter. For example, if a compound is described as having a particular optical isomer D- or L-, both optical isomers are intended to be included in this specification. For example, if a compound is described as having one of two tautomers, both tautomers are intended to be included in this specification. Thus, the compounds provided herein may be enantiomerically pure or mixtures of stereoisomers or diastereomers. The compounds provided herein may contain a chiral center. Such a chiral center may be in either the (R) or (S) configuration, or a mixture thereof. The chiral centers of the compounds described herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that, in the case of a compound that undergoes epimerization in vivo, administering the compound in the (R) form is equivalent to administering the compound in the (S) form.

[0451] This disclosure also encompasses all suitable isotopic variants of the compounds of this disclosure, whether radioactive or otherwise. An isotopic variant of a compound according to this disclosure is understood to mean a compound in which at least one atom in the compound according to this disclosure is replaced with another atom having the same atomic number but a different atomic mass than that normally or primarily found in nature. Examples of isotopes that can be incorporated into the compounds according to this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131Examples include I. Specific isotopic variants of the compounds disclosed herein, particularly those incorporating one or more radioactive isotopes, may be useful, for example, for examining the mechanism of action or the distribution of active compounds in the body. For this purpose, 3 H, 14 C, and / or 18 Compounds labeled with 1F isotopes are suitable. Furthermore, the incorporation of an isotope (e.g., deuterium) can improve the metabolic stability of the compound, potentially resulting in specific therapeutic effects such as an extension of the half-life in the body or a reduction in the required effective amount. In some embodiments, the hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, "deuterated" is applied to a chemical group and, unless otherwise specified, refers to a chemical group that isotoped with deuterium in amounts significantly greater than its natural abundance. Isotope variants of the compounds according to this disclosure can be prepared by various methods, including, for example, those described below and in the examples, by using specific reagents and / or corresponding isotope modifications of the starting compounds.

[0452] Therefore, any embodiment described herein means that it includes salts of the compound, single stereoisomers, mixtures of stereoisomers, and / or isotopic forms.

[0453] "Pharmacologically acceptable excipients," "pharmaceutically acceptable diluents," "pharmaceutically acceptable carriers," and "pharmaceutically acceptable adjuvants" mean excipients, diluents, carriers, and adjuvants that are useful for preparing pharmaceutical compositions, are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients, diluents, carriers, and adjuvants that are acceptable for veterinary and human pharmaceutical uses. As used herein and in the claims, "pharmaceutically acceptable excipients, diluents, carriers, and adjuvants" includes one or more such excipients, diluents, carriers, and adjuvants.

[0454] The term "pharmaceutical composition" encompasses compositions suitable for administration to mammals, particularly humans. Generally, "pharmaceutical compositions" are preferably sterile and free from contaminants that could cause undesirable reactions in the subject (for example, the compounds in the pharmaceutical composition are pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients requiring treatment via various routes of administration, including oral, intraoral, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, and subcutaneous.

[0455] The term "pharmaceutically acceptable" means that it is approved by a federal or state regulatory authority, or is listed in the United States Pharmacopeia, the European Pharmacopeia, or other generally accepted pharmacopoeias for use in animals, particularly humans.

[0456] The term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions. pharmaceutically acceptable salts are well known in the art. For example, SMBerge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the conjugated compound, or separately by reacting the free basic functional group or group of the compound with a suitable 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.

[0457] "Acyl" is 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)-, substituted heteroaryl Roaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)- groups are used, while alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl contains the "acetyl" group CH3C(O)-.

[0458] The term “alkyl” refers to branched or unbranched saturated hydrocarbon groups (i.e., monoradicals) that typically contain, but not necessarily, 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and cycloalkyl groups such as cyclopentyl and cyclohexyl. Generally, but not necessarily, alkyl groups as used herein may contain 1 to about 18 carbon atoms, and such groups may contain 1 to about 12 carbon atoms. The term “lower alkyl” means alkyl groups with 1 to 6 carbon atoms. “Substituted alkyl” refers to alkyl groups that are substituted with one or more substituents, including cases where two hydrogen atoms from the same carbon atom in the alkyl substituent are substituted, such as a carbonyl group (i.e., a substituted alkyl group may contain a -C(=O)- moiety). The terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl substituents in which at least one carbon atom is replaced by a heteroatom, as will be further described below. Unless otherwise specified, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl groups, respectively.

[0459] The term "substituted alkyl" means including alkyl groups as defined herein, in which one or more carbon atoms in the alkyl chain are optionally replaced by heteroatoms such as -O-, -N-, -S-, -S(O)n- (n is 0-2), -NR- (R is hydrogen or alkyl), alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryl The molecule has 1 to 5 substituents selected from the group consisting of ruoxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NRaRb, where R' and R'' may be the same or different, and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0460] The term "alkenyl" refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicocenyl, and tetracocenyl. Generally, alkenyl groups as used herein may contain 2 to about 18 carbon atoms, for example, 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 by a heteroatom. Unless otherwise specified, the terms “alkenyl” and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyls and lower alkenyls, respectively.

[0461] The term "alkynyl" refers to a linear or branched hydrocarbon group of 2–24 carbon atoms containing at least one triple bond, such as ethynyl and n-propynyl. Generally, though not necessarily, alkynyl groups as used herein may contain 2–about 18 carbon atoms, and such groups may further contain 2–12 carbon atoms. The term "lower alkynyl" means an alkynyl group of 2–6 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 in which at least one carbon atom is replaced by a heteroatom. Unless otherwise specified, the terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyls and lower alkynyls, respectively.

[0462] The term "alkoxy" refers to an alkyl group linked by a single-terminated ether linkage; that is, the "alkoxy" group is represented as -O-alkyl, and alkyl is as defined above. A "lower alkoxy" group refers to an alkoxy group containing 1 to 6 carbon atoms, including, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and t-butyloxy. In this specification, substituents identified as "C1-C6 alkoxy" or "lower alkoxy" may contain, for example, 1 to 3 carbon atoms, and as a further example, such substituents may contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0463] The term "substituted alkoxy" refers to substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- groups, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0464] The term "aryl," unless otherwise specified, generally refers to an aromatic substituent containing 5 to 30 carbon atoms, comprising a single aromatic ring or multiple aromatic rings condensed, directly linked, or indirectly linked to one another (different aromatic rings bonded to a common group such as a methylene or ethylene moiety). For example, an aryl group may contain 5 to 20 carbon atoms, and further examples may include 5 to 12 carbon atoms. For example, an aryl group may contain one aromatic ring or two or more condensed or linked aromatic rings (i.e., biaryls, aryl-substituted aryls, etc.). Examples include phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone. "Substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl substituents in which at least one carbon atom is replaced by a heteroatom, which will be discussed in more detail below. Aryls are stable cyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated C3-C compounds, exemplified by but not limited to phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, imidazoyl, pyrimidinyl, and oxazoyl. 14 It is intended to include parts, which may be further substituted with 1 to 5 members selected from the group consisting of hydroxy, C1-C8 alkoxy, C1-C8 branched or linear alkyl, acyloxy, carbamoyl, amino, N-acylamino, nitro, halogen, trifluoromethyl, cyano, and carboxyl (see, for example, Katritzky, Handbook of Heterocyclic Chemistry). Unless otherwise specified, the term “aryl” includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0465] 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 as defined above. Generally, the aralkyl and alkaryl groups as used herein contain 6 to 30 carbon atoms. For example, aralkyl and alkaryl groups may contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.

[0466] The term "alkylene" refers to a divalent alkyl group. Unless otherwise specified, 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, or may contain heteroatoms. "Lower alkylenes" refer to alkylene links containing 1 to 6 carbon atoms. Examples include methylene (--CH2--), ethylene (--CH2CH2--), propylene (--CH2CH2CH2--), 2-methylpropylene (--CH2--CH(CH3)--CH2--), and hexylene (--(CH2)6--).

[0467] Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and "alkalene" refer to diradical alkenyl, alkynyl, aryl, aralkyl, and alkalyl groups, respectively.

[0468] The term "amino" refers to the -NRR' group, where R and R' are independently hydrogen or non-hydrogen substituents, and non-hydrogen substituents include, for example, alkyl, aryl, alkenyl, aralkyl, and their substituted and / or heteroatom-containing variants.

[0469] The terms "halo" and "halogen" are used in their traditional sense and refer to chloro, bromo, fluoro, or iodine substituents.

[0470] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or a salt thereof.

[0471] "Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having one or more cyclic rings, such as fused rings, crosslinked rings, or spirocyclic systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Such cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl, or polycyclic structures such as adamantanyl.

[0472] The term "substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 substituents selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxyalkyl, 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, or cycloalkyl groups having 1 to 3 substituents.

[0473] The term "heteroatom-containing" in "heteroatom-containing alkyl group" (also called "heteroalkyl" group) or "heteroatom-containing aryl group" (also called "heteroaryl" group) refers to a molecule, linkage, or substituent in which one or more carbon atoms are replaced by atoms other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur. Similarly, the term "heteroalkyl" refers to a heteroatom-containing alkyl substituent, the term "heterocycloalkyl" refers to a heteroatom-containing cycloalkyl substituent, the term "heterocyclic" or "heterocyclic" refers to a heteroatom-containing cyclic substituent, and the terms "heteroaryl" and "heteroaromatic" refer to heteroatom-containing "aryl" and "aromatic" substituents, respectively. Examples of heteroalkyl groups include alkoxyaryls, alkylsulfanyl-substituted alkyls, and N-alkylated aminoalkyls. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl, while examples of heteroatom-containing alicyclic groups include pyrrolidino, morpholino, piperazino, piperidino, and tetrahydrofuranil.

[0474] A "heteroaryl" refers to an aromatic group having 1 to 15 carbon atoms in a ring, for example, 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 (e.g., pyridinyl, imidazolyl, or furyl) or multiple fused rings in a ring system (e.g., groups such as indolidinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), in which case at least one ring in the ring system is aromatic, and the bonding point is by an atom of the aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms(s) of the heteroaryl group can optionally be oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. This term includes, for example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise specifically limited by the definition of heteroaryl substituents, such heteroaryl groups can be optionally substituted with 1 to 5 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, azide, 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, or 1 to 3 substituents.

[0475] The terms “heterocyclic,” “heterocyclic,” and “heterocyclic” refer to saturated or unsaturated groups having a single or multiple fused rings, including fused-bridged ring systems and spiro-ring systems, and containing 3 to 15 ring atoms with 1 to 4 heteroatoms. These ring heteroatoms are selected from nitrogen, sulfur, and oxygen, and in fused ring systems, one or more rings may be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, as long as the bonding site is via a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to form an N-oxide, -S(O)-, or -SO2- moiety.

[0476] Examples of heterocyclic and heteroaryl compounds include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenantholidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, and This includes, but is not limited to, enoxazine, 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, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, tetrahydrofuranil, etc.

[0477] Unless otherwise specifically limited by the definition of heterocyclic substituents, such heterocyclic groups may be 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, azide, 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 condensed heterocyclic groups.

[0478] "Hydrocarbyl" refers to a monovalent hydrocarbyl radical containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, further 1 to about 18 carbon atoms, and further 1 to about 12 carbon atoms, and includes linear, branched, cyclic, saturated, and unsaturated species such as alkyl groups, alkenyl groups, and aryl groups. Hydrocarbyl can be substituted with one or more substituents. The term "heteroatom-containing hydrocarbyl" refers to a hydrocarbyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise specified, the term "hydrocarbyl" is interpreted to include substituted hydrocarbyl moieties and / or heteroatom-containing hydrocarbyl moieties.

