Bifunctional molecules for degrading circulating proteins

Abstract

Described herein are bifunctional compounds for removing macrophage migration inhibitory factor (MIF) or immunoglobulin G (IgG). Further described herein are pharmaceutical compositions comprising these bifunctional compounds. Further described herein are methods for treating pathologies and / or conditions with said compounds or compositions. The pathologies and / or conditions are mediated through MIF / IgG or where MIF / IgG is a contributing factor in the development and perpetuation of diseases and / or conditions, such as autoimmune diseases and cancers, among others. TIFF2025509736000504.tif99145

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 17 / 695,259, filed March 15, 2022, which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under award GM067543 from the National Institutes of Health and award W81XWH-13-1-0062 from the U.S. Army Medical Research Materiel Command. The government has certain rights in this invention.

[0003] Sequence Listing This application contains a Sequence Listing, which was submitted in ASCII format via EFS-Web and is incorporated herein by reference in its entirety. Said ASCII copy, created on Mar. 12, 2023, is named 47162-7240WO2_Sequence Listing.xml and is 30.8 kilobytes in size. [Background technology]

[0004] background MIF is an inflammatory and pluripotent cytokine that contributes to the development and perpetuation of many diseases. These diseases include atherosclerosis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sepsis, and inflammatory bowel disease (IBD), among others. Furthermore, MIF has been shown to be involved in the progression of various cancers, including colon, prostate, breast, lung, cervical, and adenocarcinoma, among others. In preclinical models, inhibition of MIF has been shown to attenuate symptoms and delay disease progression in the above diseases.

[0005] MIF and IgG contribute significantly to the pathological process of several diseases. MIF neutralizing antibodies and small molecule MIF inhibitors have been developed, where IgG is upregulated in autoimmune and other diseases and causes adverse effects. Because MIF acts through various pathways, MIF inhibitors may need to be able to block multiple protein-protein interactions (PPIs), which creates difficulties in drug development. In the case of IgG, removal of IgG molecules that are upregulated and contribute to autoimmune and / or other diseases may be useful to inhibit and / or ameliorate the effects of pathology. Therefore, a novel approach in which MIF or IgG can be degraded and inhibited can overcome this difficulty and potentially generate a more powerful therapeutic response. Prompted by the preliminary results of bifunctional MIF and IgG degrading agents, the inventors decided to further test the degrading agents in clinically relevant in vivo models and potentially develop the degrading agents as therapeutic agents that target MIF or IgG in diseases. We also intend to use this basic bifunctional molecule strategy to direct the degradation of other circulating proteins of interest by ASGPr.

[0006] There is therefore a need for molecules that can clear MIPs and / or IgG. The present disclosure addresses this need. Summary of the Invention

[0007] overview In some aspects, the present disclosure relates to bifunctional small molecules that can be used to inhibit and remove MIF or IgG. In some embodiments, the present disclosure aims to establish a comprehensive small molecule strategy that directs the selective degradation of MIF or IgG, which contribute to the development and perpetuation of many diseases. In some embodiments, the bifunctional molecule construct comprises a MIF-binding motif derived from a known small molecule ligand of MIF, or an IgG-binding motif that comprises a ligand that binds to IgG. These moieties are collectively referred to herein as macrophage migration inhibitory factor binding moiety (MIFBM) or immunoglobulin G binding moiety (IgGBM). In some embodiments, the other end of the bifunctional molecule is a motif that binds to the hepatocyte asialoglycoprotein receptor (ASGPr), which is a triantennary N-acetylgalactosamine or other moiety described herein. These moieties may be collectively referred to herein as asialoglycoprotein receptor binding moiety (ASGPRBM). The motifs used to realize the bifunctional compounds according to some embodiments, i.e. (MIFBM or IgGBM) and (ASGPRBM), are covalently linked by a linker, such as a polyethylene glycol (PEG) linker or other linkers described herein with tunable length, optionally including one or more connector molecules connecting the linker to the MIFBM or IgGBM and / or ASGPRBM, or other linkers described herein.

[0008] In some embodiments, the bifunctional compound selectively binds to MIF or IgG in circulation to form a protein complex. As this protein complex passes through the liver, the asialoglycoprotein receptor binding portion (ASGPRBM) of the molecule, such as triantennary N-acetylgalactosamine or other motifs described herein, engages with the intralysosomal pathway of hepatocytes through ASGPr. As a result of this mechanism, MIF or IgG is removed from circulation by hepatocytes, thereby reducing the level of MIF or IgG, and thus the corresponding disease symptoms are attenuated and / or eliminated in the patient or subject to which the compound is administered. In certain cases, MIF is substantially reduced or eliminated, or harmful IgG is substantially reduced, thereby substantially reducing symptoms and even curing or eliminating the disease state or condition.

[0009] The approach of the present disclosure has inherent advantages over the classical antibody-based strategies of the prior art for targeting MIF or IgG: the small molecule-based approach of the present disclosure overcomes the limitations of traditional antibody-based strategies, including lack of oral bioavailability, need for cold storage, immunogenicity, and high cost.

[0010] Furthermore, the compounds and methods of the present disclosure are expected to have a longer-lasting effect than conventional inhibitory approaches, because MIF or IgG is substantially reduced or eliminated by degradation in liver cells, rather than simply inhibited by reversibly blocking protein-receptor interactions. The bifunctional molecular constructs of the present disclosure are also versatile in the sense that they can target various disease states and / or conditions by inhibiting and degrading MIF or IgG. Thus, previously discovered non-inhibitory protein binders that are currently of little therapeutic value could potentially be therapeutically useful in these small molecules.

[0011] In certain aspects, the present disclosure relates to compounds of the following general chemical structure, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, useful for clearing circulating proteins associated with a disease state or condition in a patient or subject: TIFF2025509736000002.tif24137In formula, [MIFBM / IgGBM] is a MIF binding moiety or IgG binding moiety that binds to circulating MIF or circulating IgG, respectively, which circulating proteins are associated with a disease state and / or condition and which are to be cleared by the action of hepatocytes on the circulating proteins (in some embodiments, the compound selectively binds to MIF or IgG in plasma); [ASGPRBM] is a binding moiety that binds to hepatocytes (e.g., in a patient or subject) via the asialoglycoprotein receptor on the surface of the hepatocytes; each [CON] is an optional connector chemical moiety, which, if present, is connected directly to a [MIFBM / IgGBM] or [ASGPRBM] or connects a [LINKER] to a [MIFBM / IgGBM] or [ASGPRBM]; [Linker] is a chemical moiety having a valency in the range of 1-15, e.g. in the range of 1-10, 1-5, or in the range of 1, 2, or 3, that is covalently attached to one or more [ASGPRM] and / or [MIFBM / IgGBM] groups, optionally via a [CON] (including a [MULTICON] group), where the [Linker] may itself contain one or more [CON] or [MULTICON] groups; k' is an integer ranging from 1 to 15, e.g., ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or ranging from 1, 2, or 3; j' is an integer ranging from 1 to 15, e.g., ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or ranging from 1, 2, or 3; h and h' are each independently an integer in the range of 0 to 15, e.g., in the range of 1 to 15, in the range of 1 to 10, in the range of 1 to 5, in the range of 1 to 3, or in the range of 1, 2, or 3, optionally where h and / or h' are at least 1; i L is an integer ranging from 0 to 15, e.g., ranging from 1 to 15, ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or ranging from 1, 2, or 3, and optionally L is an integer ranging from 1 to 5, or 1, 2, or 3, where h, h', and i L At least one of is at least 1.

[0012] In some embodiments, [MIFBM] has the following chemical structure: A portion of TIFF2025509736000003.tif54140, wherein X M Ha-(CH2) IM , -O-(CH2) IM , S-(CH2) IM , N.R. M -(CH2) IM , C(O)-(CH2) IM -, a polyethylene glycol (PEG) group containing 1 to 8, e.g. 1 to 4, ethylene glycol residues, or -C(O)(CH2) IM NR M It is a base; R M is H or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups; IM is 0 to 6, for example 1, 2, 3, or 4, for example 1.

[0013] In some embodiments, the [IgGMB] has the following chemical structure: TIFF2025509736000004.tif16128 (wherein DNP is the 2,4-dinitrophenyl group) or The chemical structure below: TIFF2025509736000005.tif18128 (in the formula, Y' is H or NO2; X is O, CH2, NR 1 , S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; R1 is H, a C1-C3 alkyl group, or a -C(O)(C1-C3) group. or The chemical structure below: TIFF2025509736000006.tif30128 (in the formula, R 1 is the same as above; K'' is 1 to 5 (e.g., 3 to 5, e.g., 4) or The chemical formula: TIFF2025509736000007.tif30128 (in the formula, X' is CH2, O, NR 1 ', or S; R 1' is H or C1-C3 alkyl; Z is a sugar group selected from a bond, a monosaccharide, a disaccharide, an oligosaccharide, e.g., a monosaccharide, including aldoses and ketoses, and a disaccharide, including a disaccharide, as described herein. It is a group represented by the following formula: Examples of monosaccharide aldoses include monosaccharides such as aldotrioses (particularly D-glyceraldehyde), aldotetroses (particularly D-erythrose and D-threose), aldopentoses (particularly D-ribose, D-arabinose, D-xylose, and D-lyxose), and aldohexoses (particularly D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, and D-talose). Sugar ketoses include monosaccharides such as ketotrioses (particularly dihydroxyacetone), ketotetroses (particularly D-erythrulose), ketopentoses (particularly D-ribulose and D-xylulose), ketohexoses (particularly D-psicose, D-fructose, D-sorbose, D-tagatose), amino sugars (including, among others, galactosamine, sialic acid, N-acetylglucosamine), and sulfosugars (including, among others, sulfoquinovose).Exemplary disaccharides that find use in the present disclosure include sucrose (wherein the glucose may be N-acetylated), lactose (wherein the galactose and / or glucose may be N-acetylated), maltose (wherein one or both glucose residues may be N-acetylated), trehalose (wherein one or both glucose residues may be N-acetylated), cellobiose (wherein one or both glucose residues may be N-acetylated), kojibiose (wherein one or both glucose residues may be N-acetylated), nigerose (wherein one or both glucose residues may be N-acetylated), isomaltose (wherein one or both glucose residues may be N-acetylated), β,β-trehalose (wherein one or both glucose residues may be N-acetylated), sophorose (wherein one or both glucose residues may be N-acetylated), among others. glucose residues may be N-acetylated), laminaribiose (one or both glucose residues may be N-acetylated), gentiobiose (one or both glucose residues may be N-acetylated), turanose (the glucose residues may be N-acetylated), maltulose (the glucose residues may be N-acetylated), palatinose (the glucose residues may be N-acetylated), gentiobiose (the glucose residues may be N-acetylated), mannobiose, melibiose (the glucose and / or galactose residues may be N-acetylated), melibiulose (the galactose residues may be N-acetylated), rutinose (the glucose residues may be N-acetylated), rutinulose, and xylobiose.

[0014] In some embodiments, the [IgGBM] has the following chemical structure: TIFF2025509736000008.tif73128, wherein X R is O, S, or NR 1 and; X M O, NR1 , or S; R 1 is H or a C1-C3 alkyl group.

[0015] In some embodiments, [IgGBM] is The chemical structure below: TIFF2025509736000009.tif21128 (in the formula, X'' is O, CH2, NR 1 , S; R 1 is H, a C1-C3 alkyl group, or a -C(O)(C1-C3) group. ; or TIFF2025509736000010.tif19128 (in the formula, X b is a bond, O, CH2, NR 1 , or S; R 1 is the same as above) or The chemical structure below: TIFF2025509736000011.tif16128 (in the formula, R N02 is a dinitrophenyl group which may be linked through CH2, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O. or The chemical structure below: TIFF2025509736000012.tif13128(X is O, CH2, NR 1 , S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; R 1 is H, a C1-C3 alkyl group, or a -C(O)(C1-C3) group. is a dinitrophenyl group.

[0016] In some embodiments, [IgGBM] is The chemical structure below: TIFF2025509736000013.tif33128 (wherein K''' is 1 to 4 (e.g., 2 to 3, e.g., 3)) or A group of the chemical structure shown in Figure 67 herein, covalently bonded to a [CON] group, a [Linker] group, or an [ASGPRBM] group through an amine group, e.g., a primary or secondary alkylamine group, which may be substituted with a C1-C3 alkyl group at the amine group. It is.

[0017] In some embodiments, [IgGBM] is a peptide of the following sequence (all references cited are incorporated herein by reference): TIFF2025509736000014.tif223157TIFF2025509736000015.tif63144

[0018] In some embodiments, [ASGPRBM] has the following chemical structure: TIFF2025509736000016.tif25128, wherein X is 1 to 4 atoms in length, and If X is the length of one atom, X can be O, S, or N(R N1 ), or C(R N1 )(R N1 ) and If X is two atoms long, not more than one atom of X can be O, S, or N (R N1 ) and If X is 3 or 4 atoms long, then no more than two atoms of X are O, S, or N (R N1 ) Like, O, S, N(R N1 ), or C(R N1 )(R N1 ) groups; Here, R N1 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F (in some embodiments, R N1 is H or methyl); R1 and R3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K OC1-C4 alkyl, C1-C4 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups, -(CH2) K Vinyl, O-(CH2) K Vinyl, -(CH2) K Alkynyl, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R1 and R3 are each independently a C1-C4 alkyl group (each of which may be substituted with one to three halo groups, e.g., F, or one or two hydroxyl groups); or an O-C1-C4 alkyl group (each of which may be substituted with one to three halo groups, e.g., F, or one or two hydroxyl groups); K is independently an integer in the range of 0 to 4 (e.g., 0, 1, 2, 3, or 4); or R1 and R3 each independently represent the following chemical structure: TIFF2025509736000018.tif15128, wherein R 7 is O-C1-C4 alkyl optionally substituted with 1-3 halo groups, e.g., F, and 1 or 2 hydroxy groups; or R 7 Ha-NR N3 R N4 Group or TIFF2025509736000019.tif6128; or R1 and R3 each independently represent the following structure: Based on TIFF2025509736000020.tif34128, or TIFF2025509736000021.tif44128, wherein CYC is TIFF2025509736000022.tif32152, and C3-C8 saturated carbocyclic rings, wherein the linker X, R C , and -(CH2) K - is each bound to an open valency (including NH) in CYC; R C is absent, H, C1-C4 alkyl optionally substituted with 1-3 halo (e.g., F) groups or 1-2 hydroxyl groups, or the structure: TIFF2025509736000023.tif19128, wherein R4, R5, and R6 are each independently H, halo (F, Cl, Br, I), CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, I) groups K O-C1-C4 alkyl, C1-C3 alkyl optionally substituted with 1-3 halo (F, Cl, Br, I) groups, -O-C1-C3-alkyl optionally substituted with 1-3 halo groups, for example, F groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R C teeth TIFF2025509736000024.tif26162, Here, R N , R N1 , and R N2are each independently H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxyl groups; K is independently an integer ranging from 0 to 4 (0, 1, 2, 3, or 4); K' is an integer ranging from 1 to 4, for example, 1; R N3 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups; R N4 is H, a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups, or R N4 teeth TIFF2025509736000025.tif9128 group, where K may be 1; TIFF2025509736000026.tif6128 is a linker group comprising at least one [MIFBM / IgGBM] group and linking said [MIFBM / IgGBM] group to [ASGPRBM] through one or more optional [CON] groups; or TIFF2025509736000027.tif6128 is a linker group comprising at least one or more functional groups that can be used to covalently attach the linker group to at least one [MIFBM / IgGBM] group or an optional [CON] group; R2 is TIFF2025509736000028.tif17128 bases, where R N1 and K is the same as above; R AM is H, a C1-C4 alkyl group optionally substituted with up to three halo groups (e.g., F) and one or two hydroxyl groups, -(CH2) K COOH group, -(CH2) optionally substituted with 1 to 3 halo groups, such as F groups KC(O)O-C1-C4 alkyl group, OC(O)-C1-C4 alkyl group optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl group optionally substituted with 1 to 3 halo groups, for example F groups, -(CH2) K -NR N3 R N4 Group (where R N3 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups; R N4 is H, a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups, or R N4 teeth TIFF2025509736000029.tif9128 group (K may be 1), or R2 is TIFF2025509736000030.tif15128 group, During the ceremony, R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K OC1-C4 alkyl, C1-C4 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R TA is C3~C 10 an aryl group or a 3-10 membered heteroaryl group containing up to five heteroaryl atoms, each of which may contain up to three (e.g., one) of CN, NR N1 R N2, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K O-C1-C4 alkyl, C1-C3 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups or 1 or 2 hydroxy groups, -O-C1-C3-alkyl optionally substituted with 1-3 halo groups, for example F groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, such as F groups, or -(CH2) optionally substituted with 1 to 3 halo groups, such as F groups. K or may be substituted with C(O)-C1-C4 alkyl; R TA teeth TIFF2025509736000031.tif26162; or R TA is optionally substituted with up to three halo (e.g., F) groups, and is optionally substituted with up to three, e.g., one, C1-C3 alkyl group. TIFF2025509736000032.tif12128; or R TA teeth TIFF2025509736000033.tif28128 group, Here, R N , R N1 , and R N2 are each independently H or a C1-C3 alkyl group optionally substituted with 1 to 3 halo groups, e.g., F, or 1 or 2 hydroxyl groups; Each -(CH2) K The group is optionally substituted with 1 to 4, e.g. 1 or 2, C1-C3 alkyl groups, which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups; K is independently 0 to 4 (0, 1, 2, 3 or 4).