[0479] The term "substituted," as used in some of the definitions above, such as "substituted hydrocarbyl," "substituted alkyl," and "substituted aryl," means that in the hydrocarbyl, alkyl, aryl, or other part, at least one hydrogen atom bonded to a carbon (or other) atom is replaced by one or more non-hydrogen substituents. Examples of such substituents include, but are not limited to, functional groups and hydrocarbyl moieties, C1-C24 alkyls (including C1-C18 alkyls, further including C1-C12 alkyls, and further including C1-C6 alkyls), C2-C24 alkenyls (including C2-C18 alkenyls, further including C2-C12 alkenyls, and further including C2-C6 alkenyls), C2-C24 alkynyls (including C2-C18 alkynyls, further including C2-C12 alkynyls, and further including C2-C6 alkynyls), C5-C30 aryls (including C5-C20 aryls, and further including C5-C12 aryls), and C6-C30 aralkyls (including C6-C20 aralkyls, and further including C6-C12 aralkyls). The above hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties, such as those specifically listed. Unless otherwise specified, all groups described herein are to be interpreted as including substituted and / or heteroatom-containing moieties in addition to non-substituted moieties.

[0480] "Sulfonyl" refers to SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic groups are as defined herein. Sulfonyls include, for example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0481] "Functional groups" include halo, hydroxyl, sulfidyl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including 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( X is a halo), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylat (-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), carbamide (-NH-(CO)-NH2), cyano (-C≡N), isocyano (-N+≡C-), cyanato (-OC≡N), isocyanato (-O-N+≡C-), isothiocyanato (-SC≡N), azide (-N=N+=N-), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), mono and di(C1~C24 alkyl) substituted aminos, mono and di(C5~C20 aryl) substituted aminos, C2~C24 alkylamide (-NH-(CO)-alkyl), C5~C20 arylamide D(-NH-(CO)-aryl), imino(-CR=NH, R=hydrogen, C1~C24 alkyl, C5~C20 aryl, C6~C20 alkaryl, C6~C20 aralkyl, etc.), alkylimino(-CR=N(alkyl), R=hydrogen, alkyl, aryl, alkaryl, etc.), arylimino(-CR=N(aryl), meaning chemical groups such as R=hydrogen, alkyl, aryl, alkaryl, etc. in the formula), nitro(-NO2), nitroso(-NO), sulfo(-SO2-OH), sulfonate(-SO2-O-), C1~C 24Alkylsulfanyl (also called -S-alkyl or alkylthio), arylsulfanyl (also called -S-aryl or arylthio), 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 with one or more hydrocarbyl moieties as specifically listed above, insofar as the particular group allows.

[0482] "Linking" or "linker" refers to a linking group or linker moiety that connects two groups by a covalent bond. Linkers can be linear, branched, cyclic, or single-atom. Examples of such linking groups include, but are not limited to, alkyl, alkenylene, alkynylene, arylene, alkylene, aralkylene, and linking moieties containing functional groups such as 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-), epiminino (-NH-), and carbonyl (-CO-). In certain circumstances, one, two, three, four, or five or more carbon atoms in the linker skeleton may be optionally substituted with sulfur, nitrogen, or oxygen heteroatoms. Bonds between skeleton atoms are saturated or unsaturated, and typically, the linker skeleton does not contain more than one, two, or three unsaturated bonds. The linker may contain one or more substituents, such as alkyl groups, aryl groups, or alkenyl groups. The linker may be a poly(ethylene glycol) unit (e.g., -(CH2-CH2-O)-), ether, thioether, amine, or alkyl (e.g., (C1-C) 12 Alkyl groups may include, but are not limited to, linear or branched alkyl groups, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The linker skeleton includes a cyclic group such as an aryl, heterocyclic, or cycloalkyl group, with two or more atoms of the cyclic group, e.g., 2, 3, or 4 atoms, included in the skeleton. The linker may be cleavable or incleavable. A convenient orientation and / or connection between the linker and the linked group can be used.

[0483] When the term "substituted" appears before a list of possible substituents, the term is intended to apply to all members of that base. For example, the phrase "substituted alkyl and aryl" is interpreted as "substituted alkyl and substituted aryl."

[0484] In addition to the disclosures herein, the term “substituted” when used to modify a particular group or radical may also mean that one or more hydrogen atoms of a particular group or radical are replaced, each independently of the other, by the same or different substituents as defined below.

[0485] In addition to the groups disclosed herein with respect to individual terms, one or more hydrogen atoms on a saturated carbon atom in a particular group or radical (any two hydrogen atoms on a single carbon atom = O, = NR) 70 、=N-OR 70 The substituent to replace (which can be replaced by =N2 or =S) is -R unless otherwise specified. 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 And in the formula, R 60 The group consists of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, and each R 70 These are independently hydrogen or R 60 And each R 80 R is independent 70 Or, alternatively, two R 80 However, together with the nitrogen atom to which they are bonded, they form a 5-membered, 6-membered, or 7-membered heterocycloalkyl, which may optionally include 1 to 4 of the same 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 + Each M is a counterion with a net single positive charge.+ Independently, for example, K + na + Li + Alkaline ions such as + N(R 60 ) Ammonium ions such as 4, or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 Alkaline earth ions such as ("0.5" means that one of the counterions for such divalent alkaline earth ions may be the ionized form of the compound of the present invention and the other may be a typical counterion such as a chloride, or the two ionized compounds disclosed herein may act as counterions for such divalent alkaline earth ions, or the biionized compound of the present invention may act as a counterion for such divalent alkaline earth ions) may also be present. For example, -NR 80 R 80 This is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, and N-morpholinyl.

[0486] In addition to the disclosures herein, substituents on hydrogen atoms on unsaturated carbon atoms in "substituted" alkenes, alkynes, aryls, and heteroaryl groups are, unless otherwise specified, -R 60 Hello, -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 + -OSO3R70 , -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 And in the formula, R 60 , R 70 , R 80 and M + This is as previously defined, however, in the case of substituted alkenes or alkynes, the substituent is -O - M + , -OR 70 , -SR 70 , or -S- M + isn't it.

[0487] In addition to the groups disclosed herein with respect to individual terms, substituents on hydrogen atoms on nitrogen atoms in "substituted" heteroalkyl and cycloheteralkyl 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 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 And in the formula, R 60 , R 70 , R 80 , and M + This is as previously defined.

[0488] In addition to the disclosures herein, in certain embodiments, the substituted group has one, two, three, or four substituents, one, two, or three substituents, one or two substituents, or one substituent.

[0489] Unless otherwise specified, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the functional groups adjacent to the bonding site. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-OC(O)- group.

[0490] It is understood that, with respect to any of the groups containing one or more substituents disclosed herein, such groups do not include any sterically unrealistic and / or synthetically impossible substitutions or substitution patterns. Furthermore, the compounds of interest include all stereochemical isomers resulting from the substitutions of these compounds.

[0491] In certain embodiments, substituents may contribute to the optical isomerism and / or stereoisomerism of the compound. The salt, solvate, hydrate, and prodrug forms of the compound are also of interest. All of these forms are encompassed in this disclosure. Thus, the compounds described herein include their salt, solvate, hydrate, prodrug, and isomer forms (including pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and isomers). In certain embodiments, the compound may be metabolized to pharmaceutically active derivatives.

[0492] Unless otherwise specified, references to atoms are intended to include their isotopes. For example, the expression H means 1 H, 2 H (i.e., D), 3 The expression C, which includes H (i.e., T), is 12 C and all carbon isotopes ( 13 Includes C, etc.

[0493] Unless otherwise specified, the terms “approximately” or “about” mean a tolerance for a particular value as determined by those skilled in the art, depending in part to the way the value is measured or determined. In certain embodiments, the terms “approximately” or “about” mean within one, two, or three standard deviations. In certain embodiments, the terms “approximately” or “about” mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1%, or 0.05% of a given value or range. In certain embodiments, where an integer is required, the term “approximately” means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.

[0494] In this specification, in the event of any discrepancy between a chemical name and a chemical structure, the chemical structure shall prevail.

[0495] Definitions of other terms and concepts are provided throughout the detailed explanation.

[0496] The M6PR-conjugated compounds and conjugates are described in international application PCT / US2021 / 012846, filed on 8 January 2021, and its disclosure is incorporated herein by reference in its entirety.

[0497] 4.11. Additional Embodiments Additional embodiments of this disclosure are also described in the following clauses.

[0498] Clause 1. Cell surface mannose-6-phosphate receptor (M6PR) binding compounds of the following formulas, [ka] or a salt thereof, in the formula, Each W is a hydrophilic head group, each Z 1 These are independently selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. each Z 2 These are O, S, and NR, independently. 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 These are independently selected from H, halogens (e.g., F), and optionally substituted (C1-C6) alkyl groups. 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 It is an independent connecting part, n is between 1 and 500. L is a linker, Y is the target part, In the formula, if m is 1 and Ar is phenyl, then i) L contains a backbone of at least 16 consecutive atoms, ii) Y is a biomolecule, and / or ii) Z 3These are cell surface mannose-6-phosphate receptor (M6PR) binding compounds, or salts thereof, which are amides, sulfonamides, urea, or thiourea.

[0499] Clause 2. 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, as described in Clause 1.

[0500] Clause 3. The compounds described in Clause 2, wherein each Ar is selected from optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, or optionally substituted 2,5-pyridylene.

[0501] Clause 4. The above compound is one of the following formulas: [ka] or a salt thereof, in the formula, Each R 11 ~R 14 These 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 Selected from, Each R 25 The compound described in Clause 3 is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0502] Clause 5. The compound according to Clause 1, wherein each Ar is optionally substituted with a condensed bicyclic aryl or condensed bicyclic heteroaryl.

[0503] Clause 6. The compound according to Clause 5, wherein each Ar is optionally substituted naphthalene or optionally substituted quinoline.

[0504] Article 7. The above compound is one of the following formulas: [ka] or a salt thereof, in the formula, Each R 11 and R 13 ~R 14 These 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 Selected from, s is between 0 and 3. Each R 25 The compound described in Clause 6 is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0505] Clause 8. The above compound is one of the following formulas: [ka] [ka] [ka] The compound described in Clause 7, or a salt thereof.

[0506] Clause 9. Each Ar is an optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl, and the compound is of the following formula: [ka] or a salt thereof, in the formula, Each Cy is independently a monocyclic aryl or monocyclic heteroaryl. Each R 11 ~R15 These 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 Selected from, s is between 0 and 4. Each R 25 The compound described in Clause 1 is independently selected from H and optionally substituted (C1-C6) alkyl groups.

[0507] Clause 10. Ar is an optionally substituted biphenyl, Cy is an optionally substituted phenyl, and the above compound has the following formula: [ka] The compound described in Clause 9, or a salt thereof.

[0508] Clause 11. The above compound is one of the following formulas: [ka] The compound described in Clause 10, or a salt thereof.

[0509] Clause 12. The compound according to any one of Clauses 1 to 10, wherein Ar is substituted with at least one OH substituent.

[0510] Clause 13.R 11 ~R 15 Each of the compounds described in any one of the clauses 4, 6, 7, 9, and 10 is H.

[0511] Clause 14.R 11 ~R 15 A compound according to any one of the clauses 4, 6, 7, 9, and 10, wherein at least one of them is an OH group (for example, at least two are OH groups).