[0019] In some embodiments, [CON] is a connector moiety (including [MULTICON]) as described elsewhere herein.

[0020] In some embodiments, [linker] links the [MIFBM / IgGBM] to the [ASGPRBM] group and optionally includes one or more connector moieties (optionally connecting two or more chemical moieties to create a linking moiety or connecting a linking moiety to the [MIFBM / IgGBM] or [ASGPRBM] group), as described elsewhere herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0021] In some embodiments, If X is two atoms long, then X is -OC(R N1 )(R N1 ), C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 ), C(R N1 )(R N1 )-S-, N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X is 3 atoms long, then X is -OC(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(RN1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-, N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 ), N(R N1 )-C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X is four atoms long, then X is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1)-(R N1 )(R N1 )-、-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-、C(R N1 )(R N1 )-(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-、N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )、C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )、N(R N1 )-C(R N1 )(R N1 )-N(R N1 )、またはC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1), where R N1 is the same as above. In some embodiments, R N1 is H.

[0022] In some embodiments, X is OCH2 or CH2O. N1 is H.

[0023] In embodiments, the [ASGPRBM] group has the following chemical structure: TIFF2025509736000034.tif21128 (wherein R1, R2, and R3 are the same as above) or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0024] In some embodiments, the [ASGPRBM] group has the following chemical structure: TIFF2025509736000035.tif49162, wherein R A is a C1-C3 alkyl group optionally substituted with 1-5 halo (e.g., F) groups (in some embodiments, R A is a methyl group or an ethyl group optionally substituted with 1 to 3 fluoro groups; Z A Ha-(CH2) IM , -O-(CH2) IM , S-(CH2) IM , N.R. M -(CH2) IM , C(O)-(CH2) IM -, a PEG group containing 1 to 8, e.g. 1 to 4, ethylene glycol residues, or -C(O)(CH2) IM NR M group (in some embodiments, a PEG-containing group containing 1 to 8 ethylene glycol residues, e.g., 2 to 4 ethylene glycol residues), where I M and R M is the same as above; Z B is non-existent, (CH2) IM , C(O)-(CH2) IM- or C(O)-(CH2) IM -NR M where IM and R M is the same as above.

[0025] In some embodiments, R1 and R3 each independently have the following chemical structure: TIFF2025509736000036.tif22128, wherein R C , TIFF2025509736000037.tif6128, and K is the same as above.

[0026] In some embodiments, the compound is TIFF2025509736000038.tif44128 is TIFF2025509736000039.tif22128, where R C , TIFF2025509736000040.tif6128, and K is the same as above.

[0027] In some embodiments, the compounds include those depicted in Figures 1, 7, and 13. In some embodiments, additional compounds are depicted in Figures 16-66, including the final compounds depicted in these figures, as well as intermediates used to make the final compounds according to the present disclosure.

[0028] In some embodiments, R1 and R3 of the [ASGPRBM] group comprise the moieties shown in Figure 68 herein. In some embodiments, R2 of the [ASGPRBM] group comprises the moiety shown in Figure 69 herein.

[0029] In some embodiments, the IgGBM group has the following chemical structure: TIFF2025509736000041.tif72128 FCIII group (this is TIFF2025509736000042.tif26128), or The FcIII-4c peptide is represented as TIFF2025509736000043.tif25128.

[0030] In some aspects, the present disclosure relates to pharmaceutical compositions comprising an effective amount of a compound of the present disclosure in combination with a pharma- ceutically acceptable carrier, excipient, or vehicle, and optionally at least one additional bioactive agent.

[0031] In some aspects, the present disclosure relates to a method for treating a disease state or condition in which MIF is associated with or contributes to the disease state and / or condition, or to symptoms associated with the disease state or condition. These disease states and / or conditions include, among others, autoimmune diseases and numerous inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer's disease, atherosclerosis, heart disease, stroke, and cancer (including leukemia). In some embodiments, the treatment method comprises administering to a patient or subject in need of treatment an effective amount of at least one compound of the present disclosure, optionally in combination with an additional bioactive agent for removing MIF associated with the disease state and / or condition from the circulation of the patient or subject, thereby reducing the likelihood of, inhibiting, and / or treating the disease state or condition.

[0032] In experiments, the bifunctional molecule MIF-GN3 of the present disclosure was able to induce the degradation of human MIF injected into mice. Further studies will focus on evaluating MIF-GN3 in autoimmune disease models, as well as exploring the optimization of bifunctional MIF degraders using various MIF and ASGPr ligands. The IgG targeting molecule was able to reproduce our results with MIF in cell culture and mediated the removal of IgG from mouse serum. Thus, the present disclosure provides a useful platform for the development of novel therapeutic agents for these critical diseases. [Brief description of the drawings]

[0033] [Figure 1-1]Representative compounds of some embodiments are shown. Note that in the figure, compound 3w (negative control for MIF inhibition), MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1, MIF-AcF3-2, and MIF-AcF3-3 are disclosed. Note that n in the PEG linker is sometimes in the range of 1-12, for example, 1-10, 2-8, 2-6, 2-5, or 1, 2, 3, or 4. [Figure 1-2] See description of Figure 1-1. [Figure 1-3] See description of Figure 1-1. [Figure 1-4] See description of Figure 1-1. [Figure 1-5] See description of Figure 1-1. [Diagram 2] 1 shows fluorescence polarization data of MIF-FITC binding to human MIF, which indicates that our MIF binding moieties bind to MIF according to some embodiments. The bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3, and NVS-PEG3-GN3 competitively bound MIF-FITC, indicating that these bifunctional molecules maintain the ability to bind to human MIF. [Diagram 3] 1 shows that bifunctional molecules according to some embodiments are capable of depleting human MIF from the supernatant of cultured HepG2 cells. [Figure 4] 1 shows that, according to some embodiments, MIF internalized in HepG2 cells is transported to lysosomes. [Figure 5-1] According to some embodiments, MIF-GN3 mediates depletion of injected human MIF from mice. [Figure 5-2] See description of Figure 5-1. [Figure 5-3] See description of Figure 5-1. [Figure 6] According to some embodiments, it is shown that MIF-GN3 can slow tumor growth in a mouse model of prostate cancer. [Figure 7-1]1 shows the molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind to anti-DNP IgG and ASGPR, according to some embodiments. [Figure 7-2] See description of Figure 7-1. [Figure 8-1] FIG. 1 shows that, according to some embodiments, DNP-GN3 and DNP-AcF3-3 mediate the formation of a ternary complex between HepG2 cells and anti-DNP. [Figure 8-2] See description of Figure 8-1. [Figure 9-1] 1 shows that, according to some embodiments, DNP-GN3 and DNP-AcF3-3 mediate uptake of alexa 488-labeled anti-DNP by HepG2 cells. [Figure 9-2] See description of Figure 9-1. [Figure 10] FIG. 1 shows that, according to some embodiments, DNP-GN3 and DNP-AcF3-3 mediate localization of alexa 568-labeled anti-DNP to late endosomes and lysosomes. [Figure 11] FIG. 1 shows that, according to some embodiments, DNP-AcF3-3 mediates the degradation of alexa 488-labeled anti-DNP in HepG2 cells. [Figure 12] FIG. 1 shows that, according to some embodiments, DNP-GN3 mediates depletion of anti-DNP from mouse serum. [Figure 13-1] 1 shows the structures of IgG degrading molecules IBA-GN3, Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3, according to some embodiments. [Figure 13-2] See description of Figure 13-1. [Figure 13-3] See description of Figure 13-1. [Figure 14] According to some embodiments, FcIII-GN3 mediates the uptake of human IgG into HepG2 cells. The experiment was performed as described above. [Figure 15]According to some embodiments, FcIII-GN3 mediates localization of IgG to late endosomes in HepG2 cells. The experiment was performed as described above. [Figure 16] 1 shows the synthesis of a PEG linker used in some molecules according to some embodiments. [Figure 17] 1 shows the synthesis of a PEG linker used in some molecules according to some embodiments. [Figure 18] 1 shows the synthesis of a PEG linker used in some molecules according to some embodiments. [Figure 19] 1 shows the synthesis of ASGPR binding precursors and ligands used in several molecules according to several embodiments. [Figure 20] 1 shows the synthesis of ASGPR binding precursors and ligands used in several molecules according to several embodiments. [Figure 21] 1 shows the synthesis of ASGPR binding precursors and ligands used in several molecules according to several embodiments. [Figure 22] 1 shows the synthesis of valence linkers used in some molecules according to some embodiments. [Figure 23] 1 shows the synthesis of valence linkers used in some molecules according to some embodiments. [Figure 24] 1 shows the synthesis of valence linkers used in some molecules according to some embodiments. [Diagram 25] 1 shows the synthesis of valence linkers used in some molecules according to some embodiments. [Figure 26] 1 shows the synthesis of valence linkers used in some molecules according to some embodiments. [Figure 27] 1 shows the synthesis of MIF ligands used in several bifunctional molecules according to some embodiments. [Figure 28] 1 shows the synthesis of MIF ligands used in several bifunctional molecules according to some embodiments. [Figure 29]According to some embodiments, the synthesis of the bifunctional molecule MIF-NVS-PEG-GN3 is described. [Diagram 30] According to some embodiments, the synthesis of the bifunctional molecules MIF-GN3 and MIF-PEG-GN3 is described. [Diagram 31] According to some embodiments, the synthesis of bifunctional molecules targeting MIF and ASGPR, containing one bicyclic ASGPR AcF3 ligand, is described. [Diagram 32] According to some embodiments, the synthesis of a bifunctional molecule targeting MIF and ASGPR containing two bicyclic ASGPr AcF3 ligands is described. [Diagram 33] According to some embodiments, the synthesis of a bifunctional molecule targeting MIF and ASGPR containing three bicyclic ASGPr ligands is described. [Diagram 34] 1 shows the synthesis of DNP-GN3, according to some embodiments. [Diagram 35] 1 shows the synthesis of DNP-AcF3-3 according to some embodiments. [Diagram 36] 1 shows the synthetic scheme used to obtain IBA-GN3, according to some embodiments. [Figure 37-1] 1 shows the synthesis of triazine-GN3, according to some embodiments. [Figure 37-2] See description of Figure 37-1. [Figure 38-1] 1 shows the synthetic scheme used to obtain FcIII-GN3, according to some embodiments. [Figure 38-2] See description of Figure 38-1. [Figure 39] 1 shows the synthetic scheme used to obtain FcIII-4c-GN3, according to some embodiments. [Diagram 40] According to some embodiments, the synthesis of bifunctional molecules targeting MIF and ASGPr is described that contain three bicyclic ASGPR ligands in which the 2-amine of the sugar is differentially substituted. [Diagram 41]According to some embodiments, the synthesis of bifunctional molecules targeting MIF and ASGPr is described that contain three bicyclic ASGPR ligands in which the 2-amine of the sugar is differentially substituted. [Diagram 42] According to some embodiments, the synthesis of bifunctional molecules targeting MIF and ASGPr is described that contain three bicyclic ASGPR ligands in which the 2-amine of the sugar is differentially substituted. [Diagram 43] According to some embodiments, the synthesis of bifunctional molecules targeting MIF and ASGPr is described that contain three bicyclic ASGPR ligands in which the 2-amine of the sugar is differentially substituted. [Figure 44-1] 1 shows the synthesis of compound MIF-18-3, according to some embodiments. [Figure 44-2] See description of Figure 44-1. [Diagram 45] 1 shows the synthesis of compound MIF-31-3, according to some embodiments. [Figure 46-1] 1 shows the synthesis of compound MIF-15-3, according to some embodiments. [Figure 46-2] See description of Figure 46-1. [Figure 47-1] 1 shows the synthesis of compound MIF-19-3, according to some embodiments. [Figure 47-2] See description of Figure 47-1. [Figure 48-1] 1 shows the synthesis of compound MIF-16-3, according to some embodiments. [Figure 48-2] See description of Figure 48-1. [Figure 49-1] 1 shows the synthesis of compound MIF-20-3, according to some embodiments. [Figure 49-2] See description of Figure 49-1. [Figure 50-1] 1 shows the synthesis of compound MIF-14-3, according to some embodiments. [Figure 50-2] See description of Figure 50-1. [Figure 51-1] 1 shows the synthesis of compound MIF-21-3, according to some embodiments. [Figure 51-2]See description of Figure 51-1. [Figure 52-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 52-2] See description of Figure 52-1. [Figure 53-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 53-2] See description of Figure 53-1. [Figure 54-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 54-2] See description of Figure 54-1. [Figure 55-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 55-2] See description of Figure 55-1. [Figure 56-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 56-2] See description of Figure 56-1. [Figure 57-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 57-2] See description of Figure 57-1. [Figure 58-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 58-2] See description of Figure 58-1. [Figure 59-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 59-2] See description of Figure 59-1. [Figure 60-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 60-2] See description of Figure 60-1. [Figure 61-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 61-2] See description of Figure 61-1. [Figure 62-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 62-2] See description of Figure 62-1. [Figure 63-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 63-2] See description of Figure 63-1. [Figure 64-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 64-2] See description of Figure 64-1. [Figure 65-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 65-2] See description of Figure 65-1. [Figure 66-1] 1 shows the synthesis of several MIF binding compounds with various ASGPRBM moieties, according to some embodiments. [Figure 66-2] See description of Figure 66-1. [Figure 67-1] FIG. 1 shows exemplary IgGBM groups, each covalently attached to a [CON] group, a [LINKER] group, or an [ASGPRBM] group through an amine group, e.g., a primary or secondary alkylamine group, optionally substituted at the amine group with a C1-C3 alkyl group, according to some embodiments. [Figure 67-2] See description of Figure 67-1. [Figure 67-3] See description of Figure 67-1. [Figure 67-4] See description of Figure 67-1. [Figure 67-5] See description of Figure 67-1. [Figure 67-6] See description of Figure 67-1. [Figure 67-7] See description of Figure 67-1. [Figure 68-1] 1 shows exemplary R1 and R3 substituents on the ASGPRBM group according to some embodiments. [Figure 68-2] See description of Figure 68-1. [Figure 69] 1 shows exemplary R2 substituents on the ASGPRBM group, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description In some aspects, the present disclosure provides bifunctional molecules that utilize the intralysosomal machinery in the liver to clear MIF and / or IgG. In some embodiments, the present disclosure utilizes bifunctional molecules to target MIF or IgG, which is versatile and versatile. This is advantageous in applying medicinal chemistry to optimize these molecules. For example, preliminary experiments have shown that incorporating a more optimized ASGPr binding motif enhances the degradation of MIF or IgG in vitro. Since bifunctional molecules can degrade MIF or IgG, the MIF binding motif (MIFBM) or IgG binding moiety (IgGBM) do not need to be inhibitors, but in fact many of these binders function as inhibitors of MIF or IgG. The reality of this dual inhibitory effect opens the opportunity for the development of potent MIF or IgG binders that may have been previously ignored due to their inability to inhibit various PPIs. The small molecule approach of the present disclosure allows for simple, inexpensive, and consistent manufacturing practices compared to monoclonal antibodies, resulting in a therapeutic approach with fewer potential immunogenic side effects.

[0035] In some aspects, the present disclosure relates to bifunctional compounds used as drugs in the treatment of pathologies and / or conditions mediated through macrophage migration inhibitory factor (MIF) or immunoglobulin G (IgG). In some aspects, the present disclosure relates to pharmaceutical compositions comprising these bifunctional compounds, and methods for treating pathologies and / or conditions that are mediated through MIF or IgG or in which MIF and IgG are contributing factors in the development and perpetuation of diseases and / or conditions, including autoimmune diseases and cancers in particular. In some aspects, the present disclosure provides molecular strategies for lowering plasma MIF or IgG levels in patients with autoimmune diseases or certain types of cancer, and other diseases. The bifunctional molecular constructs are composed of a MIF targeting motif derived from a small molecule MIF ligand, or an IgG binding motif that binds IgG, and an ASGPr targeting motif that binds to the hepatocyte asialoglycoprotein receptor (ASGPr). The compounds selectively bind to MIF or IgG in plasma and subsequently engage the intralysosomal pathway of hepatocytes through the ASGPr. As a result, MIF or IgG is internalized and degraded by hepatocytes, thus potentially attenuating the corresponding disease symptoms regulated through MIF and / or IgG.

[0036] In accordance with some embodiments, conventional methods of chemical synthesis and pharmaceutical formulation are used, as well as techniques of pharmacology, molecular biology, microbiology, and recombinant DNA within the skill of the art, which are well known and fully explained elsewhere in the literature.

[0037] When a range of values ​​is given, it is understood that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that range, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms), is included within the disclosure. The upper and lower limits of these subranges may be independently included in the subranges, and are also included in the disclosure, provided that any limit in the range is specifically excluded. Where the range includes one or both limits, ranges excluding either or both included limits are also included in the disclosure.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice and testing of this disclosure, some exemplary methods and materials are described herein.

[0039] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," "and," and "the" include plural referents unless the context clearly dictates otherwise.

[0040] Additionally, the following terms are intended to have the definitions set forth below. If a particular term is not defined below, it will be understood that the term is intended to have the meaning normally associated with it within the context of one of ordinary skill in the art.