[0512] Clause 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 These are O, S and NR 23 Selected from, R 23 and R 24 H and C are independent of each other. (1~3) -alkyl (e.g., methyl) and substituted C (1~3) - A compound selected from alkyl groups, as described in any one of clauses 1 to 14.

[0513] Clause 16.Z 3 The following applies: [ka] In the formula, X 1 is O or S, t is 0 or 1, and each R 23 H and C are independent of each other. (1~3) -alkyl (e.g., methyl) and substituted C (1~3) - A compound selected from alkyl groups, as described in any one of clauses 1 to 15.

[0514] Clause 17.Z 3 -NHC(=X 1 )NH- and X 1 The compound is one of the compounds described in Clause 16, wherein the compound is either O or S.

[0515] Item 18. Ar is a triazole, and the above compound is one of the following formulas:

Chemical formula

[0516] The compound according to any one of Items 1 to 14.

[0517] Item 19. Z 3 is an optionally substituted triazole, and the above compound is one of the following formulas:

Chemical formula

[0518] Item 20. -A-Z 3 - is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0519] A compound according to any one of clauses 1 to 20, wherein in clause 21, m is at least 2 and L is a branched linker that covalently links each Ar group to Y.

[0520] A compound according to clause 21, wherein in clause 22, m is from 2 to 20 (for example, m is from 2 to 6, for example, 2 or 3).

[0521] A compound according to clause 21, wherein in clause 23, m is from 20 to 500 (for example, from 20 to 400, from 20 to 300, or from 20 to 200, or from 50 to 500, or from 100 to 500), L is an α - amino acid polymer (for example, poly - L - lysine), and a number of -Ar-Z 3 groups are covalently linked to the polymer backbone by side chain groups (for example, by conjugation to the side chain amino group of lysine residues).

[0522] A compound according to any one of clauses 21 to 23, wherein in clause 24, m is at least 2, and each Z 3 linking moiety is separated from every other Z by a chain of at least 16 consecutive atoms (for example, by a chain of at least 20, at least 25, or at least 30 consecutive atoms, and in some cases, by a chain of up to 100 consecutive atoms) by the linker L. 3 A compound according to any one of clauses 21 to 23, wherein in clause 24, m is at least 2, and each Z

[0523] A compound according to clause 25, the compound being of the following formula,

Chemical formula

[0524] Clause 26. The above-mentioned linear or branched linker is formed by a chain of at least 16 consecutive atoms (e.g., at least 20 consecutive atoms, at least 30 consecutive atoms, or 16 to 100 consecutive atoms) in each Z 2 The compound described in Clause 25, which separates Y.

[0525] Clause 27.n is a compound described in any one of Clauses 25 to 26, which is 1 to 20.

[0526] Clause 28.n is at least 2 (for example, n is 2 or 3), a compound as described in any one of Clauses 25 to 27.

[0527] Clause 29.d > 0, L 4 Each L 1 The compound described in Clause 28, which is a branched joint portion covalently connected to a joint portion.

[0528] Article 30. The above compound has the following formula: [ka] 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 The linking part is (for example, a covalent bond, a heteroatom, a group having a skeleton of 1 to 3 atoms in length, or a triazole), r is either 0 or 1. n is a compound according to any one of clauses 25 to 29, where n is 1 to 6.

[0529] 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.

[0530] Clause 32. The compound according to Clause 31, wherein Ar is optionally substituted 1,4-phenylene.

[0531] Clause 33. The compound according to any one of Clauses 30 to 32, wherein Ar is substituted with at least one hydroxyl group.

[0532] Clause 34.L 1 or -Ar-(Z 11 ) r -teeth, [ka] and [ka] Selected from, During the ceremony, Cy is a monocyclic aryl or heteroaryl compound. r is either 0 or 1. s is between 0 and 4. R 11 ~R 14 and each R 15 These 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 Selected from, each R 25 H and C are independent of each other. (1~6)-alkyl and substituted C (1~6) - Selected from alkyl groups, Z 11 These are independently covalent, -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 -Selected from and optionally substituted triazoles, where X 1 and X 2 These are O, S and NR 23 Selected from, R 23 and R 24 H, C (1~3) -alkyl (e.g., methyl) and substituted C (1~3) - Compounds selected from alkyl groups, as described in any one of clauses 25 to 33.

[0533] Clause 35.L 1 teeth, [ka] or [ka] The compound described in Article 34.

[0534] Clause 36.L 1 teeth, [ka] or [ka] Compounds as described in Clause 34, including those listed in Clause 34.

[0535] Clause 37.L 1 teeth, [Chemical formula] and [Chemical formula] The compound according to clause 34, selected from

[0536] For clause 38, r is 0, and the compound according to any one of clauses 34 - 37.

[0537] For clause 39, r is 1, and Z 11 is -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 =N-X 2 -, where X 1 and X 2 are selected from O, S and NR 23 , and R 23 and R 24 are independently selected from H, C (1~3) -alkyl (e.g., methyl) and substituted C (1~3) -alkyl, and the compound according to any one of clauses 34 - 37.

[0538] For clause 40, r is 1, and Z 11 is as follows: [Chemical formula] In the formula, X 1 is O or S, t is 0 or 1, and each R 23 is independently selected from H, C (1~3) -alkyl (e.g., methyl) and substituted C (1~3) -alkyl, and the compound according to any one of clauses 34 - 37.

[0539] Clause 41.Z 11 -NHC(=X 1 )NH- and X 1 The compound described in Clause 40, wherein O or S.

[0540] Clause 42.r is 1, Z 11 The compound is a triazole, as described in any one of clauses 34 to 37.

[0541] Clause 43.Y is a compound according to any one of Clauses 1 to 42, selected from small molecules, dyes, fluorophores, monosaccharides, disaccharides, trisaccharides, and chemoselective ligation groups or their precursors.

[0542] Clause 44.Y is a biomolecule, a compound as described in any one of Clauses 1 to 42.

[0543] Clause 45. The biomolecules described above are compounds selected from peptides, proteins, polynucleotides, polysaccharides, glycoproteins, lipids, enzymes, antibodies, and antibody fragments, as described in Clause 44.

[0544] Clause 46.Y is a compound according to any one of Clauses 1 to 45, which is a portion that specifically binds to a target protein.

[0545] Clause 47. The target protein is a membrane-bound protein, as described in Clause 46.

[0546] Clause 48. The target protein is an extracellular protein, as described in Clause 46.

[0547] Clause 49.Y is a compound described in any one of Clauses 46 to 49, selected from antibodies, antibody fragments (e.g., antigen-binding fragments of antibodies), chimeric fusion proteins, engineered protein domains, D protein binders for target proteins, aptamers, peptides, enzyme substrates, and small molecule inhibitors or ligands.

[0548] Clause 50.Y is an antibody or antibody fragment that specifically binds to the target protein, wherein the compound has the following formula: [ka] or a pharmaceutically acceptable salt thereof, in the formula, n is between 1 and 20. m is the average load from 1 to 80. Ab is an antibody or antibody fragment that specifically binds to a target protein. The compound according to Clause 49, wherein each Z is a residual portion resulting from covalent linkage between a chemoselective ligation group and a compatible group of Ab.

[0549] Clause 51.Y is a compound according to Clause 49, which is a small molecule inhibitor or ligand of the target protein described above.

[0550] Article 52. The hydrophilic head group W above 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, -CR1 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] and [ka] Or selected from those salts, In the formula, R 1 and R 2 Independently, hydrogen, SR 3 , halo, or CN, R 3 and R 4 H and C are independent of each other. 1~6 Alkyl or substituted C 1~6 A compound according to any one of the clauses 1 to 51, wherein the compound is alkyl (e.g., -CF3 or -CH2CF3), and A, B, and C are each independently CH or N, and D is each independently O or S.

[0551] Article 53. W is -P=O(OH)2, -SO3H 、 -COOH 、 A compound selected from -CH(COOH)2 or salts thereof, as described in Clause 52.

[0552] Clause 54.Z 1 is, -(CH2) j -or-(C(R 22 )2) j - and each R 22The compound described in any one of Clauses 1 to 53, wherein is independently selected from H, a halogen (e.g., F), and an optionally substituted (C1-C6) alkyl, and j is 1 to 3.

[0553] Clause 55.Z 1 is a compound described in any one of clauses 1 to 53, wherein the compound is -CH=CH-.

[0554] Clause 56.Z 2 The compound is one of the compounds described in any one of the clauses 1 to 55, wherein the compound is O or S.

[0555] Clause 57.Z 2 -NR 21 -A compound as described in any one of the clauses 1 to 55.

[0556] Clause 58.Z 2 -C(R 22 )2-, and in the formula, each R 22 The compound is independently selected from H, a halogen (e.g., F), and an optionally substituted (C1-C6) alkyl, as described in any one of Clauses 1 to 55.

[0557] Clause 59.Z 1 is, -(CH2) j - is selected from substituted (C1~C3) alkylenes and -CH=CH-, j is 1~3, and Z 2 is a compound selected from O and CH2, as described in any one of clauses 1 to 53.

[0558] Clause 60.Z 1 These are -(CH2)2-, -CH2-CF2-, or -CH2-CHF-, and Z 2 The compound described in clause 60 is O.

[0559] Clause 61.Z 1 These are -(CH2)2-, -CH2-CF2-, or -CH2-CHF-, and Z 2 The compound described in Clause 60 is CH2.

[0560] Clause 62.Z 1 -CH=CH- and Z 2 The compound described in clause 60 is O.

[0561] Clause 63.Z 1 -CH=CH- and Z 2 The compound described in Clause 60 is CH2.

[0562] Clause 64.X is, [ka] and [ka] A compound selected from any one of the clauses 1 to 63.

[0563] Clause 65.n is 1 to 6 (for example, n is 1 to 5, or 2 to 6, or 1, 2, or 3), If d is 0, then n is 1, If d is 1, then n is between 1 and 3. If d is 2, then n is 1 to 6, the compound as described in any one of clauses 25 to 64.

[0564] Article 66. Each L 2 -C 1~6 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkylene-, -O(CH2) p -and-(OCH2CH2) p - is selected from, where p is between 1 and 10. Each L 3 Independently, [ka] and -(OCH2CH2) qA compound selected from -, in which q is 1 to 10, u is 0 to 10, and w is 1 to 10, as described in any one of clauses 25 to 65.

[0565] If clause 67.n is 2 or more, at least one L 4 The compound described in any one of clauses 25 to 66, which is present and is a branched linkage portion.

[0566] Clause 68. Each L 4 Independently, -OCH2CH2-, [ka] and [ka] Selected from, A compound according to any one of clauses 25 to 67, wherein each x and y is independently between 1 and 10.

[0567] Article 69. Each L 5 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, [ka] or -(OCH2CH2) r -and, Each L 6 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkylene-, or -(OCH2CH2)- s -and, Each L 7 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, -(OCH2CH2) t-or -OCH2- A compound according to any one of clauses 25 to 68, wherein r, s, and t are each independently 1 to 20.

[0568] Clause 70.a is a compound described in any one of Clauses 25 to 69, which is 1.

[0569] At least one of Clause 71.b, c, e, f, and g is not 0, and is a compound as described in any one of Clauses 25 to 70.

[0570] A compound as described in any one of Clauses 25 to 71, wherein at least one of Clause 72.b or c is not 0, and at least one of e, f, and g is not 0.

[0571] Clauses 73.a, b, and c are, independently, 1 or 2 of the compounds described in any one of Clauses 25 to 72.