[0041] definition The term "compound" as used herein, unless otherwise indicated, refers to any specific compound disclosed herein, including its tautomers, positional isomers, geometric isomers, stereoisomers, and, where appropriate, its optical isomers (enantiomers), as well as its pharma- ceutically acceptable salts and derivatives (including prodrug forms). Within the context of use, the term compound generally refers to one compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. Within the context, the term also refers to prodrug forms of the compounds, modified to facilitate administration and delivery of the compounds to the active site. It should be noted that in describing the present compounds, numerous substituents, linkers, and connector molecules, as well as variables associated therewith, are specifically described. The use of the bond shown as TIFF2025509736000044.tif1128 means that a single bond may or may not be present, depending on the context of the chemical reaction being described, including the attachment of a bond to another moiety. The use of the bond shown as TIFF2025509736000045.tif2128 means that a single or double bond is intended, depending on the context of the chemical reaction being described.Those of skill in the art will appreciate that the molecules described herein are stable compounds, generally as described below.

[0042] The term "patient" or "subject" is used throughout the present specification within the context to describe an animal, generally a mammal, such as a human, to whom treatment, including prophylactic treatment (prophylactic, particularly when the term is used in relation to reducing the likelihood of metastasis of an existing cancer), with the compositions of the present disclosure is administered. With respect to the treatment of an infection, condition, or pathology specific to a particular animal, such as a human patient, or a patient of a particular gender, such as a human male or female patient, the term patient refers to that particular animal. The compounds of the present disclosure are useful in the treatment of numerous pathologies, including autoimmune disease pathologies and / or conditions, and inflammatory disease pathologies and / or conditions, as well as in the treatment of cancer, particularly including use in reducing the likelihood of cancer metastasis or recurrence.

[0043] The term "effective" is used herein, unless otherwise indicated, to describe the amount of a compound or composition used to produce or achieve a desired result, whether it is for inhibiting the effects of a condition on a subject (e.g., autoimmune diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among others, atherosclerosis, heart disease, or stroke, or cancer, including leukemia, among others), or for treating or preventing a subject from a secondary condition, condition, or symptom of a condition as described elsewhere herein. This term encompasses all other effective amount or concentration terms (including the term "therapeutically effective") as described elsewhere in this application.

[0044] As used herein, terms such as "treat", "treating" and "treatment" refer to the benefit of a patient at risk for a disease state or condition for which removal of MIF protein can be performed, e.g., autoimmune diseases, including in particular rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), atherosclerosis, heart disease, stroke, and cancer (including leukemia), including recurrence and / or metastasis of cancer, particularly amelioration of the condition through attenuation or inhibition of at least one symptom of the disease state or condition, reduction in one or more symptoms of the disease state (e.g., plaque), and / or reduction in the severity of the disease state or condition. "Preventive" refers to any action that prevents, reduces the likelihood of, or delays the progression of a disease state or condition or a symptom of the disease state or condition (including, in particular, plaque formation in atherosclerosis, tissue deterioration and inflammation in rheumatoid arthritis, further damage to cardiovascular tissue in heart disease, further damage to central nervous tissue in stroke, cancer, recurrence or metastasis of the cancer), or prevents or delays the onset of a disease state or condition secondary to the disease state or condition, including recurrence or metastasis of cancer. As used herein, treatment encompasses both prophylactic and therapeutic treatment, depending on the context of the treatment. When the term "prophylactic" is used, it means reducing the likelihood of onset or the severity of onset within the context of the treatment of a disease state or condition as described elsewhere above.

[0045] As used in this application, the terms "about" and "approximately" are used synonymously. Any numbers used in this application with or without "about" are intended to cover any normal variations that one of ordinary skill in the art would recognize.

[0046] The term "macrophage migration inhibitory factor binding moiety" or "MIFBM" refers to a chemical moiety at one end of a bifunctional compound of the present disclosure that can bind to a circulating MIF protein associated with or contributing to a disease state or condition as described elsewhere herein. In the present disclosure, MIFBM can bind to a circulating MIF protein, form a complex with the compound, and deliver the binding protein to a hepatocyte, where the other end of the bifunctional molecule containing an asialoglycoprotein receptor binding moiety (ASGPRBM) can be separately bound to the surface of the hepatocyte. When bound to a hepatocyte, the bifunctional molecule with the circulating protein bound thereto is internalized into the hepatocyte through an endocytic mechanism, whereupon the cell destroys the protein by lysosomal or other degradative pathways. The term "immunoglobulin G binding moiety" or "IgGBM" is used to describe a moiety that binds to circulating IgG immunoglobulins, thereby forming a complex with a bifunctional molecule of the present disclosure that is ultimately destroyed in the hepatocyte. In certain cases, the terms MIFBM and IgGBM are used interchangeably in describing the present disclosure.

[0047] Exemplary MIFBMs contained in the bifunctional compounds of the present disclosure include moieties found in the bifunctional chemical structure appearing in Figure 1 attached hereto. In some embodiments, the MIFBM has the following chemical structure: TIFF2025509736000046.tif54128, wherein X M Ha-(CH2) IM , -O-(CH2) IM , S-(CH2) IM , N.R. M -(CH2) IM , C(O)-(CH2) IM -, a PEG group containing 1 to 8, e.g. 1 to 4, ethylene glycol residues, or -C(O)(CH2) IM NR M It is a base; R M is H or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups; IM is 0 to 6, for example 1, 2, 3, or 4.

[0048] The term "asialoglycoprotein receptor binding moiety" ("ASGPRBM") refers to a binding moiety that binds to a hepatocyte asialoglycoprotein receptor. This binding moiety is also a component of the bifunctional compounds claimed herein that bind to the MIHBM moiety through a linker. ASGPRBM selectively binds to the hepatocyte asialoglycoprotein receptor on the surface of hepatocytes. It is through this moiety that the bifunctional compound that complexes with the circulating protein binds to the hepatocyte. Upon binding to the hepatocyte, the circulating MIF protein is taken up by the hepatocyte through the phagocytic mechanism where the circulating protein is degraded through lysosomal degradation.

[0049] Exemplary ASGPRBM groups for use in the compounds of the present disclosure include, inter alia, the following chemical structures: TIFF2025509736000047.tif21128, wherein X is 1 to 4 atoms in length, and If X is the length of one atom, X can be O, S, or N(R N1 ), or C(R N1 )(R N1 ) and If X is two atoms long, not more than one atom of X can be O, S, or N (R N1 ) and If X is 3 or 4 atoms long, then no more than two atoms of X are O, S, or N (R N1 ) Like, O, S, N(R N1 ), or C(R N1 )(R N1 ) groups; Here, R N1 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F (in some embodiments, R N1 is H or methyl); R1 and R3 are each independently H, -(CH2) KOH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K OC1-C4 alkyl, C1-C4 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups, -(CH2) K Vinyl, O-(CH2) K Vinyl, -(CH2) K Alkynyl, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R1 and R3 are each independently TIFF2025509736000048.tif9128 radicals (optionally substituted with up to three (e.g. one) halo groups (e.g. F)), C1-C4 alkyl groups (each of which may be substituted with one to three halo groups, e.g. F, or one or two hydroxyl groups), or O-C1-C4 alkyl groups (each of which may be substituted with one to three halo groups, e.g. F, or one or two hydroxyl groups), and K is independently an integer in the range of 0 to 4 (0, 1, 2, 3, or 4), or R1 and R3 each independently represent the following chemical structure: TIFF2025509736000049.tif15128, wherein R 7 is O-C1-C4 alkyl optionally substituted with 1-3 halo groups, e.g., F, and 1 or 2 hydroxy groups; or R 7 Ha-NR N3 R N4 Group or TIFF2025509736000050.tif7128; or R1 and R3 each independently represent the following structure: Based on TIFF2025509736000051.tif34128, or TIFF2025509736000052.tif44128, wherein CYC is TIFF2025509736000053.tif32152, and C3-C8 saturated carbocyclic rings, wherein the linkers X, R C , and -(CH2) K - is each bound to an open valency (including NH) in CYC; R C is absent, H, C1-C4 alkyl optionally substituted with 1-3 halo (e.g., fluoro) groups or 1-2 hydroxyl groups, or the following structure: TIFF2025509736000054.tif20128, wherein R4, R5, and R6 are each independently H, halo (F, Cl, Br, I), CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K O-C1-C4 alkyl, C1-C3 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups, -O-C1-C3-alkyl optionally substituted with 1-3 halo groups, for example F groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R C teeth TIFF2025509736000055.tif26162, Here, R N , R N1 , and R N2 are each independently H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxyl groups; K is independently an integer ranging from 0 to 4 (0, 1, 2, 3, or 4); K' is an integer ranging from 1 to 4, for example, 1; R N3 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups; R N4 is H, a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups, or R N4 teeth TIFF2025509736000056.tif9128 group, where K may be 1; TIFF2025509736000057.tif6128 is a linker group comprising at least one [MIFBM / IgGBM] group and linking said [MIFBM / IgGBM] group to [ASGPRBM] through one or more optional [CON] groups; or TIFF2025509736000058.tif6128 is a linker group, comprising at least one or more functional groups that can be used to covalently attach the linker group to at least one [MIFBM / IgGBM] group or an optional [CON] group; R2 is TIFF2025509736000059.tif17128 bases, where R N1 and K is the same as above; R AM is H, a C1-C4 alkyl group optionally substituted with up to three halo groups (e.g., F) and one or two hydroxyl groups, -(CH2) K COOH group, -(CH2) optionally substituted with 1 to 3 halo groups, such as F groups K C(O)O-C1-C4 alkyl group, OC(O)-C1-C4 alkyl group optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl group optionally substituted with 1 to 3 halo groups, for example F groups, -(CH2) K -NR N3 R N4 Group (where RN3 is H or a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups; R N4 is H, a C1-C3 alkyl group optionally substituted with 1-3 halo groups, e.g., F, or 1 or 2 hydroxy groups, or R N4 teeth TIFF2025509736000060.tif9128 group (K may be 1), or R2 is TIFF2025509736000061.tif15128 group, During the ceremony, R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups K OC1-C4 alkyl, C1-C4 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, -C(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, for example F groups, or R TA is C3~C 10 an aryl group or a 3-10 membered heteroaryl group containing up to five heteroaryl atoms, each of which may contain up to three (e.g., one) of CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo (F, Cl, Br, or I) groups KO-C1-C4 alkyl, C1-C3 alkyl optionally substituted with 1-3 halo (F, Cl, Br, or I) groups or 1 or 2 hydroxy groups, -O-C1-C3-alkyl optionally substituted with 1-3 halo groups, for example F groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 halo groups, e.g., F groups K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl optionally substituted with 1 to 3 halo groups, such as F groups, or -(CH2) optionally substituted with 1 to 3 halo groups, such as F groups. K or may be substituted with C(O)-C1-C4 alkyl; R TA teeth TIFF2025509736000062.tif26162 (in some embodiments, R TA is optionally substituted with up to three halo (e.g., F) groups, and is optionally substituted with up to three, e.g., one, C1-C3 alkyl group. TIFF2025509736000063.tif12128 or R TA teeth TIFF2025509736000064.tif29128 base), Here, R N , R N1 , and R N2 are each independently H or a C1-C3 alkyl group optionally substituted with 1 to 3 halo groups, e.g., F, or 1 or 2 hydroxyl groups; Each -(CH2) K The group is optionally substituted with 1 to 4, e.g. 1 or 2, C1-C3 alkyl groups, which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups; K is independently 0 to 4 (0, 1, 2, 3 or 4).

[0050] In some embodiments, [CON] is a connector moiety (including [MULTICON]) as described elsewhere herein.

[0051] In some embodiments, [linker] links the [MIFBM / IgGBM] to the [ASGPRBM] group and optionally includes one or more connector moieties (which optionally connect two or more chemical moieties to create a linking moiety or which connects a linking moiety to the [MIFBM / IgGBM] or [ASGPRBM] group), as described elsewhere herein, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0052] In some embodiments, If X is two atoms long, then X is -OC(R N1 )(R N1 ), C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 ), C(R N1 )(R N1 )-S-, N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X is 3 atoms long, then X is -OC(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1), C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-, N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 ), N(R N1 )-C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X is four atoms long, then X is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1 )-(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-OC(RN1 )(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-, N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 ), N(R N1 )-C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), where R N1 is the same as above. Most frequently, R N1 is H.

[0053] In some embodiments, X is OCH2 or CH2O. In some embodiments, R N1 is H.

[0054] In embodiments, the [ASGPRBM] group has the following chemical structure: TIFF2025509736000065.tif21128 (wherein R1, R2, and R3 are the same as above) or Pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof It is.

[0055] In embodiments, the [ASGPRBM] group has the following chemical structure: TIFF2025509736000066.tif49162, wherein R A is a C1-C3 alkyl group optionally substituted with 1-5 halo (e.g., fluoro) groups (in some embodiments, R A is a methyl group or an ethyl group optionally substituted with 1 to 3 fluoro groups; Z A Ha-(CH2) IM , -O-(CH2) IM , S-(CH2) IM , N.R. M -(CH2) IM , C(O)-(CH2) IM -, a polyethylene glycol (PEG) group containing 1 to 8, e.g. 1 to 4, ethylene glycol residues, or -C(O)(CH2) IM NR M group (e.g., a PEG-containing group containing 1 to 8 ethylene glycol residues, e.g., 2 to 4 ethylene glycol residues), where I M and R M is the same as above; Z B is non-existent, (CH2) IM , C(O)-(CH2) IM - or C(O)-(CH2) IM -NR Mwhere IM and R M is the same as above.

[0056] In some embodiments, the ASPGRM group above is represented as follows: TIFF2025509736000067.tif77128

[0057] Throughout the present specification, the term "neoplasia" or "cancer" is used to mean a pathological process that results in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation more rapidly than normal tissues and continue to grow even after the stimuli that initiated the new proliferation have ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues, and most often invade surrounding tissues, metastasize to several sites, likely recur after attempted removal, and likely cause the death of the patient if not treated appropriately. The term neoplasia, as used herein, is used to describe all cancerous pathologies and encompasses or includes the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Neoplasia includes, but is not limited to, morphological irregularities in cells in the tissues of a subject or host, and a proliferation of cells in the tissues of a subject that is pathological compared to normal proliferation in the same type of tissue. In addition, neoplasia includes benign and malignant tumors, which may be invasive or noninvasive (e.g., colon tumors). Malignant neoplasms (cancer) are distinguished from benign neoplasms in that the former exhibit a greater degree of anaplasia, or loss of cellular differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoplasias from which target cells of the present disclosure may be derived include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma); These include, but are not limited to, germ line tumors (e.g., intestinal, breast, prostate, cervical, uterine, lung, ovarian, testicular, thyroid, astrocytoma, esophageal, pancreatic, gastric, hepatic, colonic, and melanoma); mixed neoplasias, particularly carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratocarcinoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms are treatable using the compounds of the present disclosure.

[0058] Representative common cancers that may be treated with the compounds of the present disclosure include, for example, prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, renal cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, and lymphoma, among others, which may be treated with one or more compounds of the present disclosure. Because of the activity of the compounds, the disclosure is generally applicable to treating virtually any cancer in any tissue, and thus the compounds, compositions, and methods of the disclosure are generally applicable to the treatment of cancer, as well as to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0059] In certain aspects of the present disclosure, the cancer to be treated is metastatic cancer, recurrent cancer, or drug-resistant cancer (including drug-resistant cancer in particular).Apart from this, metastatic cancer can be found in virtually any tissue of cancer patients in late stage of disease, and usually metastatic cancer is found in virtually any tissue, including lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor).Therefore, the present disclosure is generally applicable and can be used to treat any cancer in any tissue, regardless of etiology.

[0060] The term "tumor" is used to describe a malignant or benign growth or tumour.

[0061] The term "autoimmune disease" refers to a disease or illness that occurs when the body's tissues are attacked by its own immune system. The immune system is a complex system within the body that is usually designed to "search and destroy" invaders to the body, including infectious agents. In diseases described as autoimmune diseases, MIF levels are often elevated. The present disclosure seeks to inhibit or reduce the elevation of MIF levels in patients with autoimmune diseases (as well as inflammatory diseases and conditions, and cancer), and to reduce MIF levels to ameliorate many of the symptoms and sequelae of these pathologies and conditions. Examples of autoimmune diseases that often exhibit high expression levels of MIF include, for example, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among others.

[0062] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of the disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutrophil leukemia, and autoimmune pulmonary fibrosis. Autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful adiposity, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatism, Parry-Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, related Rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barro concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis (pattern II), Oshtoran syndrome, Pediatric autoimmune streptococcal neuropsychiatric disorder (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sydenham chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Ligninous conjunctivitis, Mooren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease,Particularly including eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, and pyoderma gangrenosum.

[0063] The term "inflammatory disease" is used to describe diseases or conditions that involve acute, but often chronic, inflammation as a primary symptom of the disease or condition. Inflammatory diseases include neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias), immune response deficiency diseases that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis to combat damaging inflammation), chronic inflammatory diseases including, for example, inflammatory bowel diseases including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren's disease; Hyperglycemic disorders, diabetes mellitus (types I and II) that affect lipid metabolism and pancreatic islet function and / or structure, pancreatic β-cell death, and associated hyperglycemic disorders including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, leprechaunism, and lipoatrophic diabetes), as well as dyslipidemia (e.g., hyperlipidemia, high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), high triglycerides, as occurs in obese subjects) and metastases. In particular, the autoimmune syndrome, liver disease, kidney disease (apoptosis in plaque, glomerular disease), cardiovascular disease (including infarction, ischemia, stroke, pressure overload, and reperfusion complications), muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological signs (both central and peripheral), including stroke, age-related dementia, and sporadic Alzheimer's disease, as well as psychiatric conditions, including depression, stroke and spinal cord injury, arteriosclerosis.In these diseases, high MIF levels are often observed, and therefore these pathologies and / or conditions respond to treatment using the compounds and / or pharmaceutical compositions of the present disclosure.It should be noted that there is some overlap between certain autoimmune and inflammatory diseases described herein.