[0572] Clause 74. The linker L described above is a compound described in any one of Clauses 1 to 73, selected from any one of the structures in Tables 2 to 3.

[0573] Clause 75. The above-mentioned compound is a compound selected from the compounds in Tables 5 to 9, as described in any one of Clauses 1 to 74.

[0574] Clause 76. Cell surface receptor-binding conjugate of formula (I), [ka] or a salt thereof, in the formula, X is the portion that binds to the cell surface mannose-6-phosphate receptor (M6PR), n is between 1 and 500 (for example, n is between 1 and 20, 1 and 10, 1 and 6, or 1 and 5), L is a linker, Y is a biomolecule that specifically binds to a target protein, a cell surface receptor-binding conjugate of formula (I), or a salt thereof.

[0575] Article 77. The above conjugate is of the following formula: [ka] or a pharmaceutically acceptable salt thereof, in the formula, n is between 1 and 20. m is the average load from 1 to 80. Ab is an antibody or antibody fragment that specifically binds to a target protein. Each Z is a residual portion resulting from covalent linkage between a chemoselective ligation group and a compatible group of Ab, as described in Clause 76.

[0576] Clause 78.n is the conjugate described in Clause 76 or 77, which is 1 through 6.

[0577] Clause 79.n is a conjugate described in Clause 76 or 77, which is 2 or less.

[0578] Clause 80.n is 1, the conjugate described in Clause 79.

[0579] Clause 81.n is a conjugate described in Clause 76 or 77, which is at least 2.

[0580] Clause 82.n is 2, the conjugate described in Clause 81.

[0581] Clause 83.n is 3, the conjugate described in Clause 81.

[0582] Clause 84.n is 4, the conjugate described in Clause 81.

[0583] Clause 85.m refers to conjugates specified in any one of Clauses 76-84, which are 1-20.

[0584] Clause 86.m refers to any conjugate described in any one of Clauses 76-84, which is 1-12.

[0585] Clause 87.m is a conjugate described in any one of Clauses 76-86, which is at least about 2.

[0586] Clause 88.m is a conjugate described in any one of Clauses 76-86, which is at least approximately 3.

[0587] Clause 89.m is a conjugate described in any one of Clauses 76-86, which is at least about 4.

[0588] Clause 90.Z is a conjugate according to any one of Clauses 77 to 89, which is a residual portion obtained by covalent linking of thiol-reactive chemoselective ligation groups to one or more cysteine ​​residues of Ab.

[0589] Clause 91.Z is a conjugate according to any one of Clauses 76 to 89, which is a residual portion obtained by covalent linking of amine-reactive chemoselective ligation groups to one or more lysine residues of Ab.

[0590] Clause 92.X is the part that joins to M6PR and is of the following formula: [ka] or a salt thereof, in the formula, Each W is a hydrophilic head group, each Z 1 These are independently selected from optionally substituted (C1-C3) alkylenes and optionally substituted ethenylenes. each Z 2 These are O, S, and NR, independently. 21 and C(R 22 ) Selected from 2, in the formula, each R 21 Each R is independently selected from H and optionally substituted (C1-C6) alkyl groups. 22 The conjugate described in any one of the clauses 76 to 91 is independently selected from H, a halogen (e.g., F), and an optionally substituted (C1-C6) alkyl.

[0591] Article 93. The hydrophilic head group W above 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] and [ka] Or selected from those salts,

[0592] In the formula, R 1 and R 2 Independently, hydrogen, SR 3 , halo, or CN, R 3 and R 4 H and C are independent of each other. 1~6 Alkyl or substituted C 1~6 The conjugate described in Clause 92, which is alkyl (e.g., -CF3 or -CH2CF3), where A, B, and C are each independently CH or N, and D is each independently O or S.

[0593] Clause 94.W is -P=O(OH)2, -SO3H 、 -CO2H 、 The conjugates described in Clause 93, selected from and -CH(CO2H)2, or their salts.

[0594] Clause 95.Z 1 is, -(CH2) j - and j is a conjugate as described in any one of clauses 92-94, where j is 1-3.

[0595] Clause 96.Z 1 is a conjugate as described in any one of clauses 92 to 95, where -CH=CH-.

[0596] Clause 97.Z 2 is a conjugate as defined in any one of the clauses 92-96, which is either O or S.

[0597] Clause 98.Z 2 -NR 21 -A conjugate as described in any one of the clauses 92 to 96.

[0598] Clause 99.Z 2 -C(R 22 )2-, any conjugate as described in any one of clauses 92 to 96.

[0599] Clause 100.Z 1 is, -(CH2) j - is selected from substituted (C1~C3) alkylenes and -CH=CH-, j is 1~3, and Z 2 The conjugate is selected from O and CH2, as described in any one of clauses 92 to 94.

[0600] Clause 101.Z 1 These are -(CH2)2-, -CH2-CF2-, or -CH2-CHF-, and Z 2 The conjugate described in clause 100 is O.

[0601] Clause 102.Z 1 These are -(CH2)2-, -CH2-CF2-, or -CH2-CHF-, and Z 2 CH2 is the conjugate described in Clause 100.

[0602] Clause 103.Z 1 -CH=CH- and Z 2 The conjugate described in clause 100 is O.

[0603] Clause 104.Z 1 -CH=CH- and Z 2 CH2 is the conjugate described in Clause 100.

[0604] Clause 105.X is, [ka] [ka] [ka] A conjugate selected from any one of the clauses 92-104.

[0605] Article 106. The above linker L is of formula (IIa), [ka] During the ceremony, L 1 ~L 7 Each of them is independently a connecting part, and together provides a linear or branched linker between X and Y. a is either 1 or 2. b, c, d, e, f, and g are each independently 0, 1, or 2. n is 1 to 6 (for example, n is 1 to 5, or 2 to 6, or 1, 2, or 3), a conjugate as described in any one of clauses 76 to 105.

[0606] If clause 107.d is 0, then n is 1. If d is 1, then n is between 1 and 3. If d is 2, then n is 1 to 6, as per the conjugates described in Clause 108.

[0607] Clause 111.-(L 1 ) a - is a conjugate as described in Clause 109 or 110, which includes optionally substituted aryl or heteroaryl conjugate portions.

[0608] Clause 112. Each L 1 Independently, [ka] and [ka] A conjugate as described in Clause 111, selected from the following, where v is between 0 and 10 and z is between 0 and 10.

[0609] Clause 113. Each L 2 -C 1~6 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkylene-, -O(CH2) p -and-(OCH2CH2)p - is selected from, where p is between 1 and 10. Each L 3 Independently, [ka] and -(OCH2CH2) q - A conjugate as described in any one of clauses 109 to 112, selected from the following, where q is between 1 and 10, u is between 0 and 10, and w is between 1 and 10.

[0610] If clause 114.n is 2 or more, at least one L 4 A conjugate described in any one of clauses 109-113, which exists and is a branched conjugate.

[0611] Clause 115. Each L 4 Independently, -OCH2CH2-, [ka] and [ka] Selected from, A conjugate as described in any one of clauses 109 to 114, wherein each x and y is independently between 1 and 10.

[0612] Clause 116. Each L 5 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, [ka] or -(OCH2CH2) r -and, Each L 6 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C1~6 -Alkylene-, or -(OCH2CH2)- s -and, Each L 7 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, -(OCH2CH2) t - or -OCH2-, where r, s, and t are each independently 1 to 20, the conjugate as described in any one of clauses 109 to 115.

[0613] Clause 117.a is a conjugate that is one of the conjugates described in any one of Clauses 109-116.

[0614] At least one of Clauses 118.b, c, e, f, and g is a conjugate described in any one of Clauses 109-117, not zero.

[0615] A conjugate as described in any one of Clauses 109-118, wherein at least one of Clauses 119.b or c is not 0, and at least one of Clauses e, f, and g is not 0.

[0616] Clauses 120.a, b, and c are, independently, one or two of the conjugates described in any one of Clauses 109-119.

[0617] Clause 121. The above linker L is a conjugate described in any one of Clauses 109 to 120, selected from any one of the structures in Tables 2 to 3.

[0618] Clause 122. The above conjugate is, i) A conjugate derived from the conjugation of any one of the compounds in the compound table described herein with a biomolecule, ii) A conjugate derived from the conjugation of any one of the compounds in the compound table described herein with a polypeptide, or iii) A conjugate according to Clause 76 or 77, selected from a conjugate derived from the conjugation of any one of the compounds in the compound table described herein with an antibody or antibody fragment.

[0619] Clause 123. The antibody or antibody fragment described above is an IgG antibody, as described in any one of Clauses 77 to 122.

[0620] Clause 124. The antibody or antibody fragment described above is a humanized antibody, as described in any one of Clauses 77 to 122.

[0621] Clause 125. The antibody or antibody fragment described above is a conjugate according to any one of Clauses 77 to 124, which specifically binds to a secreted protein or a soluble protein.

[0622] Clause 126. The antibody or antibody fragment described above is a conjugate according to any one of Clauses 77 to 124, which specifically binds to a cell surface receptor.

[0623] Clause 127. A method for internally transferring a target protein into cells containing the M6PR cell surface receptor, A method comprising contacting a cell sample containing the above-mentioned cells and the above-mentioned target protein with an effective amount of the compound described in any one of clauses 1 to 75 or the conjugate described in any one of clauses 76 to 132, wherein the compound or the conjugate specifically binds to the above-mentioned target protein and specifically binds to the above-mentioned cell surface receptor to promote cellular uptake of the above-mentioned target protein.

[0624] Clause 128. The method according to Clause 127, wherein the target protein is a membrane-bound protein.

[0625] Clause 129. The method according to Clause 127, wherein the target protein is an extracellular protein.

[0626] Clause 130. The method according to 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.

[0627] Clause 131. A method for reducing the level of a target protein in a biological system, A method comprising contacting the above-mentioned biological system with an effective amount of a compound described in any one of clauses 1 to 75 or a conjugate described in 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 the cells in the biological system, thereby promoting the cellular uptake and degradation of the target protein.

[0628] Clause 134. The above-mentioned biological system is a human subject and is a method described in any one of Clauses 131 to 133.

[0629] Clause 135. The above biological system is an in vitro cell sample, as described in any one of Clauses 131 to 133.

[0630] Clause 136. The method according to Clauses 131-135, wherein the target protein is a membrane-bound protein.

[0631] Clause 137. The method according to any one of Clauses 131 to 135, wherein the target protein is an extracellular protein.

[0632] Clause 138. A method for treating a disease or disorder related to a target protein, A method comprising administering an effective amount of a compound described in any one of clauses 1 to 75 or a conjugate described in any one of clauses 76 to 126 to a subject in need of treatment, wherein the compound or conjugate specifically binds to the target protein.

[0633] Clause 139. The disease or disorder described above is an inflammatory disease, as described in Clause 138.

[0634] Clause 140. The disease or disorder described above is an autoimmune disease, as described in Clause 138.

[0635] Clause 141. The disease or disorder described above is cancer, as described in Clause 138.

[0636] Article 151. Compounds of the following formula (I), [ka] or a salt thereof, a single stereoisomer, a mixture of stereoisomers, or an isotope thereof, in the formula, X is the portion that binds to the M6PR cell surface receptor, L is the linker in the following equation: [ka] and During the ceremony, Each L 1 Independently, [ka] or [ka] And, Each L 2 -C 1~6 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkylene-, -(OCH2) p -, or -(OCH2CH2) p -and, Each L 3 Independently, [ka] or -(OCH2CH2) q -and, Each L 4 Independently, -OCH2CH2-, [ka] or [ka] And, Each L 5 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, [ka] or -(OCH2CH2) r -and,

[0637] Each L 6 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkylene-, or -(OCH2CH2)- r -and, Each L 7 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, -(OCH2CH2) r -, or -OCH2- p, q, r, s, and t are each independently integers between 1 and 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 integers between 1 and 10. n is an integer between 1 and 5. When d is 0, n is 1. When d is 1, n is an integer between 1 and 3. When d is 2, n is an integer between 1 and 5. Y is [ka] [ka] It is a site selected from a group consisting of the following: [ka] and [ka] During the ceremony, [ka] This represents the connection point to L, R is either hydrogen or fluorine. Each R' is independently either a hydrogen or a 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 a compound of formula (I) that is -C1-C8 alkyl or -aryl, or a salt thereof, a single stereoisomer, a mixture of stereoisomers, or an isotope thereof.

[0638] Clause 154.a is a compound described in Clause 151, which is 1.

[0639] The compound described in Clause 151, wherein at least one of b, c, e, f, and g is not 0.

[0640] The compounds described in Clause 151, wherein at least one of Clause 156.b or c is not 0, and at least one of e, f, and g is not 0.

[0641] Clauses 157.a, b, and c are each independently one or two of the compounds described in Clause 151.

[0642] Article 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] and [ka] Selected from the group consisting of, j is an integer between 1 and 3. R 1 and R 2 These are, independently, hydrogen, halo, or CN, R 3 and R 4Each of them is independent of C 1~6 It is alkyl, A, B, and C are each independently CH or N. The compound described in Clause 151, wherein D is independently either O or S.

[0643] 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] and [ka] Selected from the group consisting of, j is an integer between 1 and 3. R 1 and R 2 These are, independently, hydrogen, halo, or CN, R 3 and R 4 Each of them is independent of C 1~6 It is alkyl, A, B, and C are each independently CH or N. The compound described in Clause 151, wherein D is independently either O or S.

[0644] Article 161. Conjugate the following expressions: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is the portion that binds to the M6PR cell surface receptor, L is the linker in the following equation: [ka] and During the ceremony, Each L 1 Independently, [ka] or [ka] And, Each L 2 -C 1~6 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkylene-, -(OCH2) p -, or -(OCH2CH2) p -and, Each L 3 Independently, [ka] or -(OCH2CH2) q -and, Each L 4 Independently, -OCH2CH2-, [ka] or [ka] And, Each L 5 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, [ka] or -(OCH2CH2) r -and, Each L 6 It is independently, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkylene-, or -(OCH2CH2)- r -and, Each L 7 It is independently, -NHCO-C 1~6 -Alkylene-, -CONH-C1~6-Alkylene-, C 1~6 -Alkilen-, -(OCH2CH2) t -or -OCH2- p, q, r, s, and t are each independently integers between 1 and 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 integers between 1 and 10. n is an integer between 1 and 5. When d is 0, n is 1. When d is 1, n is an integer between 1 and 3. When d is 2, n is an integer between 1 and 5. Z is [ka] and [ka] Selected from, During the ceremony, [ka] This represents the connection point to L, During the ceremony, [ka] This represents the connection point to L, X is CH2, NH, O, or S. P is a polypeptide, a conjugate of the formula, or a pharmaceutically acceptable salt thereof.

[0645] Clause 162.P is a conjugate as described in Clause 161, comprising an antibody or an antigen-binding fragment of an antibody.

[0646] Article 163. Conjugate the following expressions: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is the portion that binds to the M6PR cell surface receptor, L is the linker in the following equation: [ka] or During the ceremony, Each L 1 Independently, [ka] or [ka] And, Each L 2 -C 1~6 -Alkilen-, -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkylene-, -(OCH2) p -, or -(OCH2CH2) p -and, Each L 3 Independently, [ka] or -(OCH2CH2) q -and, Each L 4 Independently, -OCH2CH2-, [ka] or [ka] And, Each L 5 is -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, [ka] or -(OCH2CH2) r -and, Each L 6 is -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkylene-, or -(OCH2CH2)- s -and, Each L 7 is -NHCO-C 1~6 -Alkilen-, -CONH-C 1~6 -Alkilen-, -C 1~6 -Alkilen-, -(OCH2CH2) t -or -OCH2- p, q, r, s, and t are each independently integers between 1 and 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 1, 2, 3, 4, 5, or 6. n is an integer between 1 and 5. When d is 0, n is 1. When d is 1, n is an integer between 1 and 3. When d is 2, n is an integer between 1 and 5. m is an integer between 1 and 8. Z is [ka] and [ka] Selected from the group consisting of, [ka] This represents the connection point to L, [ka] teeth, [ka] Represents the connection point to, [ka] is an antibody, a conjugate of the formula, or a pharmaceutically acceptable salt thereof.

[0647] Article 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 R2 )-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] and [ka] Selected from the group consisting of, j is an integer between 1 and 3. R 1 and R 2 These are, independently, hydrogen, halo, or CN, R 3 and R 4 Each of them is independent of C 1~6 It is alkyl, A, B, and C are each independently CH or N. D is a conjugate as defined in any one of the clauses 161-165, which is independently either O or S.

[0648] Article 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] and [ka] Selected from the group consisting of, j is an integer between 1 and 3. R 1 and R 2 These are, independently, hydrogen, halo, or CN, R 3 and R 4 Each of them is independent of C 1~6 It is alkyl, A, B, and C are each independently CH or N. D is a conjugate as defined in any one of the clauses 161-165, which is independently either O or S.

[0649] Article 169. A pharmaceutical composition comprising a conjugate or pharmaceutically acceptable salt as described in any one of Articles 161 to 168, and a pharmaceutically acceptable carrier.

[0650] Clause 170.m is an integer between 4 and 8, the pharmaceutical composition as described in Clause 169.

[0651] Clause 171.m is a pharmaceutical composition comprising a conjugate or pharmaceutically acceptable salt as described in Clause 170, which is 4.

[0652] Clause 172. The above antibody is an IgG antibody, a conjugate as described in any one of Clauses 163 to 168.

[0653] Clause 173. The above antibody is a humanized antibody, a conjugate as described in any one of Clauses 163 to 168.

[0654] Clause 174. A conjugate according to any one of Clauses 163 to 168, wherein the antibody described above specifically binds to a secreted protein or a soluble protein.

[0655] Clause 175. The antibody described above is a conjugate according to any one of Clauses 163 to 168, which specifically binds to a cell surface receptor.

[0656] Clause 176. The antibody described above is a conjugate as described in any one of Clauses 163 to 168, which specifically binds to the programmed death ligand-1 (PD-L1) protein.

[0657] Clause 177. The antibody described above is a conjugate as described in any one of Clauses 163 to 168, which specifically binds to vascular endothelial growth factor (VEGF) protein.

[0658] Clause 178. The antibody described above is a conjugate according to any one of Clauses 163 to 168, which specifically binds to fibroblast growth factor receptor 2 (FGFR2) protein or fibroblast growth factor receptor 3 (FGFR3) protein.

[0659] Clause 179. The antibody described above is cetuximab, a conjugate as described in any one of Clauses 163-168.

[0660] Clause 180. The antibody described above is matsuzumab, a conjugate as described in any one of Clauses 163-168.

[0661] Clause 181. The antibody described above is atezolizumab, a conjugate as described in any one of Clauses 163-168.

[0662] Clause 182. A method of treating a disease or disorder by administering an effective amount of a conjugate or pharmaceutically acceptable salt described in any one of Clauses 163 to 168 or a pharmaceutical composition described in Clause 169 to a subject in need thereof.

[0663] Clause 183. The disease or disorder described above is an inflammatory disease, as described in Clause 182.

[0664] Clause 184. The disease or disorder described above is an autoimmune disease, as described in Clause 182.

[0665] Clause 185. The disease or disorder described above is cancer, as described in Clause 182. [Examples]

[0666] 5. Examples The examples in this section are provided for illustrative purposes only and are not intended to be limiting.

[0667] 5.1. Preparation of Compounds The following are exemplary schemes and examples of methods by which the compounds described herein can be prepared and tested. While examples may represent only a limited number of embodiments, it should be understood that the following examples are illustrative and not limiting. All substituents are as defined above unless otherwise specified. Reagents and starting materials are readily available to those skilled in the art. For the preparation of the compounds described herein, specific synthetic steps for each of the described routes may be combined in different ways or in conjunction with steps from different schemes.

[0668] The synthetic methods for preparing the M6PR binding moiety, its precursor, and its conjugate, which are adaptable for use in the preparation of the compound and its synthone, are described in the international application PCT / US2021 / 012846, published as WO2021 / 142377, and PCT publication WO2020132100, which are incorporated herein by reference in their entirety.

[0669] 5.1.1. Preparation of M6PR binding part synthons Synton A-10 and compound A. Synthesis of (2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-isothiocyanatephenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphate (compound A) [ka] (((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) A solution of (2R,3S,4S,5S,6R)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (A-1) (1.0 equivalent, 26.0 g, 86.37 mmol) in DMF (500 mL) was cooled to 0°C. Next, triethylamine (6.4 equivalents, 288 mL, 552.0 mmol) and trimethylsilyl chloride (24.0 equivalents, 70 mL, 2071.0 mmol) were added to the solution under a nitrogen atmosphere. The resulting mixture was stirred under nitrogen at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and purified by silica gel chromatography (0-5% ethyl acetate in hexane) to obtain intermediate A-2 as a colorless oil. Yield: 36.8 g (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).

[0670] ((2R,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol(A-3) To a stirred solution of intermediate A-2 (1.0 equivalent, 10.0 g, 16.97 mmol) in a mixture of DCM:methanol (8:2 ratio, 100 mL), ammonium acetate (1.5 equivalent, 1.96 g, 25.46 mmol) was added under nitrogen at room temperature. The resulting mixture was stirred under nitrogen at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted 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 in hexane) to obtain intermediate A-3 as a white solid. Yield: 7.0 g (80%); LC-MS m / z 516.13 [M-1] - .

[0671] (2S,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-carbaldehyde(A-4) To a stirred solution of oxalyl chloride (1.1 equivalents, 0.5 mL, 5.31 mmol) in DCM (5 mL), a solution of DMSO (2.2 equivalents, 0.76 mL, 10.62 mmol) in DCM (5 mL) was added over 5 minutes at -78°C. After stirring at -78°C for 20 minutes, a solution of intermediate A-3 (1.0 equivalent, 2.5 g, 4.83 mmol) in DCM (10 mL) was added to the mixture. The reaction mixture was stirred at -78°C for a further 60 minutes, followed by the addition of triethylamine (5.0 equivalents, 3.4 mL, 24.15 mmol). The resulting mixture was allowed to reach room temperature over 1 hour. This turbid 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 obtain intermediate A-4 as a light brown gel (2.2 g, crude product). The light brown gel was used in the next step without further purification.

[0672] Diethyl((E)-2-((2R,3R,4S,5S,6R)-6-(4-nitrophenoxy)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)vinyl)phosphonate(A-5) A stirred suspension of tetraethylmethylenebis(phosphonate) (1.5 equivalents, 1.85 g, 6.40 mmol) in dry THF (20 mL) was cooled to -78°C, and n-BuLi (1.25 equivalents, 2.6 ml, 5.33 mmol) in 2.0 M hexane was added. The resulting mixture was stirred at -78°C for 1 hour, and then intermediate A-4 (1.0 equivalent, 2.2 g, 4.27 mmol) in dry THF (10 mL) was added at -78°C. The bath was removed, allowing the reaction mixture to come to room temperature, and stirring was continued for 12 hours. A saturated aqueous solution of NH4Cl was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, followed by washing with 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 in hexane) to obtain intermediate A-5 as a colorless gel. Yield (1.3g, 48%), LC-MS m / z 650.57[M+1] + .