[0064] The term "linker" refers to a chemical entity comprising a composite linker that connects an asialoglycoprotein receptor binding moiety (ASGPRBM) to a macrophage migration inhibitory factor binding moiety (MIFBM) through a covalent bond in the compounds of the present disclosure, optionally through at least one (e.g., one or two) connector moiety [CON]. The linker between the two active portions of the molecule, i.e., between the MIFBM and the ASGPRBM, ranges from about 5 Å to about 50 Å or more in length, from about 6 Å to about 45 Å in length, from about 7 Å to about 40 Å in length, from about 8 Å to about 35 Å in length, from about 9 Å to about 30 Å in length, from about 10 Å to about 25 Å in length, from about 7 Å to about 20 Å in length, from about 5 Å to about 16 Å in length, from about 5 Å to about 15 Å in length, from about 6 Å to about 14 Å in length, from about 10 Å to about 20 Å in length, from about 11 Å to about 25 Å in length, etc. Linkers based on ethylene glycol units and having lengths of 2-15 glycol units, 1-8 glycol units, 1, 2, 3, 4, 5, and 6 glycol units may be used, although the length of a particular linker may be much greater. Linkers having lengths as otherwise disclosed herein may be obtained to position the MIFBM and ASGPRBM groups to advantageously exploit the biological activity of the disclosed compounds binding to the asialoglycoprotein receptor on hepatocytes, thereby causing selective and targeted degradation of MIF circulating protein within the lysosomal or other degradation machinery of hepatocytes. The selection of linker components is based on literature-described properties such as biocompatibility, solubility in aqueous and organic media, and low immunogenicity / antigenicity. Although numerous linkers can be used as described elsewhere herein, linkers based on polyethylene glycol (PEG) linkages, polypropylene glycol linkages, or polyethylene glycol-co-polypropylene oligomers (up to about 100 units, about 1-100, about 1-75, about 1-60, about 1-50, about 1-35, about 1-25, about 1-20, about 1-15, 2-10, about 4-12, about 1-8, 1-3, 1-4, 2-6, 1-5 units, etc.) may be preferred as linkers due to the chemical and biological properties of these molecules. Polyethylene (PEG) linkages of 2-15 ethylene glycol units are sometimes used.When describing linkers of the present disclosure that include polyethylene glycol linkers or other linkers, one or more additional groups (e.g., methylene groups, amide groups, keto groups, amine groups, etc.) may be covalently attached at either end of the linker group to bond to an ASGPRBM group, a [CON] group, another linker group, or a CPBM group.

[0065] Alternative linkers can include, for example, polyamino acid linkers of up to 100 amino acids (of any type, e.g., D- or L-amino acids, e.g., natural L-amino acids) in length (about 1-75, about 1-60, about 1-50, about 1-45, about 1-35, about 1-25, about 1-20, about 1-15, 2-10, about 4-12, about 5-10, about 4-6, about 1-8, about 1-6, about 1-5, about 1-4, about 1-3, etc. in length), optionally including one or more connecting groups (e.g., one or two connecting groups at one or both ends of the polyamino acid linker).

[0066] Exemplary linkers include those having the following chemical structures: Linker for TIFF2025509736000068.tif25133; or polypropylene glycol or polypropylene-co-polyethylene glycol linkers having 1 to 100, for example, about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10, about 4 to 6, about 1 to 8, about 1 to 6, about 1 to 5, about 1 to 4, or about 1 to 3 alkylene glycol units; Here, R a is H, C1-C3 alkyl or alkanol, or R 3 (proline) forms a cyclic ring, and R 3are, for example, alanine (methyl), arginine (propylene guanidine), asparagine (methylene carboxamide), aspartic acid (ethanoic acid), cysteine ​​(thiol, reduced or oxidized di-thiol), glutamine (ethyl carboxamide), glutamic acid (propanoic acid), glycine (H), histidine (methylene imidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butylene amine), methionine (ethyl methyl thioether), phenylalanine (benzyl), proline hydroxyproline (R 3 is R a and the adjacent nitrogen groups form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methylene indole), tyrosine (methylene phenol), or valine (isopropyl); m (within the context of this use) is an integer from 1 to 100, e.g., 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5.

[0067] Other exemplary linkers include polyethylene glycol linkers comprising 1-1-100, e.g., 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5 ethylene glycol units attached to a lysine group or other amino acid moiety (which may consist of 1-10 amino acids capable of binding to a MIFBM and / or ASGPRBM group) at one or both ends of the linker. Still other linkers include amino acid residues (D or L) attached to a MIFBM and / or ASGPRBM moiety as described elsewhere herein. In other embodiments, as described elsewhere herein, the amino acid has 1-15 methylene groups separating the amino group from the acid (acyl) group to create a linker to the MIFBM and / or ASGPRBM groups, where the linker includes 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5 amino acid groups linked together through peptide bonds to form the linker, which has the following chemical structure: TIFF2025509736000069.tif23128, wherein: R am is H or C1-C3 alkyl optionally substituted with 1 or 2 hydroxyl groups; na is an integer ranging from 1 to 15, e.g., 1 to 12, 1 to 10, 1 to 8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; m is an integer ranging from 1 to 100, for example, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5.

[0068] Alternatively, the alternative linker has the formula: TIFF2025509736000070.tif7128, wherein Z and Z' are each independently a bond, -(CH2) i -O, -(CH2) i -S, -(CH2) i -NR, TIFF2025509736000071.tif16154; Here, the -(CH2) i The group, when present in Z or Z', is attached to a connector (CON), MIFBM, or ASGPRBM; each R is H, or a C1-C3 alkyl or alkanol group; Each R 2 are independently H or a C1-C3 alkyl group; each Y is independently a bond, O, S, or NR; each i is independently an integer ranging from 0 to 100, e.g., from 0 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 0, 1, 2, 3, 4, or 5; D is TIFF2025509736000072.tif56128 or a bond, with the proviso that Z, Z', and D are not each simultaneously a bond; j is an integer ranging from 1 to 100, e.g., 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5; m' is an integer ranging from 1 to 100, e.g., 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5; n is an integer ranging from 1 to 100, e.g., 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5; X 1 is O, S, or NR; R is H, or a C1-C3 alkyl or alkanol group, or a pharmaceutical salt thereof.

[0069] Other linkers included herein include those having the following chemical structure: TIFF2025509736000073.tif17128, wherein n and n' are each independently an integer ranging from 1 to 25, e.g., from 1 to 15, from 1 to 12, from 2 to 11, from 2 to 10, from 2 to 8, from 2 to 6, from 2 to 5, from 2 to 4, and from 2 to 3, or from 1, 2, 3, 4, 5, 6, 7, or 8; Each n'' is independently an integer ranging from 0 to 8, for example, from 1 to 7, or 1, 2, 3, 4, 5, or 6.

[0070] The linker may comprise two or more linker segments (based on the linkers described above) that are either directly bonded to each other or bonded via [CON] groups to form a composite linker. Particular linkers that include a [CON] group (particularly a diamide [CON] group as described elsewhere herein) connecting a first linker group to a second (PEG) linker group have the structure: TIFF2025509736000074.tif37128, wherein n and n' are each independently an integer ranging from 1 to 25, e.g., from 1 to 15, from 1 to 12, from 2 to 11, from 2 to 10, from 2 to 8, from 2 to 6, from 2 to 5, from 2 to 4, and from 2 to 3, or from 1, 2, 3, 4, 5, 6, 7, or 8; Each n'' is independently an integer ranging from 0 to 8, e.g., 1 to 7, or 1, 2, 3, 4, 5, or 6. Note that each of these linkers may contain an alkylene group containing 1 to 4 methylene groups at the distal end of the linker group to facilitate attachment of each linker group.

[0071] Other linkers containing a connector group [CON] have the formula: PEG-[CON]-PEG wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and [CON] is a connector group as described elsewhere herein, e.g., a triazole group. The file is TIFF2025509736000075.tif16128.

[0072] The term "connector," represented in the general formula by the symbols "CON" or [CON], is used to describe a chemical moiety that may be included in a bifunctional compound of the present disclosure, formed from the reaction product of an activated linker with a MIFBM moiety (sometimes also activated to covalently bond the linker to the moiety), or the reaction product of an ASGPRBM group with an activated linker. In many cases, the connector group is the result of the facile condensation of two or more separate chemical fragments that contain reactive groups that can give rise to a connector group as described elsewhere to produce a bifunctional or polyfunctional compound of the present disclosure. It should be noted that while connectors can be distinguished from linkers in that the connector is the result of the specific chemical reactions used to produce the bifunctional compounds of the present disclosure, and the reaction products of these groups result in a identifiable connector group, or a portion of a connector group that is distinguishable from the linker group, in certain cases, the connector group is incorporated into and integral with the linker group, as described elsewhere herein. It should also be noted that a connector group may be linked to several linkers to create multifunctionality (i.e., more than one CPBM moiety and / or more than one ASGPRBM / FCRNBM moiety) within the same molecule. It should also be noted that there may be some overlap between the descriptions of connector groups and linker groups, where the connector group is actually incorporated into or forms part of the linker, particularly with respect to relatively common connector groups such as amide groups, oxygen (ether) linkages, sulfur (thioether) linkages, or amine linkages, urea groups, or carbonate -OC(O)O- groups, or groups as described elsewhere herein. Additionally, the symbol Note that at positions depicted as being linked to another group using TIFF2025509736000076.tif11128, a connector (or linker) may be attached to the MIFBM, ASGPRBM, or linker.

[0073] When more than one of the above groups is present in a linker or connector, either the ASGPRBM, the linker, or the MIFBM may be attached to the above group. When that symbol is not used, the linker may be present at one or more positions in a moiety.

[0074] Common connector groups used in this disclosure include the following chemical groups: TIFF2025509736000077.tif86143 (in the formula, R CON1 and R CON2 are each independently H, methyl, or a bond (for attachment to another moiety); or the following structure: TIFF2025509736000078.tif18128 containing a diamide group, During the ceremony, X 2 are CH2, O, S, and NR 4 , C(O), S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; X 3 O, S, NR 4 and; R 4 is H, a C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group; R1 is H or a C1-C3 alkyl group; n'' is independently an integer ranging from 0 to 8, e.g., from 1 to 7, or 1, 2, 3, 4, 5, or 6; Alternatively, the connector group [CON] has the following chemical structure: TIFF2025509736000079.tif18128, wherein R 1CON , R 2CON , and R 3CONare each independently H, -(CH2) MC1 , -(CH2) MC1a C(O) XA (NR 4 ) XA -(CH2) MC1a , -(CH2) MC1a (NR 4 ) XA C(O) XA -(CH2) MC1a , or -(CH2) MC1a O-(CH2) MC1 -C(O)NR 4 -, where R 1CON , R 2CON , and R 3CON but not simultaneously H; each MC1 is independently an integer ranging from 1 to 4, e.g., 1 or 2; each MC1a is independently an integer ranging from 0 to 4, e.g., 0, 1, or 2; R 4 is H, a C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group.

[0075] The triazole group shown above is one example of a connector group. Further exemplary connector groups are TIFF2025509736000080.tif36128, which is linked to at least one MIFBM and / or at least one ASPRGBM (e.g., three ASPRGBM moieties). This connector group can be used to form GN3.

[0076] Note that each connector can be extended with one or more methylene groups to facilitate connection to a linker group, another CON group, a MIFBM group, or an ASGPRBM. Note that in certain cases, and within circumstances, the diamide group may independently function as a linker group.

[0077] Further galactose- and talose-based ASGPR binding moieties In certain aspects, the disclosure relates to compounds of the general chemical structure of Formula II that are useful for clearing circulating proteins associated with a disease state or condition in a patient or subject. TIFF2025509736000081.tif19128

[0078] As used herein, the term "extracellular protein targeting ligand" is used interchangeably with the term CPBM (cellular protein binding moiety). As used herein, the term "ASGPR ligand" is used interchangeably with the asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0079] In compounds of formula II, each [CON] is an optional connector chemical moiety, which, if present, is either directly connected to a [CPBM] or a [CRBM] or connects a [Linker-2] to a [CPBM] or a [CRBM].

[0080] In the compound of formula II, [Linker-2] is a chemical moiety having a valence of 1-15 that is covalently attached to one or more [CRBM] and / or [CPBM] groups through [CON], optionally containing a [MULTICON] group, where said [Linker-2] may itself contain one or more [CON] or [MULTICON] groups; k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer of 0 to 15; i L is an integer from 0 to 15, where h, h', and i L at least one of is at least 1, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0081] [MULTICON] groups may connect one or more [CRBM]s or [CPBM]s to one or more [Linker-2]s. In various embodiments, [Linker-2] has a valence of 1-10. In various embodiments, [Linker-2] has a valence of 1-5. In various embodiments, [Linker-2] has a valence of 1, 2, or 3. In various embodiments, in compounds of formula II, [Linker-2] may be one or more linkers as defined herein. A , Linker B , Linker C , Linker D , and / or combinations thereof.

[0082] In compounds of formula II, xx is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0083] In compounds of Formula II, yy is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0084] In compounds of formula II, zz is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0085] In the compound of formula II, X 1 is O, S, N(R b ), and C(R 4 )(R 4 ) 1 to 5 adjacent atoms independently selected from 1 If is one atom, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 If there are two atoms, X 1Not more than one atom of 6 ) and X 1 If X has 3, 4, or 5 atoms, 1 Up to two atoms of are O, S, or N(R 6 ) and; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 More selected; R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 More selected; R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0086] A. Galactose-Based ASGPR-Binding Cell Receptor Binding Moieties of Formula II In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000082.tif69128TIFF2025509736000083.tif229123TIFF2025 509736000084.tif222123TIFF2025509736000085.tif216117TIFF20255097360 00086.tif223116TIFF2025509736000087.tif155128TIFF2025509736000088.t if233122TIFF2025509736000089.tif102135TIFF2025509736000090.tif144128 TIFF2025509736000091.tif149128TIFF2025509736000092.tif163132TIFF202 5509736000093.tif176137TIFF2025509736000094.tif161128TIFF20255097360 00095.tif175141TIFF2025509736000096.tif213111TIFF2025509736000097.t if186128TIFF2025509736000098.tif184128TIFF2025509736000099.tif137128

[0087] In certain embodiments, the compound of formula II has one of the following structures: TIFF2025509736000100.tif124128

[0088] In various embodiments, the ASGPR ligand is reacted with C to form a decomposition compound. 1 or C 5 (R 1 or R 5 In various embodiments, the ASGPR ligand is linked at the C 6 For example, the ASGPR ligand is TIFF2025509736000101.tif18128, non-limiting examples of ASGPR binding compounds of formula II include TIFF2025509736000102.tif55128, or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives bound to the linker moiety.

[0089] In any embodiment herein in which an ASGPR ligand is selected for use in a degradation agent, the ASGPR ligand is typically linked to an extracellular protein targeting ligand. 5 At the position (e.g., adjacent C 6 The linker and the extracellular protein targeting ligand are linked via a C 1 When attached through a position, the carbon is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group.

[0090] In various embodiments, the ASGPR ligand is C 3 C rank 4 The ASGPR ligands are not linked at any of the positions listed above, since these positions chelate with calcium for ASGPR binding in the liver. In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are selected from the following: TIFF2025509736000103.tif74128TIFF2025509736000104.tif146131TIFF2025509736000105.tif216123 TIFF2025509736000106.tif236135TIFF2025509736000107.tif232137TIFF2025509736000108.tif168139 TIFF2025509736000109.tif197133TIFF2025509736000110.tif189134TIFF2025509736000111.tif159132 TIFF2025509736000112.tif169128TIFF2025509736000113.tif171137TIFF2025509736000114.tif142139

[0091] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000115.tif47128TIFF2025509736000116.tif153141TIFF20255097360 00117.tif96139TIFF2025509736000118.tif206125TIFF2025509736000119.tif132128

[0092] B. Talc-based ASGPR-binding cell receptor binding moieties of formula II In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000120.tif74128TIFF2025509736000121.tif205112TIFF2025509736000122.tif186128TIFF2025509736000123.tif199104TIFF2025509736000124.tif199102TIFF2025509736000125.tif158128TIFF2025509736000126.tif202123TIFF2025509736000127.tif20799TIFF2025509736000128.tif233122TIFF2025509736000129.tif170128TIFF2025509736000130.tif219117TIFF2025509736000131.tif174128TIFF2025509736000132.tif108128TIFF2025509736000133.tif145140TIFF2025509736000134.tif149140TIFF2025509736000135.tif219145TIFF2025509736000136.tif109135TIFF2025509736000137.tif235143TIFF2025509736000138.tif233134TIFF2025509736000139.tif24494TIFF2025509736000140.tif226117TIFF2025509736000141.tif230134TIFF2025509736000142.tif197119TIFF2025509736000143.tif210126TIFF2025509736000144.tif193125TIFF2025509736000145.tif242130TIFF2025509736000146.tif137131TIFF2025509736000147.tif182128TIFF2025509736000148.tif181128TIFF2025509736000149.tif217105TIFF2025509736000150.tif228106TIFF2025509736000151.tif140128TIFF2025509736000152.tif171128TIFF2025509736000153.tif171128TIFF2025509736000154.tif184128TIFF202550 9736000155.tif161128TIFF2025509736000156.tif157128TIFF2025509736000157.tif74128.