[0673] Diethyl((E)-2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-nitrophenoxy)tetrahydro-2H-pyran-2-yl)vinyl)phosphonate(A-6) To a stirred solution of intermediate A-5 (1.0 equivalent, 1.3 g, 1.54 mmol) in methanol (15 mL), Dowex 50WX8 hydrogen type was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen at room temperature for 2 hours. The reaction mixture was filtered, washed with methanol, and the filtrate was concentrated under vacuum to obtain 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] + .

[0674] (2R,3R,4S,5S,6R)-2-((E)-2-(diethoxyphosphoryl)vinyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate(A-7) To a stirred solution of intermediate A-6 (1.00 equivalent, 0.78 g, 1.80 mmol) in pyridine (10 mL), acetic anhydride (10.0 equivalent, 1.8 mL, 18.0 mmol) was added dropwise at 0°C under nitrogen. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 16 hours. Pyridine was removed under high vacuum, and the residue was partitioned between ethyl acetate and 1N HCl aqueous solution. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (2.5% methanol in dichloromethane) to obtain intermediate A-7 as a white solid. Yield: 1.0 g (100%); LC-MS m / z 560.17 [M+1] + .

[0675] (2R,3S,4S,5R,6R)-2-(4-aminophenoxy)-6-(2-(diethoxyphosphoryl)ethyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(A-8) To a stirred solution of intermediate A-7 (1.0 equivalent, 1.0 g, 1.78 mmol) in methanol (15 mL), 10% palladium-carbon (0.200 g) was added under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 16 hours under hydrogen gas pressure (100 psi). The reaction mixture was filtered through a Celite bed, washed with methanol, and the filtrate was concentrated under vacuum to obtain intermediate A-8 as a brown viscous gel. Yield: 0.700 g (73.6%); LC-MS m / z 532.21 [M+1] + .

[0676] (2-((2R,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(4-aminophenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphate (A-9) To a stirred solution of intermediate A-8 (1.00 equivalent, 2.0 g, 5.73 mmol) in acetonitrile (15 mL), bromotrimethylsilane (5.0 equivalent, 3.8 mL, 28.65 mmol) was added dropwise under nitrogen at 0°C. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 16 hours. Volatile matter was removed from the rotary evaporator, and the residue was dried under high vacuum. The crude residue was triturated with diethyl ether and dried under high vacuum to obtain intermediate A-9 as a brown solid. Yield: 2.2 g, crude product. LC-MS m / z 476.0 [M+1] + .

[0677] (2-((2R,3S,4S,5S,6R)-6-(4-aminophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)ethyl)phosphate (A-10) To a stirred solution of intermediate A-9 (1.0 equivalent, 2.0 g, 4.21 mmol) in a methanol:water mixture (8:2, 15 mL), triethylamine (5.0 equivalent, 2.93 mL, 21.05 mmol) was added dropwise under nitrogen at 0°C. The cold bath was removed, and the resulting mixture was stirred at room temperature for 16 hours. Methanol was removed on a rotary evaporator, and the residue was dried under high vacuum. The residue was dissolved in water and purified by preparative HPLC (2-10% acetonitrile in water with 5 mM ammonium acetate). The fractions containing the desired product were combined and freeze-dried to dryness, yielding intermediate A-10 as a brown solid. Yield: 0.350 g (25%); LC-MS m / z 348.0 [MH] - .

[0678] (2-((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(4-isothiocyanatephenoxy)tetrahydro-2H-pyran-2-yl)ethyl)phosphate (compound A) To a stirred solution of intermediate A-10 (1.0 equivalent, 1.75 g, 5.01 mmol) in a mixture of ethanol:water (7:3) (20 ml), thiophosgene (5.00 equivalent, 1.92 mL, 25.05 mmol) was added dropwise at 0°C under nitrogen. The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 3 hours. Volatile substances were removed on a rotary evaporator, and the residue was dried under high vacuum. The residue was dissolved in water and purified by prep-HPLC (20-40% acetonitrile in water with 5.0 mmol ammonium acetate). The fractions containing the desired product were combined and freeze-dried to dryness, yielding 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)δ7.32(d,J=8.92Hz,2H),7.12(d,J=8.96Hz,2H),5.57(s,1H),4.13(s,1H),3.96(d d,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).

[0679] Preparation of Synton 8D [ka] DBU (0.05 equivalents, 0.025 mL, 0.168 mmol) was added under nitrogen at 0°C to a stirred solution of (2R,3R,4S,5S,6S)-2-(2-(diethoxyphosphoryl)ethyl)-6-hydroxytetrahydro-2H-pyran-3,4,5-triyltriacetate (8A) (1.00 equivalents, 1.48 g, 3.36 mmol) and trichloroacetonitrile (10.0 equivalents, 3.4 mL, 33.6 mmol) in DCM (30 mL). The resulting mixture was stirred under nitrogen at 0°C. More DBU (0.0500 equivalents, 0.025 mL, 0.168 mmol) was added, and the cold bath was removed. The resulting mixture was stirred at room temperature for 45 minutes. Most of the solvent was removed on a rotary evaporator. The residue was loaded onto a silica gel-loaded column pre-equilibriumized with 0.1% triethylamine in dichloromethane and purified by silica gel chromatography (column pre-equilibriumized with 0.1% triethylamine in 30% ethyl acetate / hexane) (30-100% ethyl acetate in hexane). The fractions containing the desired product were combined and concentrated on a rotary evaporator. The residue was stripped twice from dry dichloromethane, dried under high vacuum for 30 minutes, and then stored under nitrogen at -80°C to obtain compound 8B as a colorless semi-solid. Yield: 1.26 g, 64%; 1 ¹H 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).

[0680] Compound 8B (1.00 equivalent, 1.25 g, 2.14 mmol) was dissolved in dry DCM (10 mL) under nitrogen with stirring. Buto-3-in-1-ol (2.00 equivalent, 0.32 mL, 4.28 mmol) was added, and the resulting mixture was cooled to -78°C under nitrogen with stirring. A solution of boron trifluoride diethyl etherate (0.500 equivalent, 0.13 mL, 1.07 mmol) in dichloromethane (5 mL) was slowly added. The -78°C cold bath was removed, and the reaction mixture was slowly heated under nitrogen for 50 minutes. The reaction mixture was cooled in a water / ice bath, stirred for a further 30 minutes under nitrogen at 0°C, and then post-treatment was performed. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution. The aqueous layer was re-extracted with dichloromethane. The combined organic matter was dried over sodium sulfate, filtered, and purified by silica gel chromatography (20-100% ethyl acetate in dichloromethane) to obtain 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)δ5.35-5.19(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).

[0681] Bromotrimethylsilane (5.00 equivalents, 0.47 mL, 3.57 mmol) was slowly added under nitrogen at 0°C to a stirred solution of compound 8C (1.00 equivalent, 352 mg, 0.715 mmol) in MeCN (7 mL). The cold bath was removed, and the resulting mixture was stirred under nitrogen at room temperature for 3.5 hours. Volatile matter was removed on a rotary evaporator, and the residue was dried briefly under high vacuum. The residue was dissolved in methanol (7 mL) while stirring under nitrogen, and 25 wt% sodium methoxide in methanol (2.50 equivalents, 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 equivalents, 0.1...

Claims

1. Cell surface M6PR-binding compound of formula (XIIa), 【Chemistry 372】 or its prodrug, or its salt, During the ceremony, W is a non-hydrolyzable hydrophilic head group, Z １ (C １ ~C ３ ) Selected from alkylenes and optionally substituted ethenylenes, Z ２ is selected from O, S, NR ２１ and C(R ２２ ) ２ , where 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 arbitrarily substituted aryl or heteroaryl linkage (for example, an arbitrarily substituted monocyclic or bicyclic aryl or heteroaryl), Each Z ３ It is an independent connecting part, n is between 1 and 500. m is between 1 and 100. L is a linker, Y is the target part, A is phenyl, Z ２ If O, (i) W is -P(O)(OH) ２ is, or (ii) The linker L comprises a backbone of at least 16 consecutive atoms, and Y is a cell surface M6PR-binding compound of formula (XIIa), or a prodrug thereof, or a salt thereof, which is a target binding moiety.

2. A cell surface mannose-6-phosphate receptor (M6PR) conjugating compound of formula (XIa), 【Chemistry 373】 or its prodrug, or its salt, During the ceremony, W is a non-hydrolyzable hydrophilic head group, Z １ (C １ ~C ３ ) Selected from alkylenes and optionally substituted ethenylenes, Z ２ O, S, NR ２１ and C(R ２２ ) ２ Selected from, in the formula, R ２１ These are independently H, and optionally substituted (C １ ~C ６ ) Selected from alkyl groups, each R ２２ These are independently H, halogens (e.g., F), and optionally substituted (C). １ ~C ６ ) Selected from alkyl groups, A is an arbitrarily substituted cyclic group (for example, an arbitrarily substituted aryl, an arbitrarily substituted heteroaryl, an arbitrarily substituted heterocyclic, or an arbitrarily substituted cycloalkyl), Each Z ３ It is an independent connecting part, n is between 1 and 500. m is between 1 and 100. L is a linker, Y is the target part, a cell surface mannose-6-phosphate receptor (M6PR) conjugating compound of formula (XIa), or a prodrug thereof, or a salt thereof.

3. Z ２ The compound according to claim 2, wherein is S.

4. The compound according to claim 2 or 3, wherein W is a phosphonate, thiophosphonate, carboxylic acid, or malonic acid, or a salt thereof.

5. The aforementioned compound contains one M6PR bond (X) from the following formula: 【Chemistry 374】 In the formula, R ａ , R ｂ , R ｃ , and R ｄ The compound according to any one of claims 2 to 4, wherein is independently H or F.

6. The aforementioned compound contains one M6PR bond (X) from the following formula: 【Chemistry 375】 In the formula, R ａ , R ｂ , R ｃ , and R ｄ The compound according to claim 1, wherein is independently H or F.

7. A is an 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 phenylene-triazole, the compound according to any one of claims 1 to 6.

8. The compound according to claim 7, wherein A is selected from optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, optionally substituted 2,5-pyridylene, and triazole.

9. A is, 【Transformation 376】 and 【Chemical 377】 Selected from, During the ceremony, R １１ ~R １４ These are independently H, halogen, OH, and optionally substituted (C １ ~C ６ ) alkyl, optionally substituted (C １ ~C ６ ) Alkoxy, COOH, NO ２ , CN, NH ２ , -N(R ２５ ) ２ , -OCOR ２５ , -COOR ２５ , -CONHR ２５ , and -NHCOR ２５ Selected from, R ２５ These are independently H, and optionally substituted (C １ ~C ６ The compound according to claim 8, selected from alkyl groups.

10. The compound according to any one of claims 1 to 6, wherein A is an optionally substituted condensed bicyclic aryl or an optionally substituted condensed bicyclic heteroaryl.

11. The compound according to claim 10, wherein A is optionally substituted naphthalene or optionally substituted quinoline.

12. A is, 【Chemistry 378】 and 【Chemistry 379】 Selected from, During the ceremony, R １１ and R １３ ~R １４ These are independently H, halogen, OH, and optionally substituted (C １ ~C ６ ) alkyl, optionally substituted (C １ ~C ６ ) Alkoxy, COOH, NO ２ , CN, NH ２ , -N(R ２５ ) ２ , -OCOR ２５ , -COOR ２５ , -CONHR ２５ , and -NHCOR ２５ Selected from, s is between 0 and 3. Each R ２５ These are independently H, and optionally substituted (C １ ~C ６ The compound according to claim 11, selected from alkyl groups.

13. A is, 【Chemical 380】 【Chemistry 381】 A compound according to claim 12, selected from the above.

14. A is given by the following formula 【Chemistry 382】 A optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl, or a salt thereof, During the ceremony, Cy is independently a monocyclic aryl or monocyclic heteroaryl, R １１ ~R １５ These are independently H, halogen, OH, and optionally substituted (C １ ~C ６ ) alkyl, optionally substituted (C １ ~C ６ ) Alkoxy, COOH, NO ２ , CN, NH ２ , -N(R ２５ ) ２ , -OCOR ２５ , -COOR ２５ , -CONHR ２５ , and -NHCOR ２５ Selected from, s is between 0 and 4. Each R ２５ is independently selected from H and optionally substituted (C １ to C ６ ) alkyl, and is a compound according to any one of claims 1 to 6.

15. The compound according to claim 14, wherein Cy is an optionally substituted phenyl and A is an optionally substituted biphenyl of the following formula: 【Chemistry 383】

16. A is, 【Chemical 384】 【Chem.385】 A compound according to claim 15, selected from the above.

17. Cy is triazole, and A is 【Chemical 386】 【Chemistry 387】 A compound according to claim 14, selected from the above.

18. A is a compound according to any one of claims 6 to 17, wherein A is substituted with at least one OH substituent.

19. R １１ ~R １５ The compound according to any one of claims 9 and 12 to 17, wherein at least one of them is an OH group (for example, at least two are OH groups).

20. R １１ ~R １５ The compound according to any one of claims 9 and 12 to 17, wherein each of the elements is H.

21. Z ３ is selected from covalent bonds, -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 O, S and NR ２３ Selected from, R ２３ and R ２４ H and C are independent of each other. （１～３） - Alkyl (e.g., methyl) and substituted C （１～３） - A compound selected from alkyl groups, according to any one of claims 1 to 20.

22. Z ３ The following applies: 【Chemical 388】 During the ceremony, X １ is either O or S, t is either 0 or 1. Each R ２３ H and C are independent of each other. （１～３） - Alkyl (e.g., methyl) and substituted C （１～３） - A compound selected from alkyl groups, according to any one of claims 1 to 21.

23. Z ３ The compound according to claim 22, wherein is -NHC(=O)NH-.

24. -A-Z ３ -teeth, 【Chemistry 389-1】 【Chemistry 389-2】 【Chemical 390】 A compound according to any one of claims 1 to 23, selected from the above.

25. Z ２ The compound according to any one of claims 1 and 4 to 24, wherein is O.

26. Z ２ The compound according to any one of claims 1 to 24, wherein is S.

27. Z ２ is, -NR ２１ - The compound according to any one of claims 1 and 4 to 24.

28. Z ２ is -C(R ２２ ) ２ - and in the formula, each R ２２ These are independently H, halogens (e.g., F), and optionally substituted (C). １ ~C ６ A compound according to any one of claims 1 and 4 to 24, selected from alkyl groups.

29. Z ２ is, -CH ２ - or -CF ２ - The compound according to claim 28.

30. -Z ２ -Ar-Z ３ - is as follows: 【Chemistry 391】 During the ceremony, X is O, S, -CH ２ - or -CF ２ And, R １６ It is OH, The compound according to any one of claims 1 and 5 to 24, wherein w is 0 to 4 (for example, w is 0, 1, or 2).

31. -Z ２ -A-Z ３ -は、 【Chemistry 392】 The compound according to claim 30.

32. Cell surface M6PR-binding compound of formula (XV), 【Chemistry 393】 or its prodrug, or its salt, During the ceremony, W is a non-hydrolyzable hydrophilic head group, Z １ (C １ ~C ３ ) Selected from alkylenes and optionally substituted ethenylenes, Z ４ is, -Z １４ -, -Z １４ -A-, -A-, and -CH ２ -Z １４ - Selected from, Z １４ O, S, NR ２１ and C(R ２２ ) ２ Selected from, in the formula, R ２１ These are independently H, and optionally substituted (C １ ~C ６ ) Selected from alkyl groups, each R ２２ These are independently H, halogens (e.g., F), and optionally substituted (C). １ ~C ６ ) Selected from alkyl groups, A is an arbitrarily substituted cyclic group (for example, an arbitrarily substituted aryl, an arbitrarily substituted heteroaryl, an arbitrarily substituted heterocyclic, or an arbitrarily substituted cycloalkyl), n is between 1 and 500. m is between 1 and 100. L is a linker, Y is the target part, a cell surface M6PR-conjugated compound of formula (XV), or its prodrug, or a salt thereof.

33. Z ４ is, -CH ２ -Z １４ - and Z １４ O, S, NR ２１ , and C(R ２２ ) ２ A compound according to claim 32, selected from the above.

34. Z ４ is, -CH ２ The compound according to claim 32, which is -A-.

35. Z ４ The compound according to claim 32, wherein is -A-.

36. The compound according to claim 34 or 35, wherein A is an optionally substituted aryl or optionally substituted heteroaryl.

37. The compound according to claim 36, wherein A is a triazole.

38. Z ４ teeth, 【Chem. 394】 The compound according to claim 35, wherein "*" indicates bonding to the linker L.

39. Foreword: Non-hydrolyzable hydrophilic head group W, -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(すなわち、-SO ３ H), -S (O)OH, -COOH, -CN, -CONH ２ -CONHR ３ -CONR ３ R ４ , -CONH (OH), -CONH (OR ３ ), -CONHSO ２ R ３ -CONHSO 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 ,-NHC(O)CO ２ H, -NHSO ２ NHR ３ , -NHC (O) NHS (O) ２ R ３ ,-NHSO ２ R ３ ,-NHSO ３ H, 【Chemical 395】 【Chemistry 396】 During the ceremony, R １ and R ２ Independently, hydrogen, SR ３ , halo, or CN, R ３ and R ４ H and C are independent of each other. 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. The compound according to any one of claims 1 to 38, wherein D is independently either O or S.

40. W is -P = O(OH) ２ -P = S(OH) ２ -P=O(SH)(OH), -P=S(SH)(OH), -COOH, and -CH(COOH) ２ The compound according to claim 39, or selected from salts thereof.

41. Z １ is, -(C(R ２２ ) ２ ) ｊ - and in the formula, each R ２２ These are independently H, halogens (e.g., F), and optionally substituted (C). １ ~C ６ A compound according to any one of claims 1 to 40, wherein j is selected from alkyl groups and j is 1 to 3.

42. Z １ is, -(CH ２ ) ２ -ien-CH ２ -CF ２ -, or -CH ２ The compound according to claim 41, wherein it is -CHF-.

43. Z １ is, -CH ２ - or -CF ２ - The compound according to claim 41.

44. Z １ The compound according to any one of claims 1 to 40, wherein -CH=CH-.

45. Z １ is, -(CH ２ ) ２ -ien-CH ２ -CF ２ - or -CH ２ -CHF-, W is -P = O(OH) ２ -P = S(OH) ２ The compound according to claim 41, selected from -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or salts thereof.

46. Z １ -CH=CH-, W is -P = O(OH) ２ -P = S(OH) ２ The compound according to claim 60, selected from -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or salts thereof.

47. Z １ is, -CH ２ - or -CF ２ - and W is -CH(COOH) ２ The compound according to claim 41, or a salt thereof.

48. The compound according to any one of claims 1 to 47, wherein n is 1 to 20 (for example, 1 to 10, 1 to 6, or 1 to 3).

49. The compound according to claim 48, wherein n is 1.

50. L is Z ３ The compound according to claim 49, comprising a linear linker having a skeleton of 16 or more consecutive atoms covalently linked to Y (for example, a skeleton of 16 to 100 or 20 to 100 consecutive atoms).

51. The compound according to claim 48, wherein n is 2.

52. The compound according to claim 48, wherein n is 3.

53. L is the one in equation (II), 【Chemistry 397】 During the ceremony, L １ and L ３ It is independently a linker, L ２ This is the branching connection part, L １ ~L ３ Together, they form a linear or branched linker between X and Y. a, b, and c are independently either 0 or 1. ** is Z １ L of X via １ Represents the connection point to, *** represents the connection point to Y, When n is 1, a is 1 and b is 0. The compound according to any one of claims 1 to 52, wherein if n > 1, a is 1 and b is 1.

54. L １ ~L ３ These are, independently, -C １～２０ -Alkilen-, -NHCO-C １～６ -Alkilen-, -CONH-C １～６ -Alkilen-, -NHC １～６ -Alkilen-, -NHCONH-C １～６ -Alkilen-, -NHCSNH-C １～６ -Alkilen-, -C １～６ -Alkilen-NHCO-, -C １～６ -Alkilen-CONH-, -C １～６ -Alkilen-NH-,-C １～６ -Alkilen-NHCONH-, -C １～６ -Alkylene-NHCSNH-, -O(CH ２ ) ｐ -, - (OCH ２ CH ２ ) ｐ -, -NHCO-, -CONH-, -NHSO ２ -, -SO ２ NH-, -CO-, -SO ２ The compound according to claim 53, comprising one or more linking moieties independently selected from -, -O-, -S-, pyrrolidine-2,5-dione, 1,2,3-triazole, -NH-, and -NMe-, wherein each p is independently 1 to 50.

55. L is a repeating ethylene glycol moiety (e.g., -CH ２ CH ２ O- or -OCH ２ CH ２ The compound according to claim 53 or 54, comprising -).

56. The compound according to claim 55, wherein L comprises 1 to 25 ethylene glycol moieties (for example, 3, 7, or 24 ethylene glycol moieties).

57. L is a compound according to any one of claims 53 to 56, comprising one or more 1,2,3-triazole linkages.

58. L is 【Chem.398】 The compound according to claim 57, comprising one or more linking parts selected from the following structure, wherein w1, u1, and q1 are independently 1 to 25 (e.g., 1 to 12, e.g., 1 to 6).

59. The compound according to any one of claims 53 to 58, wherein n is 1.

60. The compound according to any one of claims 53 to 58, wherein n is 2 or more.

61. L ２ teeth, 【Chem.399】 【Chemical 400】 Selected from, The compound according to claim 60, wherein each x and y is independently 1 to 10.

62. L １ ~L ２ is, Z ２ or Z ４ The compound according to any one of claims 53 to 61, comprising a skeleton of 14 or more consecutive atoms (for example, 14 to 50 or 14 to 30 atoms) between the branched atom and the compound according to any one of claims 53 to 61.

63. L ３ The compound according to any one of claims 53 to 62, comprising a skeleton of 10 to 80 consecutive atoms (for example, 12 to 50 atoms).

64. L ３ is, (C １０ ~C ２０ - Alkylene (for example, C １２ -Alkylene) or -(OCH ２ CH ２ ) ｐ The compound according to claim 63, comprising a linking portion selected from, wherein p is 1 to 25 (e.g., 3, 7, or 24).