[0093] In certain embodiments, the compound of formula II is an extracellular proteolytic compound, where the ASGPR ligand is a ligand described herein. TIFF2025509736000158.tif55128

[0094] In certain embodiments, in the compound of formula II, the ASGPR ligand is a C1 or C5 (R 1 or R 5 In certain embodiments, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is TIFF2025509736000159.tif18128, non-limiting examples of ASGPR binding compounds of formula II include TIFF2025509736000160.tif120128, or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives attached to the linker moiety. In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000161.tif159128 wherein, in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0095] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000162.tif152128TIFF2025509736000163.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0096] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000164.tif152128TIFF2025509736000165.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0097] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000166.tif152128TIFF2025509736000167.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0098] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000168.tif152128TIFF2025509736000169.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0099] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000170.tif152128TIFF2025509736000171.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0100] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000172.tif152128TIFF2025509736000173.tif159128In certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0101] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000174.tif152128TIFF2025509736000175.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0102] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000176.tif166128TIFF2025509736000177.tif159128In certain embodiments, R 2 Ha-NR b COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0103] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000178.tif166128TIFF2025509736000179.tif159128TIFF2025509736000180.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0104] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000181.tif166128TIFF2025509736000182.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0105] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000183.tif166128TIFF2025509736000184.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0106] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000185.tif166128TIFF2025509736000186.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0107] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000187.tif166128TIFF2025509736000188.tif159128In certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0108] In certain embodiments, the compound of formula II is selected from the following: TIFF2025509736000189.tif166128TIFF2025509736000190.tif179128TIFF2025509736000191.t if218128TIFF2025509736000192.tif218122TIFF2025509736000193.tif216125TIFF2025509736 000194.tif179128TIFF2025509736000195.tif218122TIFF2025509736000196.tif219122TIFF20 25509736000197.tif221122TIFF2025509736000198.tif213142TIFF2025509736000199.tif79137

[0109] In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are selected from the following: TIFF2025509736000200.tif65131TIFF2025509736000201.tif165135TIFF2025509736000202.tif123135TIFF2025 509736000203.tif172132TIFF2025509736000204.tif146128TIFF2025509736000205.tif176137TIFF20255097360 00206.tif152140TIFF2025509736000207.tif209117TIFF2025509736000208.tif206140TIFF2025509736000209.t if236136TIFF2025509736000210.tif67128TIFF2025509736000211.tif169134TIFF2025509736000212.tif216138

[0110] C. ASGPR Ligand / Binding Moieties in Compounds of Formula II In certain embodiments, in the compound of formula II, R 1 is hydrogen.

[0111] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000213.tif6128.

[0112] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000214.tif6128.

[0113] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000215.tif6128.

[0114] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000216.tif6128.

[0115] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000217.tif6128.

[0116] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509736000218.tif6128.

[0117] In certain embodiments, in the compound of formula II, R 1 is a C0-C6 alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.

[0118] In certain embodiments, in the compound of formula II, R 1 is alkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0119] In certain embodiments, in the compound of formula II, R 1 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is haloalkyl, optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is F.

[0120] In certain embodiments, in the compound of formula II, R 1 is Cl.

[0121] In certain embodiments, in the compound of formula II, R 1 is Br.

[0122] In certain embodiments, in the compound of formula II, R 1is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0123] In certain embodiments, in the compound of formula II, R 1 is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0124] In certain embodiments, in the compound of formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0125] In certain embodiments, in the compound of formula II, R 1 is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0126] In certain embodiments, in the compound of formula II, R 1 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0127] In certain embodiments, in the compound of formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0128] In certain embodiments, in the compound of formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.

[0129] In certain embodiments, in the compound of formula II, R 1 -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6 , C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R 3, C0-C6 alkyl-S(O)2R 3 , C0-C6 alkyl-N(R 8 )-C(O)R 3 , C0-C6 alkyl-N(R 8 )-S(O)R 3 , C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-OC(O)R 3 , C0-C6 alkyl-OS(O)R 3 , C0-C6 alkyl-OC(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkylN3, or C0-C6 alkyl-OS(O)2R 3 each of which is optionally substituted with 1, 2, 3, or 4 substituents.

[0130] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0131] In certain embodiments, in the compound of formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0132] In certain embodiments, in the compound of formula II, R 2 is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, 3, or 4 substituents.

[0133] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509736000219.tif40128.

[0134] In certain embodiments, in the compound of formula II, R 2is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0135] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)-R 3 It is.

[0136] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(S)-R 3 It is.

[0137] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)(NR 6 )-R 3 It is.

[0138] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with one, two, three or four substituents -N=S(O)(R 3 )2.

[0139] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 C(O)NR 9 S(O)2R 3 It is.

[0140] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)2-R 10 It is.

[0141] In certain embodiments, in the compound of formula II, R 2is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(NR 6 )-R 3 It is.

[0142] In certain embodiments, in the compound of formula II, R 2 is hydrogen.

[0143] In certain embodiments, in the compound of formula II, R 2 is R 10 It is.

[0144] In certain embodiments, in the compound of formula II, R 2 is alkyl-C(O)-R 3 It is.

[0145] In certain embodiments, in the compound of formula II, R 2 -C(O)-R 3 It is.

[0146] In certain embodiments, in the compound of formula II, R 2 is alkyl.

[0147] In certain embodiments, in the compound of formula II, R 2 is haloalkyl.

[0148] In certain embodiments, in the compound of formula II, R 2 HA-OC(O)R 3 It is.

[0149] In certain embodiments, in the compound of formula II, R 2 Ha-NR 8 -C(O)R 10 It is.

[0150] In certain embodiments, in the compound of formula II, R 2 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0151] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0152] In certain embodiments, in the compound of formula II, R 2 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0153] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkenyl.

[0154] In certain embodiments, in the compound of formula II, R 2 is --O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0155] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkynyl.

[0156] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -heteroaryl.

[0157] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -aryl.

[0158] In certain embodiments, in the compound of formula II, R 2 is --O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0159] In certain embodiments, in the compound of formula II, R2 is --O-aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0160] In certain embodiments, in the compound of formula II, R 2 is --O-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0161] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000220.tif11128

[0162] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000221.tif18139

[0163] In certain embodiments, in the compound of formula II, R 2 is selected from: TIFF2025509736000222.tif106135 where R is an optional substituent as defined herein.

[0164] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000223.tif45128

[0165] In certain embodiments, in the compound of formula II, R 2A is selected from: TIFF2025509736000224.tif108135 where R is an optional substituent as defined herein.

[0166] In certain embodiments, in the compound of formula II, R 2A is selected from the following: TIFF2025509736000225.tif47128

[0167] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000226.tif151136

[0168] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000227.tif146149

[0169] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000228.tif9128

[0170] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000229.tif9128

[0171] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000230.tif41128

[0172] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000231.tif41128

[0173] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000232.tif19128

[0174] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000233.tif15128

[0175] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000234.tif45128

[0176] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000235.tif45128

[0177] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000236.tif12128

[0178] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000237.tif12128

[0179] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000238.tif41129

[0180] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000239.tif38137

[0181] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000240.tif62128

[0182] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000241.tif62128

[0183] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000242.tif34128

[0184] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000243.tif34128

[0185] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000244.tif75128

[0186] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000245.tif75128

[0187] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000246.tif23128

[0188] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000247.tif23128

[0189] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000248.tif23128

[0190] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000249.tif24128

[0191] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000250.tif19128

[0192] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000251.tif19128

[0193] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000252.tif21128

[0194] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000253.tif21128

[0195] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000254.tif99131

[0196] In certain embodiments, in the compound of formula II, R 2 or R 2A is selected from the following: TIFF2025509736000255.tif104128

[0197] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000256.tif28128

[0198] In certain embodiments, in the compound of formula II, R 2is selected from the following: TIFF2025509736000257.tif28128

[0199] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000258.tif10128

[0200] In certain embodiments, in the compound of formula II, R 2 is selected from the following: TIFF2025509736000259.tif10128

[0201] In certain embodiments, in the compound of formula II, R 2 is selected from the following:

[0202] In certain embodiments, in the compound of formula II, R 2 is a spirocyclic heterocycle, e.g. TIFF2025509736000260.tif12128 but not limited to it.

[0203] In certain embodiments, in the compound of formula II, R 2 is a silicon-containing heterocycle, e.g. TIFF2025509736000261.tif15128 but not limited to it.

[0204] In certain embodiments, in the compound of formula II, R 2 is replaced by SF5, e.g. TIFF2025509736000262.tif22128 but not limited to it.

[0205] In certain embodiments, in the compound of formula II, R 2 is substituted with sulfoxime, e.g. TIFF2025509736000263.tif22128 but not limited to it.

[0206] In certain embodiments, in the compound of formula II, R 10 is selected from bicyclic heterocycles.

[0207] In certain embodiments, in the compound of formula II, R 10 is selected from spirocyclic heterocycles.

[0208] In certain embodiments, in the compound of formula II, R 10 Ha-NR 6 -heterocycles.

[0209] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2025509736000264.tif13128

[0210] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2025509736000265.tif41128

[0211] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2025509736000266.tif19128

[0212] In certain embodiments, in the compound of formula II, R 10 is selected from the following: TIFF2025509736000267.tif32128

[0213] In certain embodiments, in the compound of formula II, the ring is selected from the following: TIFF2025509736000268.tif137137

[0214] In certain embodiments, in the compound of formula II, R 30 is selected from the following: TIFF2025509736000269.tif34135

[0215] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000270.tif14128.

[0216] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000271.tif12128.

[0217] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000272.tif14128.

[0218] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000273.tif12128.

[0219] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000274.tif14128.

[0220] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000275.tif14128.

[0221] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000276.tif14128.

[0222] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000277.tif14128.

[0223] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000278.tif12128.

[0224] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000279.tif12128.

[0225] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000280.tif12128.

[0226] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509736000281.tif12128.

[0227] Linker In a non-limiting embodiment, in the compound of formula II, the linker A and linker B are independently selected from: TIFF2025509736000282.tif10128 formula, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 represents independently at each occurrence a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-, -P(O)(R 3 )O-, -P(O)(R 3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, and heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -, -[-(CH2)2-O-] n -, -[O-(CH2)2] n -, -[O-CH(CH3)C(O)] n -, -[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -, -[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or dicarboxylic acid; each of which is selected from the group consisting of R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 represents independently at each occurrence hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl, and heterocycle; The remaining variables are as defined herein.

[0228] In certain embodiments, in the compound of formula II, the linker A is a bond and a linker B teeth The file is TIFF2025509736000283.tif10128.

[0229] In certain embodiments, in the compound of formula II, the linker B is a bond and a linker A teeth The file is TIFF2025509736000284.tif10128.

[0230] In certain embodiments, in the compound of formula II, the divalent residue of an amino acid is selected from the following: TIFF2025509736000285.tif194142 where the amino acids can be oriented in either direction and the amino acids can be in the L- or D-form, or a mixture thereof.

[0231] In certain embodiments, in the compound of formula II, the divalent residue of a dicarboxylic acid is capable of undergoing a nucleophilic addition reaction: Generated by TIFF2025509736000286.tif20128.

[0232] Non-limiting examples of divalent residues of dicarboxylic acids produced by nucleophilic addition reactions include the following: TIFF2025509736000287.tif52128

[0233] In certain embodiments, in the compound of formula II, the divalent residue of a dicarboxylic acid is a condensation reaction: Generated by TIFF2025509736000288.tif20128.

[0234] Non-limiting examples of divalent residues of dicarboxylic acids produced by the condensation reaction include the following: TIFF2025509736000289.tif63128

[0235] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: TIFF2025509736000290.tif48132

[0236] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: TIFF2025509736000291.tif22128

[0237] Non-limiting examples of divalent residues of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 CH2-).

[0238] Non-limiting embodiments of divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paulic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid. TIFF2025509736000292.tif85132

[0239] Non-limiting examples of divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y- Linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3, (CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), paulinic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)3CH2-), mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0240] In certain embodiments, in the compound of formula II, the linker C is selected from: TIFF2025509736000293.tif29128 formula, R 22 is independently at each occurrence alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6R 7 ) selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; The remaining variables are as defined herein.

[0241] In certain embodiments, in the compound of formula II, the linker D is selected from: TIFF2025509736000294.tif42128 formula, R 32 is independently alkyl in each occurrence, N + is selected from the group consisting of X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; X- is an anionic group, e.g., Br- or Cl - and; All other variables are as defined herein.

[0242] In certain embodiments, in the compound of formula II, the linker A is selected from: TIFF2025509736000295.tif22128 wherein the heteroaryl, heterocycle, cycloalkyl, and aryl may each be substituted with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl, as valences permit.

[0243] In certain embodiments, in the compound of formula II, the linker A is selected from: TIFF2025509736000296.tif87128 wherein heteroaryl, heterocycle, cycloalkyl, and and may each be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences allow.

[0244] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000297.tif81128

[0245] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000298.tif194106

[0246] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2025509736000299.tif88128, wherein tt is independently selected from 1, 2, or 3, and ss is 3 minus tt (3-tt).

[0247] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2025509736000300.tif49139 where tt and ss are as defined herein.

[0248] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2025509736000301.tif150128TIFF2025509736000302.tif186128TIFF2025509736000303.tif186128TIFF2025509736000304.tif236166 wherein heteroaryl, heterocycle, cycloalkyl, and aryl may each be optionally substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences permit; and tt and ss are as defined herein.

[0249] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2025509736000305.tif132128TIFF2025509736000306.tif170128 wherein heteroaryl, heterocycle, cycloalkyl, and aryl may each be substituted, valences permitting, with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl; tt and ss are as defined herein.

[0250] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D is selected from: TIFF2025509736000307.tif57128 wherein heteroaryl and aryl may each be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences permit; tt and ss are as defined herein.

[0251] In certain embodiments, in the compound of formula II, the linkerA is selected from the following: TIFF2025509736000308.tif52128

[0252] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000309.tif65128

[0253] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000310.tif53133

[0254] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000311.tif55133

[0255] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000312.tif85128

[0256] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000313.tif72128

[0257] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000314.tif182128

[0258] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000315.tif75128TIFF2025509736000316.tif172138

[0259] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000317.tif32128

[0260] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000318.tif94128

[0261] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000319.tif126128

[0262] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000320.tif64128

[0263] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000321.tif135138

[0264] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000322.tif69144

[0265] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000323.tif133128

[0266] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000324.tif153134

[0267] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000325.tif128135

[0268] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000326.tif170128

[0269] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000327.tif94128

[0270] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000328.tif196140

[0271] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000329.tif62170

[0272] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000330.tif123128

[0273] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000331.tif209141

[0274] In certain embodiments, in the compound of formula II, the linkerA is selected from the following: TIFF2025509736000332.tif24132

[0275] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000333.tif14136

[0276] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000334.tif105132

[0277] In certain embodiments, the linker A is the following: TIFF2025509736000335.tif149139, each of which is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0278] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000336.tif18128

[0279] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000337.tif36128

[0280] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000338.tif36128

[0281] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000339.tif37131

[0282] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000340.tif51134

[0283] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000341.tif15128

[0284] In certain embodiments, in the compound of formula II, the linker A is selected from the following:

[0285] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000342.tif148134TIFF2025509736000343.tif150134

[0286] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000344.tif99128

[0287] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000345.tif142148

[0288] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000346.tif41128

[0289] In certain embodiments, in the compound of formula II, the linker Ais selected from the following: TIFF2025509736000347.tif37128

[0290] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000348.tif72128

[0291] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000349.tif61133

[0292] In certain embodiments, in the compound of formula II, the linker A is selected from the following: TIFF2025509736000350.tif73131

[0293] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000351.tif32128

[0294] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000352.tif12128

[0295] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000353.tif43130

[0296] In certain embodiments, in the compound of formula II, the linker B are selected from the following, each of which is R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0297] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000354.tif62132

[0298] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000355.tif27135

[0299] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000356.tif29128

[0300] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000357.tif37128

[0301] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000358.tif60128

[0302] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000359.tif47136

[0303] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000360.tif111138

[0304] In certain embodiments, in the compound of formula II, the linker B is selected from the following: TIFF2025509736000361.tif66140

[0305] In certain embodiments, in the compound of formula II, the linker B -Linker A is selected from the following: TIFF2025509736000362.tif20128

[0306] In certain embodiments, in the compound of formula II, the linker B -Linker A is selected from the following: TIFF2025509736000363.tif40128

[0307] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000364.tif41133

[0308] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000365.tif65128

[0309] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000366.tif41129

[0310] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000367.tif94134

[0311] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000368.tif53128

[0312] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000369.tif82128

[0313] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000370.tif94129TIFF2025509736000371.tif178135TIFF2025509736000372.tif54128

[0314] In certain embodiments, in the compound of formula II, the linker C are selected from the following, each of which is R 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0315] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000373.tif72128

[0316] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000374.tif22128

[0317] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000375.tif22128

[0318] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000376.tif45128

[0319] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000377.tif45140

[0320] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000378.tif33128

[0321] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000379.tif49132

[0322] In certain embodiments, in the compound of formula II, the linker C is selected from the following: TIFF2025509736000380.tif81128

[0323] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2025509736000381.tif69132

[0324] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2025509736000382.tif126128

[0325] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is selected from the following: TIFF2025509736000383.tif26134

[0326] In certain embodiments, in the compound of formula II, the linkerC -(Linker A )2 is selected from the following: TIFF2025509736000384.tif201109

[0327] In certain embodiments, in the compound of formula II, the linker D is selected from the following: TIFF2025509736000385.tif50128

[0328] In certain embodiments, in the compound of formula II, the linker D is the following: TIFF2025509736000386.tif88128, each of which is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0329] In certain embodiments, in the compound of formula II, the linker B -(Linker A ) is selected from the following: TIFF2025509736000387.tif65128

[0330] In certain embodiments, in the compound of formula II, the linker C -(Linker A ) is selected from the following: TIFF2025509736000388.tif180135

[0331] In certain embodiments, in the compound of formula II, the linker D -(Linker A ) is selected from the following: TIFF2025509736000389.tif96128

[0332] In various embodiments, R 4 represents independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from.

[0333] In various embodiments, in the compound of formula II, R 5 are independently hydrogen, heteroalkyl, TIFF2025509736000390.tif21128, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6 , C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R 3 , C0-C6 alkyl-S(O)2R 3 , C0-C6 alkyl-N(R 8 )-C(O)R 3 , C0-C6 alkyl-N(R 8 )-S(O)R 3 , C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-OC(O)R 3 , C0-C6 alkyl-OS(O)R 3 , C0-C6 alkyl-OC(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkylN3, and C0-C6 alkyl-OS(O)2R 3 each of which is optionally substituted with 1, 2, 3, or 4 substituents.

[0334] In various embodiments, in the compound of formula II, R 6 and R 7 independently at each occurrence, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from.

[0335] In various embodiments, in the compound of formula II, R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0336] In various embodiments, the compound of formula II has the structure of formula II-A: In various embodiments, the compound of formula II-A, [MIFBM] and [IgGBM] are as defined herein.

[0337] A compound of formula II-A, or a salt, stereoisomer, or solvate thereof, having the structure: TIFF2025509736000391.tif19144In formula, [MIFBM / IgGBM] is a MIF or IgG binding moiety that binds to circulating MIF or IgG, respectively, in a subject, which circulating MIF or IgG, respectively, is associated with a disease state or condition and is to be cleared by the action of hepatocytes or other cells of the subject; [ASGPBM]: an asialoglycoprotein receptor binding portion having a structure selected from TIFF2025509736000392.tif240122; Each [CON] is an optional connector chemical moiety that, if present, connects [LIN] to [CPBM] or [ASGPBM]; [LIN] is [Linker] or [Linker-2], each of which is a chemical moiety having a valence of 1 to 15 that is covalently attached to one or more [ASGPBM] or [CPBM] groups, optionally through [CON], where said [LIN] may itself contain one or more [CON] groups; Z B is non-existent, (CH2) IM , C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M and; R M is H or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups; R2 is TIFF2025509736000393.tif17128; During the ceremony, R AM is H, C1-C4 alkyl optionally substituted with up to three halo groups and one or two hydroxyl groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, -C(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -(CH2) K -NR N3 R N4 or R2 is TIFF2025509736000394.tif15128, During the ceremony, R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo groups KO(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 halo groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K -C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -C(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing up to five heteroaryl atoms, each of which may contain up to three of the following: CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo groups K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 halo groups or 1-2 hydroxy groups, -O-(C1-C3-alkyl) optionally substituted with 1-3 halo groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -(CH2) optionally substituted with 1 to 3 halo groups. K or may be substituted with C(O)-(C1-C4 alkyl); R TA may be substituted with up to three halo groups, and may be substituted with up to three C1-C3 alkyl groups. TIFF2025509736000395.tif53128; or R TA teeth The file is TIFF2025509736000396.tif63128.

[0338] D. ASGPR binding moieties of other series Furthermore, the ASGPR activity is Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem, doi: 199-201. 10.1021 / acs.bioconjchem.0c00202; Majouga, AG, et al., “Identification of Novel Small-Molecule ASGP-R Ligands,” Current Drug Delivery, 2016, 13, 1303–1312; Olshanova, AS, et al., "Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the targeted delivery to hepatocellular carcinoma cells," Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., "New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids," Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019; Congdon , MD , et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00555; and Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509 (2021) 108417, doi: 10.1016 / j.carres.2021.108417. The following ASGPR binding moieties are exemplary and are not intended to be limiting.

[0339] 1. GalNAc-tyrosine moiety In some embodiments, the ASGPR binding moiety may be a moiety having the structure of M1, M2, M3, or M4, or a combination thereof. In the structures of M1, M2, M3, and M4, X is independently O, NH, or S at each occurrence. In various embodiments, a compound of formula I or formula II may have one, two, or three ASGPR binding moieties having the structure of M1, M2, M3, or M4. TIFF2025509736000397.tif99138

[0340] In various embodiments, the ASGPR binding moieties M1-M4 may be conjugated to any suitable [CON], [Linker], or [Linker-2], as described herein and in Congdon, MD, et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00555.

[0341] 2. Trivalent triazole moiety In some embodiments, the ASGPR binding moiety can be a moiety having the structure M5. TIFF2025509736000398.tif37128

[0342] In structure M5, each R at each occurrence is independently R1 or R2. TIFF2025509736000399.tif53128

[0343] In various embodiments, the compound of formula I or formula II comprises an ASGPR binding moiety having the structure M5. In various embodiments, each R in M5 is R1. In various embodiments, each R in M5 is R2.

[0344] In various embodiments, the ASGPR binding moiety M5 may be conjugated / attached to any suitable [CON], [Linker], or [Linker-2], as described herein and in Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00202.

[0345] 3. Galactose-derived and agarose-derived behenate moieties In various embodiments, the ASGPR binding moiety can be the galactose behenate derived moiety M7. TIFF2025509736000400.tif27128

[0346] In structure M7, Y is OH or NHAc.

[0347] In various embodiments, the ASGPR binding moiety is an agarose behenate derived moiety M8: It could be TIFF2025509736000401.tif68128.

[0348] In various embodiments, the ASGPR binding moieties M7 and M8 can be conjugated to any suitable [CON], [Linker], or [Linker-2], as described herein and in Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509 (2021) 108417, doi: 10.1016 / j.carres.2021.108417.

[0349] 4. Other small molecule ASGPR binding moieties In various embodiments, the ASGPR binding moiety can be any of compounds 2-18 below. TIFF2025509736000402.tif211156

[0350] In various embodiments, in compounds 15 and 16, R is CHOAc, COOH, or CHOH. Compounds 2-18 are described herein and Majouga, AG, et al., "Identification of Novel Small-Molecule ASGP-R Ligands," Current Drug Delivery, 2016, 13, 1303-1312, doi: 10.2174 / 1567201813666160719144651; Olshanova, AS, et al. al., "Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the delivery to hepatocellular carcinoma cells," Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., "New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids," Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019, can be conjugated / attached to any suitable [CON], [Linker], or [Linker-2]. Compounds 2-18 can be attached through any suitable reactive group contained therein. Without being limited thereto, compounds 2-13 can be attached to [CON], [Linker], or [Linker-2] through or by reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone, or aromatic halogen contained in compounds 2-18.Suitable reaction modes for attaching compounds 2-18 to [CON], [Linker], or [Linker-2] as described herein include, but are not limited to, substitution (e.g., alkylation of an OH or NH group), esterification (forming an ester), amidation (forming an amide), transesterification (exchanging one ester for another), transamidation (exchanging one amide for another), azide-alkyne cycloaddition, and other reactions capable of forming CC, NC, or OC bonds with vinyl and alkynyl groups, such as cycloaddition, amination, oxidation, alkylation, rearrangement reactions (e.g., Claisen, Cope, etc.), etc.

[0351] The term "pharmaceutically acceptable salt" or "salt" is used throughout the present specification to describe the salt form of one or more compositions herein, which is provided to increase the solubility of the compound in saline for parenteral delivery or in the gastric juices of the patient's gastrointestinal tract in order to facilitate the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Among the many acid salts well known in the pharmaceutical field, suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium. In some embodiments, sodium and potassium salts are used as neutralizing salts of the carboxylic acid and free acid phosphate-containing compositions according to the present disclosure. The term "salt" is intended to mean any salt consistent with the use of the compounds of the present disclosure. When the compounds are used in pharmaceutical indications, including the treatment of prostate cancer, including metastatic prostate cancer, the term "salt" is intended to mean a pharmaceutically acceptable salt consistent with the use of the compounds as a drug.

[0352] The term "co-administration" means that at least two compounds or compositions are administered to a patient at the same time, so that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time.The compounds of the present disclosure can be administered to a patient simultaneously, but this term includes both administration of two or more agents at the same time and administration at different times, provided that an effective concentration of all co-administered compounds or compositions is found in the patient at a given time.The chimeric antibody supplement compound of the present disclosure can be administered with one or more additional anti-cancer or other agents used to treat or ameliorate the symptoms of cancer, particularly prostate cancer, including metastatic prostate cancer.

[0353] The term "anti-cancer agent" or "additional anti-cancer agent" refers to a compound other than the chimeric compounds of the present disclosure that can be used in combination with the compounds of the present disclosure to treat cancer. Exemplary anti-cancer agents that can be co-administered in combination with one or more chimeric compounds of the present disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., taxol), among others. Exemplary anti-cancer compounds for use in the present disclosure include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gymatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY 317615, neuradiab, vitespam, Rta 744, Sdx 102, talampanel, atrasentan, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258,; 3-[5-(Methylsulfonylpiperazinemethyl)-indolyl]-quinolone, Vatalanib, AG-013736, AVE-0005, Acetate of [D-Ser(But)6,Azgly10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 Acetate [C 59 H 84 N 18 Oi4-(C2H4O2) X, where x = 1 to 2.4]), goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladodecane, Liposide, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopropionate Phosphorus, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenyl Alanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin,SU5416, SU6668, EMD121974, interleukin 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, Bevacizumab (monoclonal antibody) and Erbitux, Cremophor-free paclitaxel, Epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, Azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin 11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin 2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists,Particular mention may be made of palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, immunotherapeutic agents such as indoximod (NL In particular, these include IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) such as GDC-8187, Navoximod (GDC-0919), and NLG802, PDL1 inhibitors (programmed death-ligand 1 inhibitors) including, for example, nivolumab, durvalumab, and atezolizumab, PD1 inhibitors such as pembrolizumab (Merck), and CTLA-4 inhibitors (cytotoxic T-lymphocyte-associated protein 4 / cluster of differentiation 152 inhibitors) including ipilimumab and tremelimumab.

[0354] In addition to anticancer drugs, some other agents can be co-administered with the chimeric compounds of the present disclosure in the treatment of cancer.These include active agents, minerals, vitamins, and nutritional supplements that have shown some effectiveness in inhibiting cancer tissue or its growth, or are otherwise useful in the treatment of cancer.For example, one or more of the following phytoestrogens, including dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and beta-sitosterol, can be used in combination with the present compounds to treat cancer.

[0355] Without being limited by theory, the compounds of the present disclosure, which include a MIF binding moiety (MIFBM) or an antibody binding moiety and an ASGPR binding moiety, selectively bind to hepatocytes and through this binding, promote the introduction of MIFBM groups into hepatocytes that selectively bind to ASGPRBM, whereupon MIF protein in hepatocytes is degraded and removed from circulation.Thus, the compounds of the present disclosure bind to MIF protein and remove MIF protein from circulation, which provides a dual effect that is particularly effective for treating disease states and conditions.

[0356] A further aspect of the disclosure is a pharmaceutical composition comprising an effective amount of at least one compound disclosed herein, frequently a bifunctional chimeric compound disclosed herein (comprising at least one MIFBM group or antibody binding moiety and at least one ASGPRBM), and one or more compounds described elsewhere herein, each in an effective amount, in combination with a pharma- ceutical effective amount of a carrier, additive, or excipient, which can be used in combination with at least one additional, optional anti-cancer agent as otherwise disclosed herein.

[0357] The composition of the present disclosure can be conventionally formulated with one or more pharma- ceutically acceptable carriers, and can be administered as controlled release formulations.The pharma-ceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, buffer substances such as glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block copolymers, polyethylene glycol, and wool fat.

[0358] In some embodiments, the composition of the present disclosure is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, or by implanted reservoir.The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.In some embodiments, the composition is administered orally (including by intubation into the stomach through the mouth or nose), intraperitoneally, or intravenously.

[0359] Sterile injectable forms of the compositions of the present disclosure may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0360] The pharmaceutical composition of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or aqueous solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavors, or colorants can be added.

[0361] Alternatively, the pharmaceutical composition of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0362] The pharmaceutical compositions of the present disclosure can also be administered locally, specifically to treat skin cancer, psoriasis, or other diseases occurring in or on the skin.Suitable topical formulations are easily prepared for each of these areas or organs.Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation.Topically acceptable transdermal patches may also be used.

[0363] For topical application, pharmaceutical compositions can be formulated as suitable ointments, which contain active ingredient suspended or dissolved in one or more carriers.The carrier for topical administration of the compound of the present disclosure includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0364] Alternatively, the pharmaceutical compositions can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers, including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0365] For ophthalmic applications, the pharmaceutical compositions can be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or as solutions in isotonic, pH-adjusted, sterile saline, with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutical compositions can be formulated as an ointment such as petrolatum.

[0366] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. These compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0367] The amount of the compound in the pharmaceutical composition of the present disclosure that can be combined with the carrier material to produce a dosage form varies depending on the host and disease to be treated, and the specific mode of administration. In some embodiments, the composition is formulated to contain about 0.05 mg to about 1.5 g, 0.1 mg to 1 g, 0.5 mg to 750 mg, more often about 1 mg to about 600 mg, and even more often about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one additional compound that can be used to treat cancer, prostate cancer, or metastatic prostate cancer, or secondary effects or conditions thereof.

[0368] Methods of treating patients or subjects in need of treatment for certain disease states or conditions, particularly cancer, as described elsewhere herein, include administration of an effective amount of a pharmaceutical composition comprising a therapeutic amount of one or more novel compounds described herein, and optionally a therapeutic amount of at least one additional bioactive agent (e.g., anti-cancer agent, anti-inflammatory agent). The amount of active ingredient used in the treatment methods of the present disclosure, which can be combined with the carrier materials to produce a single dosage form, will vary depending on the host being treated and the particular mode of administration. For example, the compositions may be formulated such that a therapeutically effective amount of about 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 100 mg / kg, or in some embodiments greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / kg of the novel compounds per patient per day can be administered to a patient receiving these compositions.

[0369] It should also be understood that the specific dosage and treatment regimen in any particular patient will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease or condition being treated.

[0370] A patient or subject (e.g., a human) suffering from an autoimmune disease, an inflammatory disease, or a cancer can be treated by administering to the patient (subject) an effective amount of the chimeric / bifunctional compound of the present disclosure (including its pharma- ceutically acceptable salts, solvates, or polymorphs), optionally in a pharma- ceutically acceptable carrier or diluent, alone or in combination with other known agents, exemplary agents that may be useful in treating autoimmune and / or inflammatory diseases, or cancer, including metastatic or recurrent cancer, or in ameliorating secondary effects and / or symptoms associated with these pathologies and / or conditions. This treatment may be performed in combination with other conventional therapies for cancer, such as radiation treatment or surgery.

[0371] The compounds, alone or in combination with other agents described herein, can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically in the form of a liquid, cream, gel, or solid, or in the form of an aerosol.

[0372] The active compound is included in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the target indication without causing significant toxic effects in the treated patient. Exemplary doses of the active compound for all conditions referred to herein range from about 10 ng / kg to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, e.g., 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Some exemplary dosages range from about 0.01 to 3% wt / wt in a suitable carrier.

[0373] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, unit dosage forms containing less than 1 mg, between 1 mg and 3000 mg, for example, between 5 and 500 mg of active ingredient per unit dosage form. In many cases, oral dosages of about 25 to 500 mg are convenient.

[0374] The active ingredient is sometimes administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, for example about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient (optionally in saline or an aqueous medium), or by administration of the active ingredient as a bolus. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0375] The concentration of the active compound in the drug composition depends on the absorption rate, distribution rate, inactivation rate, and excretion rate of the drug, as well as other factors known to those skilled in the art.It should also be noted that the value of the dosage varies with the severity of the condition to be alleviated.It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed compositions.The active ingredient may be administered at once or divided into several small doses that are administered at various time intervals.

[0376] Oral compositions generally include an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivatives can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition.

[0377] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to the above types of materials, a liquid carrier such as fatty oil. In addition, the unit dosage form may contain various other materials that modify the physical form of the unit dosage form, such as sugar coating, shellac, or enteric coating.

[0378] The active compound or its pharma- ceutically acceptable salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0379] The active compound or a pharma- ceutically acceptable salt thereof may be mixed with other active substances that do not impair the desired action, or substances that supplement the desired action, such as other anti-cancer agents, anti-inflammatory agents, immunosuppressants, antibiotics, anti-fungal agents, or anti-viral compounds. In certain aspects of the present disclosure, one or more chimeric / bifunctional MIFBM binding compounds of the present disclosure are co-administered with another anti-cancer agent and / or another bioactive agent, as described elsewhere herein.

[0380] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate buffers, and agents for the adjustment of tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0381] If administered intravenously, the carrier is sometimes physiological saline or phosphate buffered saline (PBS).

[0382] In certain embodiments, controlled and / or sustained release formulations of the active compounds, including, for example, implants and microencapsulated delivery systems, are prepared with carriers that will protect the compounds against rapid elimination from the body. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for the preparation of these formulations will be apparent to those skilled in the art.