65. The compound according to any one of claims 53 to 64, wherein the linker of formula (II) comprises 20 to 100 consecutive atoms.

66. The compound according to claim 65, wherein the linker of formula (II) comprises 25 or more consecutive atoms.

67. The compound according to claim 65, wherein the linker of formula (II) comprises 30 or more consecutive atoms.

68. The compound according to any one of claims 1 to 67, wherein m is 1.

69. The compound according to any one of claims 1 to 67, wherein m is at least 2.

70. The compound according to claim 69, wherein m is 2 to 20 (for example, m is 2 to 10).

71. m is between 20 and 500 (for example, 20 to 400, 20 to 300, or 20 to 200, or 50 to 500, or 100 to 500), L is an α-amino acid polymer (e.g., poly-L-lysine), and has a large number of -Ar-Z ３ The compound according to claim 69, wherein the group is covalently linked to the polymer backbone by a side chain group (for example, by conjugation of a lysine residue to a side chain amino group).

72. The compound according to any one of claims 1 to 71, wherein Y is selected from small molecules, dyes, fluorophores, monosaccharides, disaccharides, trisaccharides, and chemoselective ligation groups or their precursors.

73. Y is a biomolecule, the compound according to any one of claims 1 to 71.

74. The compound according to claim 73, wherein the biomolecule is selected from peptides, proteins, polynucleotides, polysaccharides, glycoproteins, lipids, enzymes, antibodies, and antibody fragments.

75. The compound according to any one of claims 1 to 74, wherein Y is a portion that specifically binds to a target protein.

76. The compound according to claim 76, wherein the target protein is a membrane-bound protein.

77. The compound according to claim 76, wherein the target protein is a soluble extracellular protein.

78. Y is selected from antibodies, antibody fragments (e.g., antigen-binding fragments of antibodies), chimeric fusion proteins, engineered protein domains, D protein binders for target proteins, aptamers, peptides, and small molecule inhibitors or ligands, and is a compound according to any one of claims 74 to 77.

79. The target protein degradation conjugate of formula (XXI), 【Chemical 401】 or its prodrug, or a pharmaceutically acceptable salt thereof, During the ceremony, n is between 1 and 3. m is the average load from 1 to 10. L is a linker, P is a biomolecule that specifically binds to target proteins. Z ５ This is a residual linkage portion formed by covalent linkage between the chemically selective ligation group of the linker L and the compatible group of P. W is a non-hydrolyzable hydrophilic head group, Z １ (C １ ~C ３ ) Selected from alkylenes and optionally substituted ethenylenes, Z ２ O, S, NR ２１ and C(R ２２ ) ２ Selected from, in the formula, R ２１ These are independently H, and optionally substituted (C １ ~C ６ ) Selected from alkyl groups, each R ２２ These are independently H, halogens (e.g., F), and optionally substituted (C). １ ~C ６ ) Selected from alkyl groups, A is an arbitrarily substituted cyclic group, Z ３ is the linking portion, which is the target protein degradation conjugate of formula (XXI), or its prodrug, or a pharmaceutically acceptable salt thereof.

80. The conjugate according to claim 79, wherein the conjugate is of formula (XXIb). 【Chemical 402】

81. Z ２ The conjugate according to claim 79 or 80, wherein S is the conjugate.

82. Z ２ The conjugate according to claim 79 or 80, wherein O.

83. Z ２ is, -CH ２ - or -CF ２ - The conjugate according to claim 79 or 80.

84. The conjugate according to any one of claims 79 to 83, wherein A is an optionally substituted aryl or optionally substituted heteroaryl.

85. The conjugate according to any one of claims 79 to 84, wherein A is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted triazole, and optionally substituted phenylene-triazole.

86. A is, 【Chemical 403】 【Chemical 404】 Selected from, During the ceremony, R １１ ~R １４ These are independently H, halogen, OH, and optionally substituted (C １ ~C ６ ) alkyl, optionally substituted (C １ ~C ６ ) Alkoxy, COOH, NO ２ , CN, NH ２ , -N(R ２５ ) ２ , -OCOR ２５ , -COOR ２５ , -CONHR ２５ , and -NHCOR ２５ Selected from, R ２５ These are independently H, and optionally substituted (C １ ~C ６ ) A conjugate according to any one of claims 79 to 85, selected from alkyl groups.

87. A is substituted with at least one OH substituent, the conjugate according to any one of claims 84 to 86.

88. R １１ ~R １４ The conjugate according to claim 86, wherein at least one of them is an OH group (for example, at least two are OH groups).

89. R １１ ~R １５ The conjugate according to claim 86, wherein each of them is H.

90. Z ３ is 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 ) - Selected from, in the formula, X １ and X ２ O, S and NR ２３ Selected from, R ２３ and R ２４ H and C are independent of each other. （１～３） - Alkyl (e.g., methyl) and substituted C （１～３） - A conjugate according to any one of claims 79 to 89, selected from alkyl groups.

91. Z ３ The following applies: 【Chemical 405】 During the ceremony, X １ is either O or S, t is either 0 or 1. Each R ２３ H and C are independent of each other. （１～３） - Alkyl (e.g., methyl) and substituted C （１～３） - A conjugate according to any one of claims 79 to 90, selected from alkyl groups.

92. Z ３ The conjugate according to claim 91, wherein is -NHC(=O)NH-.

93. -A-Z ３ -teeth, 【Chemical 406】 【Chemical 407】 A conjugate according to any one of claims 79 to 90, selected from the above.

94. Foreword: Non-hydrolyzable hydrophilic head group W, -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(すなわち、-SO ３ H), -S (O)OH, -COOH, -CN, -CONH ２ -CONHR ３ -CONR ３ R ４ , -CONH (OH), -CONH (OR ３ ), -CONHSO ２ R ３ -CONHSO 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 ,-NHC(O)CO ２ H, -NHSO ２ NHR ３ , -NHC (O) NHS (O) ２ R ３ ,-NHSO ２ R ３ ,-NHSO ３ H, 【Chemical 408】 【Chemical 409】 Or selected from those salts, During the ceremony, R １ and R ２ Independently, hydrogen, SR ３ , halo, or CN, R ３ and R ４ H and C are independent of each other. 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. The conjugate according to any one of claims 79 to 93, wherein D is independently either O or S.

95. W is -P = O(OH) ２ -P = S(OH) ２ -P=O(SH)(OH), -P=S(SH)(OH), -COOH, and -CH(COOH) ２ The conjugate according to claim 94, or selected from salts thereof.

96. The aforementioned conjugate includes one M6PR coupling portion from the following formula: 【Chemical 410】 During the ceremony, W is -P = O(OH) ２ -P = S(OH) ２ -P=O(SH)(OH), -P=S(SH)(OH), and -COOH, or selected from their salts, R ａ , R ｂ , R ｃ , and R ｄ The conjugate according to any one of claims 79 to 95, wherein H or F is independently present.

97. The conjugate according to any one of claims 79 to 96, wherein n is 1.

98. The conjugate according to any one of claims 79 to 96, wherein n is 2.

99. The conjugate according to any one of claims 79 to 96, wherein n is 3.

100. The conjugate according to any one of claims 79 to 99, wherein Y is an antibody or antibody fragment that specifically binds to the target protein.

101. The conjugate according to any one of claims 76 to 99, wherein m is 1 to 8 (for example, 1 to 7 or 1 to 6).

102. The conjugate according to claim 101, wherein m is approximately 8, approximately 6, approximately 5, approximately 4, approximately 3, or approximately 2.

103. The conjugate according to any one of claims 79 to 96, wherein n is 1 and m is 1 to 10.

104. The conjugate according to claim 103, wherein m is 2 to 8 (for example, 2 to 6 or 3 to 5).

105. The conjugate according to claim 104, wherein m is approximately 4.

106. The conjugate according to any one of claims 79 to 96, wherein n is 2 and m is 1 to 6 (for example, 2 to 6 or 3 to 5).

107. The conjugate according to claim 106, wherein m is approximately 4.

108. Z ５ The conjugate according to any one of claims 79 to 107, wherein the residual portion is formed by covalent linkage between a thiol-reactive chemoselective ligation group (e.g., maleimide) and one or more cysteine ​​residues of P.

109. Z ５ The conjugate according to any one of claims 79 to 107, wherein is a residual portion formed by covalent linkage between an amine-reactive chemoselective ligation group (e.g., a PFP ester or TFP ester) and one or more lysine residues of P.

110. L is Z ３ The conjugate according to any one of claims 79 to 109, which is a linear linker having a skeleton of 16 or more consecutive atoms (for example, a skeleton of 16 to 100 or 20 to 100 consecutive atoms) covalently linked to Y.

111. L is Z ２ The conjugate according to any one of claims 79 to 109, wherein the branched linker has a skeleton of 14 or more consecutive atoms (for example, 14 to 50 or 14 to 30 atoms) between the branched atom of the linker and the branched atom of the linker.

112. The linker L is selected from any one of the structures in Tables 4 to 5, the conjugate according to any one of claims 79 to 111.

113. The conjugate according to any one of claims 79 to 112, wherein the conjugate is derived from the conjugation of any one compound from the structures in Tables 7 to 9, 12 and 13 with the biomolecule P.

114. The conjugate according to claim 113, wherein P is an antibody or antibody fragment.

115. The conjugate according to claim 114, wherein the antibody or antibody fragment is an IgG antibody.

116. The conjugate according to claim 114 or 115, wherein the antibody or antibody fragment is a humanized antibody.

117. The conjugate according to any one of claims 114 to 116, wherein the antibody or antibody fragment specifically binds to a secreted protein or a soluble protein.

118. The conjugate according to any one of claims 114 to 116, wherein the antibody or antibody fragment specifically binds to a cell surface receptor.

119. A method for internally transporting a target protein into cells containing cell surface M6PR, A method comprising contacting a cell sample containing the cells and the target protein with an effective amount of the compound according to any one of claims 1 to 78 or the conjugate according to any one of claims 79 to 118, wherein the compound or the conjugate specifically binds to the target protein and specifically binds to the cell surface receptor to promote cellular uptake of the target protein.

120. The method according to claim 119, wherein the target protein is a membrane-bound protein.

121. The method according to claim 119, wherein the target protein is an extracellular protein.

122. The method according to any one of claims 119 to 121, wherein the compound or the conjugate comprises an antibody or antibody fragment (Ab) that specifically binds to the target protein.

123. A method for reducing the level of a target protein in a biological system, A method comprising contacting the biological system with an effective amount of the compound according to any one of claims 1 to 78 or the conjugate according to any one of claims 79 to 118, wherein the compound or the conjugate specifically binds to the target protein and specifically binds to the cell surface M6PR of the cells in the biological system, thereby promoting the cellular uptake and degradation of the target protein.

124. The method according to claim 123, wherein the biological system is for human subjects.

125. The method according to claim 123, wherein the biological system is an in vitro cell sample.

126. The method according to claims 123 to 125, wherein the target protein is a membrane-bound protein.

127. The method according to any one of claims 123 to 125, wherein the target protein is an extracellular protein.

128. A method for treating a disease or disorder related to a target protein, A method comprising administering an effective amount of a compound according to any one of claims 1 to 78 or a conjugate according to any one of claims 79 to 118 to a subject in need of treatment, wherein the compound or conjugate specifically binds to the target protein.

129. The method according to claim 128, wherein the disease or disorder is an inflammatory disease.

130. The method according to claim 128, wherein the disease or disorder is an autoimmune disease.

131. The method according to claim 128, wherein the disease or disorder is cancer.

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