[0383] Liposomal suspensions or cholestosomes may be pharma- ceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811, which is incorporated herein by reference in its entirety. For example, liposomal formulations can be prepared by dissolving suitable lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation of the inorganic solvent to leave a thin film of dry lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then manually agitated to free lipid material from the sides of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0384] chemical synthesis Figures 1, 7, and 13 attached hereto identify exemplary compounds of the disclosure that exhibit activity in binding to and reducing and / or removing undesirable circulating proteins for therapeutic and / or diagnostic purposes. These compounds are based on MIF, anti-DNP IgG, or IgG binding moieties to which an ASPGR group, e.g., a GN3 or AcF3-3 group, is covalently attached through a linker containing 1-100 ethylene glycol groups, more frequently 1-15 ethylene glycol groups, 1-10 ethylene glycol groups, frequently 2-10 ethylene glycol groups, which are optionally attached through a [CON] group, e.g., a 1,2,3-triazole group or other [CON] group, as described herein.

[0385] FIG. 16 shows the synthesis of an azide / amide carboxyl end-capped PEG linker intermediate that can be condensed to an alkynyl precursor (such as the NVS alkyne precursor in FIG. 5) to give a carboxylic acid capped intermediate that can be used to give a bifunctional molecule.

[0386] Figure 17 describes a general method for the conversion of PEG molecules to hydroxyl azides. The PEG compound is tosylated (TsCl, DCM, in the presence of base) at low temperature and further reacted with sodium azide at elevated temperature in a non-nucleophilic solvent. The final azido alcohol is used in subsequent figures.

[0387] Figure 18 describes the synthesis of a mesylated azide from a starting PEG molecule using the same synthetic steps to arrive at an intermediate azido alcohol, which is then treated with a solution of MsCl in pyridine to give the final compound.

[0388] Figure 19 shows the synthesis of a GalNAc ASGPR ligand linked to a terminal amine through PEG. Pentaacetylgalactosamine is reacted with TMSOTf in DCE at elevated temperature to generate a bicyclic intermediate, which is then reacted with an azido alcohol to give the azido intermediate (TMSOTf, DCE). This molecule is then subjected to Staudinger reduction to give the amine, which is used in subsequent figures.

[0389] Figure 20 shows the synthesis of high affinity bicyclic ASGPR ligands. Galactose pentaacetate is treated with HBr / AcOH to give a brominated intermediate, which is treated with Zn and CuSO4 (water / AcOH) to give the galactal. This is treated with cerium ammonium nitrate and sodium azide at low temperature (MeCN) to give a disubstituted intermediate compound. This is then treated with strong base (NaOMe / MeOH) to give the triol azide intermediate. This compound is fully silylated (TMSCl / pyridine), then the primary alcohol is deprotected (potassium carbonate, MeOH, low temperature) and oxidized (Dess-Martin periodinane, DCM). Treatment with strong base (NaOEt / HOEt) and paraformaldehyde gives the tetraol intermediate, which is cyclized in strong acid (H2SO4 / water) to give the bicyclic azide ligand.

[0390] Figure 21 shows the synthesis of trifluoroacetate derivatives of bicyclic ASGPR ligands. The triol azide is reduced (Pd / C, MeOH) to give the intermediate amine, which is then peracylated with trifluoroacetic anhydride. The ester is hydrolyzed with strong base (NaOMe / HOMe) to give the intermediate amide, which is protected using dimethoxypropane in the presence of camphorsulfonic acid in DMF at elevated temperature. This is then reacted with a mesylated azido alcohol in the presence of strong base (NaH / DMF) to give the intermediate azide, which is reduced (Lindlar's catalyst, MeOH) to give the final amine.

[0391] Figure 22 shows the synthesis of MIF targeting linkers for monovalent linkers, which are synthesized through methods similar to those described in the previous figures. The boc-protected methyl ester is deprotected with TFA in DCM and then coupled to the MIF targeting carboxylic acid (HBTU, DIPEA, DMF). Subsequent hydrolysis with strong base (NaOH / dioxane / H2O) gives the MIF targeting carboxylic acid.

[0392] FIG. 23 shows the synthesis of a dicarboxylic acid MIF targeting motif synthesized as described in the previous figures.

[0393] Figure 24 shows the synthesis of tris base derived trivalent linkers. Tris base is treated with di-t-butyl dicarbonate in the presence of base to give a boc protected triol, which is then reacted with acrylonitrile in the presence of base (dioxane / HO) to give a trinitrile intermediate, which is then converted to a methyl ester via treatment with a strong acid in methanol. The amine is then reacted with Cbz-glycine via DCC mediated amide formation and deprotected to give the tricarboxylic acid, which is used in subsequent figures.

[0394] Figure 25 describes the synthesis of an ASGPR targeting moiety using three GalNAc ASGPR ligands: the tricarboxylic acid is reacted with an amine-terminated GalNAc (amide bond formation in the presence of HBTU and DIPEA) and then deprotected by reduction (Pd / C, solvent) and strong base (NaOMe / MeOH) treatment.

[0395] FIG. 26 shows the synthesis of a tricarboxylic acid MIF targeting motif synthesized as described in the previous figures.

[0396] FIG. 27 shows the synthesis of a MIF NVS alkyne precursor that can be reacted with a carboxylic acid-containing azide reactant (as described in subsequent figures) to yield a MIF-NVS-carboxylic acid capped reactant to generate a bifunctional compound.

[0397] Figure 28 shows the synthesis of a carboxylic acid-terminated MIF targeting moiety. 2-Chloroquinolin-6-ol is reacted with ethyl 4-bromobutanoate in the presence of base (DMF, elevated temperature) to give an aryl chloride, which is then subjected to Sonogashira coupling with ethynyltrimethylsilane at elevated temperature. This intermediate silylated compound is deprotected with TBAF (DCM / THF). A click reaction between an alkyne intermediate and in situ synthesized 4-azido-2-fluorophenol to form a triazole gives an ethyl ester intermediate, which is hydrolyzed with strong base (NaOH / dioxane) to give the carboxylic acid, which is used in subsequent figures.

[0398] FIG. 29 describes the synthesis of the bifunctional molecule MIF-NVS-PEG-GN3 through HBTU-mediated coupling in DMF of an ASPGR targeting amine with a MIF targeting carboxylic acid, which is prepared by first forming the MIF targeting carboxylic acid by condensing the reactant azido-PEG-carboxylic acid to a MIF moiety containing an alkyne-terminated PEG group.

[0399] FIG. 30 describes the synthesis of bifunctional molecules MIF-GN3 and MIF-PEGn-GN3 through HATU-mediated coupling of ASGPR-targeting amines with MIF-targeting carboxylic acids (DMF, DIPEA).

[0400] Figure 31 describes the synthesis of a bifunctional molecule targeting MIF and ASGPR, containing one bicyclic ASGPR AcF3 ligand. The MIF-bound monocarboxylic acid is treated with HBTU, DIPEA, an amine-terminated ligand, and DMF to give the amide, which is then deprotected with 1M HCl to give the final compound.

[0401] Figure 32 describes the synthesis of a bifunctional molecule targeting MIF and ASGPR that contains two bicyclic ASGPr ligands, which is synthesized similarly to that described above.

[0402] Figure 33 describes the synthesis of a bifunctional molecule targeting MIF and ASGPR that contains three bicyclic ASGPr ligands, which are synthesized similarly to those described above.

[0403] Figure 34 shows the synthesis of DNP-GN3. 2,4-Dinitrochlorobenzene was treated with an amino carboxylic acid in the presence of a weak base to give a dinitroaniline carboxylic acid intermediate. Further steps were carried out as described for the previous molecule.

[0404] FIG. 35 shows the synthesis of DNP-AcF3-3, which was carried out in a similar manner to the previous compounds.

[0405] FIG. 36 shows the synthetic scheme used to obtain IBA-GN3. Pentaethylene glycol was treated with tosyl chloride in the presence of base to give the monotosylated alcohol, which was then treated with sodium azide at elevated temperature to give the azido alcohol. This compound was then oxidized using Jones reagent and reduced with palladium on carbon under hydrogen atmosphere to give the carboxylic acid-amine. Separately, indole butyric acid was treated with N-hydroxysuccinimide, EDC, and DIPEA to give the NHS-ester indole, which was then reacted with the carboxylic acid-amine. The product was again reacted with N-hydroxysuccinimide, EDC, and DIPEA to give the NHS ester. This NHS ester was reacted with NH2-GN3, prepared as described above. The subsequent amide was deprotected with NaOMe in MeOH to give compound IBA-GN3.

[0406] Figure 37 shows the synthesis of triazine-GN3. Cyanuric chloride was treated with (4-(methoxycarbonyl)phenyl)methanaminium in THF and diisopropylethylamine at -78°C to give the mono-substituted product. This was then treated with cyclohexylmethanamine at room temperature to give the second substitution. Final substitution was achieved with (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine at elevated temperature to give the tri-substituted triazine. Deprotection with lithium hydroxide was followed by amide coupling with a mono-protected diamine to give the Boc-protected derivative, which was deprotected and reacted with glutaric anhydride to give the carboxylic acid, which was converted to the NHS ester using standard coupling conditions. This was reacted with NH2-GN3 to give the final product.

[0407] Figure 38 shows the synthetic scheme used to obtain FcIII-GN3. The hexynyl peptide was prepared using standard solid-phase peptide synthesis techniques. The peptide was removed from the Rink resin using reagent L and then oxidized in MeOH under air using ammonium bicarbonate buffer (pH 8-9) to obtain the cyclic peptide. The peptide was reacted with the previously described GN3-azide to obtain the product triazole FcIII-GN3.

[0408] FIG. 39 shows the synthetic scheme used to obtain FcIII-4c-GN3, achieved using the methods described above.

[0409] Figures 40-43 describe the synthesis of bifunctional molecules targeting MIF and ASGPr, including three bicyclic ASGPR ligands in which the 2-amine of the sugar is differently substituted, which are synthesized through methods similar to those described above and illustrated in the accompanying figures.

[0410] FIG. 44 shows the synthesis of compound MIF-18-3. The tri-acylgalactal was deprotected with ammonia in methanol, followed by tri-benzyl protection with benzyl bromide in the presence of base. The alkene was hydrolyzed with HCl in THF / H2O overnight, followed by oxidation with PCC to give the aldehyde. Sodium azide was then added alpha to the carbonyl with KHMDS and TIBSN3 at low temperature. The intermediate was then treated with p-OMePhMgBr in THF and toluene to give the intermediate alcohol, which was then reduced using Et3SiH in the presence of BF3-Et2O at low temperature. The resulting azide was then reduced with Lindlar's catalyst under hydrogen atmosphere to give the corresponding amine, which was acylated with trifluoroacetic acid in pyridine. The benzyl group was then removed with Pd(OH2) on carbon in MeOH at reflux temperature, and the resulting triol was protected as an acetal with dimethoxypropane and camphorsulfonic acid at elevated temperature. The remainder of the synthesis was carried out as described for the previously described molecules.

[0411] Figure 45 shows the synthesis of compound MIF-31-3. Galactosamine hydrochloride was fully protected with acetic anhydride, followed by treatment with allyl alcohol in the presence of BF3 etherate to give the allyl intermediate. Treatment with pivaloyl chloride in pyridine gave the di-Piv protected intermediate, which was treated with triflic anhydride and subsequently subjected to hydrolysis in water at elevated temperature. The pivaloyl group was removed by treatment with NaOMe in MeOH to give the allyl triol intermediate. Subsequent steps were carried out as described for previous molecules.

[0412] FIG. 46 shows the synthesis of compound MIF-15-3, which was synthesized using a procedure similar to the compounds above.

[0413] Figure 47 shows the synthesis of compound MIF-19-3. This molecule is synthesized through a late triazole-forming click reaction between triazide and propionic acid in the presence of THPTA, copper sulfate, water, and sodium ascorbate in methanol. All other reactions are carried out as described above.

[0414] FIG. 48 shows the synthesis of compound MIF-16-3, which was synthesized using a procedure similar to the compounds above.

[0415] FIG. 49 shows the synthesis of compound MIF-20-3, which was synthesized using a procedure similar to the compounds above.

[0416] FIG. 50 shows the synthesis of compound MIF-14-3, which was synthesized using a procedure similar to the compounds above.

[0417] FIG. 51 shows the synthesis of compound MIF-21-3, which was synthesized using a procedure similar to the compounds above.

[0418] Figures 52-66 show the synthesis of several MIF binding compounds with various ASGPRBM moieties, which were synthesized through methods similar to those described above. EXAMPLES

[0419] The present specification will be further described with reference to the following experimental examples.These examples are presented for illustrative purposes only and are not intended to be limiting unless otherwise specified.Therefore, the present specification should not be interpreted as being limited to the following examples in any way, but rather as encompassing any variations that become evident as a result of the teachings presented herein.

[0420] Proper protein secretion and turnover are necessary processes to maintain homeostasis. Newly synthesized proteins destined for secretion are first transported to the endoplasmic reticulum, where they are post-translationally modified with N-linked glycan chains that terminate in sialic acid (1). As proteins age, terminal sialic acid residues are removed by circulating endogenous glycosidases (2). This natural protein aging process exposes galactose and N-acetylgalactose (GalNAc) residues, which bind to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes (3-5).

[0421] ASGPR is a C-type lectin that removes aged circulating proteins with exposed GalNAc residues from the circulation by transporting them to lysosomes. Multiple galactose or GalNAc residues present on the protein surface are required for high-affinity binding to and subsequent endocytosis by ASGPR (6, 7). Once endocytosed, these proteins are released from ASGPR through depletion of calcium from the endosome and a change in the protonation state of the amino acids at the binding site due to a decrease in pH (12); ASGPR is recycled back to the hepatocyte surface (13). Endocytic proteins are transported to late endosomes, which fuse with lysosomes. Lysosomal proteases then degrade endocytic proteins to permanently remove them from the circulation (14).

[0422] Nonglycosylated proteins are not known to be natural targets for ASGPR. One such protein is macrophage migration inhibitory factor (MIF), a 12.5 kDa protein that may exhibit catalytic activity (15). Genetic depletion or antibody neutralization of MIF has been shown to show positive outcomes in models of sepsis (16), multiple sclerosis (17), rheumatoid arthritis (18), and burn recovery (21). A bifunctional molecule for degrading circulating MIF is presented that utilizes ASGPR as an entry point for the protein into the endosomal-lysosomal degradation pathway. Bicyclic ASGPR-binding molecules in MIF-AcF2 and MIF-AcF3 have already been reported as high-affinity binders for ASGPR (22, 23).

[0423] Example 1: Biological Data In Example 1, exemplary compounds of several embodiments are tested to determine their biological activity. The active compounds are shown in Figures 1, 7, and 13 herein. The results of the biological experiments are described below.

[0424] Figure 1 shows exemplary compounds of the present disclosure. Note that in the figure, compound 3w (negative control for MIF inhibition), MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1, MIF-AcF3-2, and MIF-AcF3-3 are disclosed. Note that n in the PEG linker is sometimes in the range of 1-12, for example, 1-10, 2-8, 2-6, 2-5, or 1, 2, 3, or 4.

[0425] In the experiment whose results are shown in Figure 2, A. Fluorescence polarization data of MIF-FITC binding to human MIF shows that the MIF binding moieties of the present disclosure bind to MIF. B. The bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3, and NVS-PEG3-GN3 competitively bound MIF-FITC, indicating that these bifunctional molecules maintain the ability to bind human MIF.

[0426] In an experiment whose results are shown in Figure 3, the bifunctional molecules were able to deplete human MIF from the supernatant of cultured HepG2 cells. Briefly, human MIF (100 nM) was added to cell culture medium in the presence of the negative control MIF inhibitor 3w, and the bifunctional molecules MIF-NVS-PEGn-GN3, MIF-GN3, MIF-PEGn-Gn3, MIF-AcF3-1, MIF-AcF3-2, and MIF-AcF3-3. All molecules utilized known MIF binding ligands. The experiment was performed in 96-well plates (surface area of ​​approximately 0.33 cm2). 2). HepG2 cells were grown to 90% confluence in RPMI medium, washed with PBS (2x) and treated with serum-free medium (optimem + 0.1% BSA + Pen / Strep) containing 100 nM huMIF (Cayman Chemical) and compound (where appropriate). Compounds were diluted in DMSO from 1 mM stock solutions. After 24 hours, samples of supernatant (2 uL) were collected, diluted 1:100, and analyzed for MIF content by sandwich ELISA (also incubated for 24 hours in the presence or absence of compound). Residual MIF levels were determined by sandwich ELISA (biolegend monoclonal anti-MIF antibody and biotinylated anti-MIF antibody). Data represent the mean of at least three biological replicates, error bars represent standard deviation. After 24 hours, up to 95.3% of MIF was depleted from the cell medium (in the case of MIF-AcF3-3).

[0427] Figure 4 shows the results of an experiment to determine whether MIF internalized in HepG2 cells is transported to lysosomes. In this experiment, cells were incubated with rhuMIF (Cayman) at a concentration of 100 nM and MIF-GN3 at a concentration of 200 nM. After 12 hours, cells were fixed with formaldehyde, permeabilized, and probed with anti-Lamp2 antibody (mouse monoclonal, Abcam), polyclonal rabbit anti-MIF antibody (Thermo), and Alexa 488-labeled anti-mouse antibody and Alexa 568-labeled anti-rabbit antibody to demonstrate internalization in lysosomes.

[0428] Figure 5 shows that MIF-GN3 mediates depletion of injected human MIF from mice. Human MIF exhibits a half-life of approximately 40 minutes in mice. In this experiment, mice were co-injected with human recombinant MIF (Cayman chemical) along with anti-DNP IgG used as an injection positive control. Specifically, nude mice were injected with 5 μg recombinant human MIF and 200 μg anti-DNP IgG as an injection control (Figure 4). MIF-GN3 was then injected at the indicated concentrations and blood was collected every 20 minutes for 2 hours. Serum was diluted 1:100 and analyzed for MIF content by sandwich ELISA (biolegend monoclonal anti-MIF antibody and biotinylated anti-MIF antibody). The levels of injected IgG were not significantly different between the test groups. A moderate increase in huMIF levels up to 20 ng / ml was seen in mice treated with MIF-GN3, whereas serum levels up to 150 ng / ml were observed in mice injected with the PBS negative control. This demonstrates that huMIF levels were substantially increased as a result of MIF-GN3 administration.

[0429] Figure 6 shows that MIF-GN3 can slow tumor growth in a mouse model of prostate cancer. In this experiment, nude mice were implanted with PC3 human prostate cancer cells. Treatment with a nonbifunctional MIF inhibitor (3w), an anti-MIF antibody, or MIF-GN3 was then immediately initiated. MIF-GN3 showed comparable tumor growth slowing during the experiment as MIF neutralizing antibodies. 3w did not inhibit tumor growth, demonstrating that MIF degrading is required for therapeutic efficacy.

[0430] Figure 7 shows the molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind to anti-DNP IgG and ASGPR. These compounds were used in several experiments described below.

[0431] Figure 8 shows that DNP-GN3 and DNP-AcF3-3 mediate the formation of ternary complexes between HepG2 cells and anti-DNP. Thus, the bifunctionality of these molecules is demonstrated. In this experiment, ASGPR-expressing HepG2 cells were incubated with bifunctional molecules and alexa-488-labeled anti-DNP (Thermo). The readout is the mean fluorescence intensity of the cell population. Fluorescence was measured using a flow cytometer.

[0432] In further experiments, the results shown in Figure 9 indicate that DNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa 488-labeled anti-DNP by HepG2 cells. The assay performed in this experiment was as described above for MIF uptake. The reading is the percentage of Alexa 488-positive cells after 6 hours. Fluorescence was measured using a flow cytometer.

[0433] Figure 10 shows that DNP-GN3 and DNP-AcF3-3 mediate localization of alexa 568-labeled anti-DNP to late endosomes and lysosomes. This experiment was performed as described above for the MIF colocalization study.

[0434] The experimental results shown in Figure 11 show that DNP-AcF3-3 mediates the degradation of alexa 488-labeled anti-DNP in HepG2 cells. In this experiment, cells were incubated with 1 uM alexa 488-labeled anti-DNP (Thermo) and 200 nM DNP-AcF3-3. Cells were lysed at given time points (RIPA in PBS, containing protease inhibitors) and assayed by SDS-PAGE gel. The readout is the fluorescence of protein fragments.

[0435] The results shown in Figure 12 demonstrate that DNP-GN3 mediates depletion of anti-DNP from mouse serum. Mice were injected with anti-DNP on day 0 and then treated daily with a given compound for 6 days. Serum IgG levels were measured by ELISA. DNP-(OH)3 is used as a non-bifunctional control molecule.

[0436] FIG. 13 shows the structures of the IgG degrading molecules IBA-GN3, Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3.

[0437] Figure 14 shows that FcIII-GN3 mediates the uptake of human IgG into HepG2 cells. The experiment was performed as described above.

[0438] Figure 15 shows that FcIII-GN3 mediates localization of IgG to late endosomes in HepG2 cells. Experiments were performed as described above.

[0439] Example 2: Experimental Chemistry Example 2 describes the synthesis and characterization of exemplary compounds of several embodiments.

[0440] Example 2-1. MIF-binding molecules (Figure 13) Example 2-1-1: MIF-1 TIFF2025509736000403.tif19128 2-Chloroquinolin-6-ol (1.00 g, 5.57 mmol) and K2CO3 (1.53 g, 11.1 mmol, 2.0 equiv) were dissolved in DMF (20 mL). Ethyl bromobutyrate (1.63 g, 1.2 mL, 8.35 mmol, 1.5 equiv) was then added and the mixture was stirred at 80 °C for 12 h. The reaction was diluted in ethyl acetate and washed with water (2x) and brine (3x). The organic layer was dried over sodium sulfate and evaporated to give compound 30, which was used in the next step without further purification. TIFF2025509736000404.tif41159

[0441] Example 2-1-2: MIF-2 TIFF2025509736000405.tif23128 Compound 30 (1.52 g, 5.17 mmol) was dissolved in THF (20 mL) and triethylamine (2.88 mL, 20.7 mmol, 4 equiv). Copper(I) iodide (49.0 mg, 0.258 mmol, 0.05 equiv), Pd(PPh3)2Cl2 (181 mg, 0.258 mmol, 0.05 equiv), and TMS-acetylene (1.07 mL, 762 mg, 7.75 mmol, 1.5 equiv) were then added and the reaction was stirred under pressure at 65° C. for 16 h. The reaction mixture was filtered through Celite, washed with ethyl acetate, and evaporated. The residue was purified on silica (50% ethyl acetate in hexanes) to give compound 31. TIFF2025509736000406.tif42159

[0442] Example 2-1-3: MIF-3 TIFF2025509736000407.tif21128 Procedure Compound 31 (1.57 g, 4.42 mmol) was dissolved in DCM (45 mL) and TBAF (5.3 mL, 1 M in THF, 5.30 mmol, 1.2 equiv) was added dropwise. After stirring for 1 min, 10% citric acid (50 mL) was added and the reaction was stirred for 30 min. The organic phase was washed with water (1x), dried and evaporated to give compound 32, which was used in the next step without further purification. TIFF2025509736000408.tif56159

[0443] Example 2-1-4: MIF-4 TIFF2025509736000409.tif27128 2-Fluoro-4-iodophenol (126 mg, 0.529 mmol) and sodium azide (38 mg, 0.528 mmol, 1.0 equiv) were dissolved in DMSO (2.5 mL) and stirred for 2 h at 70 ° C. Compound 32 (150 mg, 0.529 mmol, 1 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol, 0.15 equiv), sodium ascorbate (10 mg, 0.053 mmol, 0.1 equiv), copper(I) iodide (15 mg, 0.079 mmol, 0.15 equiv), and HO (2.5 mL) were then added and the mixture was stirred at 70 ° C overnight. The reaction was diluted with ethyl acetate and washed with H2O (1x) and brine (1x). The organic layer was dried over sodium sulfate, evaporated and purified on silica (DCM / EtOAc) to give compound 33. TIFF2025509736000410.tif71157

[0444] Example 2-1-5: MIF-5 TIFF2025509736000411.tif28128 Compound 33 (90 mg, 0.206 mmol) was dissolved in dioxane (6 mL) and 2 M NaOH (3 mL). The reaction was stirred at room temperature for 2.5 h, at which point the reaction was diluted with water and the pH was adjusted to 3-4 with 1 M HCl. The mixture was cooled to 4 °C and filtered to provide compound 34, which was used without further purification.

[0445] Example 2-2. GaINAc spacer (Figure 14) TIFF2025509736000412.tif6128 Triethylene glycol (17.5 mL, 19.7 g, 131.13 mmol, 5 equiv) was dissolved in DCM (150 mL) and trimethylamine (5.48 mL, 3.98 g, 1.5 equiv) and cooled to 0 °C. TsCl (5.00 g, 26.23 mmol, 1 equiv) was then added and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted in DCM and washed with water (3x) and brine (1x). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified on silica (0-5% MeOH in DCM) to give compound 64 (6.89 g, 22.6 mmol) in 85% yield. TIFF2025509736000413.tif34155

[0446] TIFF2025509736000414.tif7128 Compound 64 (2.00 g, 6.57 mmol) and sodium azide (0.470 g, 7.23 mmol, 1.1 equiv) were dissolved in DMF (40 mL) and stirred at 60 °C overnight. 25 mL of DMF was then removed by rotary evaporation and the resulting mixture was diluted in water and extracted with ethyl acetate (2x). The organic layer was washed with brine (3x), dried over sodium sulfate and evaporated. The crude product was purified on silica (0-5% MeOH in DCM) to give compound 65 (932 mg, 5.32 mmol) in 81% yield.

[0447] Example 2-3. GaINAc ASGPR Ligand (Figure 15) TIFF2025509736000415.tif15128 Galactosamine pentaacetate (100 mg, 0.257 mmol) was dissolved in dichloroethane (1 mL) and stirred at room temperature before adding TMSOTf (70 μL, 86.0 mg, 0.387 mmol, 1.5 equiv). The reaction was stirred at 50° C. for 90 min, then cooled to room temperature and stirred for an additional 12 h. The reaction was poured into ice-cold saturated sodium bicarbonate and extracted into DCM. The organic layer was washed with water (2x), dried over sodium sulfate and evaporated to give compound 66 (0.236 mmol, 77.7 mmol, 92%) as a dark gum which was used without further purification. TIFF2025509736000416.tif34159

[0448] TIFF2025509736000417.tif17128 Compound 66 (200 mg, 0.607 mmol) and compound 65 (160 mg, 0.913 mmol, 1.5 equiv) were dissolved in 1,2-dichloroethane (5 mL). 4 Å molecular sieves were then added and the reaction was stirred for 30 min. TMSOTf (55 μL, 67.5 mg, 0.304 mmol, 0.5 equiv) was then added to the mixture and the reaction was stirred overnight. The mixture was diluted in DCM and washed with 1M sodium bicarbonate (1x) and water (1x) before being dried over magnesium concentrate and concentrated. The crude oil was purified on silica gel (50-100% EtoAc in DCM) to give compound 67 (245 mg, 0.486 mmol) in 80.1% yield. TIFF2025509736000418.tif56159

[0449] TIFF2025509736000419.tif17128 Compound 67 (1.80 g, 3.57 mmol) was dissolved in THF (35 mL). Triphenylphosphine (1.40 g, 5.35 mmol, 1.5 eq) and water (257 μL, 14.28 mmol, 4 eq) were then added and the reaction was stirred under nitrogen at room temperature for 36 h. The solvent was removed and the crude product was used in the next step without further purification.

[0450] Example 2-4. Trivalent glycine (Figure 16) TIFF2025509736000420.tif14128 Tris base (5.00 g, 41.3 mmol) was dissolved in dichloromethane (80 mL) and trimethylamine (20 mL). Di-tert-butyl dicarbonate (10.81 g, 49.6 mmol, 1.2 equiv) was then added and the reaction was stirred for 4 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic fraction was washed with water (1x), 1M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), then dried over sodium sulfate and evaporated to give compound 23 (9.04 g, 40.9 mmol) in 99% yield, which was used without purification in the subsequent step.

[0451] TIFF2025509736000421.tif26128 Compound 27 (9.04 g, 40.9 mmol) was dissolved in a mixture of dioxane (17 mL) and aqueous KOH (4.98 g, 88.7 mmol, 2.46 mL). Acrylonitrile (8.84 mL, 7.16 g, 135.0 mmol, 3.3 equiv) was then added dropwise over 2.5 h and the reaction was stirred under nitrogen for 24 h. The reaction was neutralized by addition of 2M HCl (30 mL) and partitioned between DCM and water. The organic layer was washed with water (2x) and brine (1x), dried over sodium sulfate and evaporated. The crude mixture was purified on silica (0-80% EtOAc in hexanes) to give compound 20 (7.87 g, 20.7 mmol) in 59% yield. TIFF2025509736000422.tif12157

[0452] TIFF2025509736000423.tif27128 Compound 28 (7.87 g, 20.7 mmol) was dissolved in MeOH (40 mL) and concentrated sulfuric acid (10 mL) was added. The reaction was stirred at reflux under nitrogen for 24 h and then neutralized with sodium bicarbonate. Methanol was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate (1x) and brine (1x) and then dried over sodium sulfate. The crude residue was purified on silica (10% MeOH in DCM) to give compound 29 (5.50 g, 14.5 mmol) in 70% yield. TIFF2025509736000424.tif19153

[0453] TIFF2025509736000425.tif29128 Compound 70 (723 mg, 1.90 mmol) was dissolved in MeCN (25 mL). HOBT (291 mg, 1.90 mmol, 1 equiv), Cbz-glycine (397 mg, 1.90 mmol, 1 equiv), and DCC (392 mg, 1.90 mmol, 1 equiv) were then added and the reaction was stirred overnight. MeCN was then evaporated and the residue was adsorbed onto silica and purified using a gradient of 0-75% EtOAc in hexanes. Compound 71 (866 mg, 1.52 mmol) was recovered in 80% yield. TIFF2025509736000426.tif41159

[0454] TIFF2025509736000427.tif29128 Compound 71 (100 mg, 0.175 mmol) was dissolved in dioxane (2 mL) and 2M NaOH (2 mL). The reaction was stirred for 3 h, then acidified and extracted twice into ethyl acetate. The organic fraction was washed with 1M HCl, then dried over sodium sulfate and evaporated to give compound 72, which was used in the next step without purification.

[0455] Example 2-5. Trivalent GaINAc (Figure 17) TIFF2025509736000428.tif84128 Compound 72 (372 mg, 0.704 mmol, 1 equiv) was dissolved in DMF (40 mL) and DIPEA (981 μL, 728 mg, 5.632 mmol, 8 equiv). HBTU (1.01 g, 2.67 mmol, 3.8 equiv) was then added and the reaction was stirred at room temperature for 10 min, after which compound 68 (1.28 g, 2.67 mmol, 3.8 equiv) was added. The reaction was stirred for 2 h, then diluted in DCM and washed with H3PO4 (1M, 1x), NaHCO3 (1M, 1x), and brine (1x). The organic layer was dried over sodium sulfate and evaporated onto silica. The residue was purified (0-20% MeOH in DCM) to give compound 73 (831 mg, 0.436 mmol) in 62% yield. TIFF2025509736000429.tif63160

[0456] TIFF2025509736000430.tif84128 Compound 73 (710 mg, 0.372 mmol) was dissolved in dry methanol (90 mL) and cooled to 0° C. under nitrogen. Pd / C (71.0 mg, 10% w / w) was then added and the reaction was stirred under hydrogen (1 atm) at 0° C. for 16 h. Upon completion, the reaction was filtered through Celite and the methanol was evaporated to give compound 74 (657 mg, 0.370 mmol) in 99.5% yield, which was used without further purification.

[0457] Compound 74 (441 mg, 0.248 mmol) was dissolved in methanol (15 mL) and cooled to 0° C. Sodium methoxide solution (400 μL, 5.4 M in MeOH) was then added and the reaction was stirred for 30 min. Dowex 50WX8 was then added until the solution was slightly acidic. The resin was filtered off and washed thoroughly with methanol. The combined methanol fractions were evaporated under reduced pressure to give compound 75 (274 mg, 0.196 mmol) in 79% yield. Compound 75 was used in the next step without purification.

[0458] Example 2-6. MIF-GN3 (Figure 18) TIFF2025509736000431.tif75163 Compound 34 (23.5 mg, 0.0575 mmol, 1.1 equiv) and HATU (20.0 mg, 0.0522 mmol, 1 equiv) were dissolved in dry DMF (5 mL) and DIPEA (23.3 μL, 16.9 mg, 0.131 mmol, 2.5 equiv) and stirred at room temperature for 10 min. Compound 75 (73.0 mg, 0.0522 mmol) was then added and the reaction was stirred for 30 min. The mixture was directly loaded onto HPLC and purified (20-30% MeCN in water, 3% TFA) to give compound 76 (12 mg, 0.0067 mmol) in 12.8% yield. TIFF2025509736000432.tif5128

[0459] Example 2-7. Bicyclic ASGPR spacer (Figure 19) TIFF2025509736000433.tif6128 Tetraethylene glycol (50.0 g, 258 mmol) was dissolved in THF (1 mL), cooled to 0 °C and stirred. A solution of NaOH (1.65 g, 41.3 mmol, 1.6 equiv) in water (1 mL) was then added, followed by the dropwise addition of a solution of p-toluenesulfonyl chloride (4.92 g, 25.8 mmol, 1 equiv) in THF (3 mL). The reaction mixture was stirred at 0 °C for 4 h and then diluted in DCM. The organic layer was washed with 150 mL ice-cold water (2x), brine (1x) and dried over sodium sulfate to give compound 16 (8.84 g, 25.4 mmol, 99% yield), which was used in the further step without purification.

[0460] TIFF2025509736000434.tif6128 Compound 16 (8.84 g, 25.4 mmol) was dissolved in 100% ethanol (200 mL) and sodium azide (4.128 g, 63.5 mmol, 2.5 equiv) was added. The reaction was heated at reflux for 16 h, then cooled to room temperature and water (150 mL) was added. The ethanol was then evaporated under reduced pressure and the product was extracted into ethyl acetate (2x). The organic layer was washed with water (1x) and brine (1x), dried over sodium sulfate and evaporated to give compound 17 (4.82 g, 22.1 mmol) as a yellow oil in 87% yield. TIFF2025509736000435.tif27159

[0461] TIFF2025509736000436.tif6128 Compound 17 (5.00 g, 22.8 mmol) was dissolved in pyridine (50 mL). Methanesulfonyl chloride (3.14 g, 27.4 mmol, 1.2 equiv) was then added and the reaction was stirred under nitrogen for 6 h. The mixture was then diluted in ethyl acetate and washed with water (3x), 0.5 M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), dried over sodium sulfate, and evaporated to give compound 18 (5.71 g, 19.2 mmol) in 84% yield. TIFF2025509736000437.tif34159

[0462] Example 2-8. Bicyclic ASGPR Precursors (Figure 20) TIFF2025509736000438.tif23128 Pentaacetylgalactose (25.0 g, 64.0 mmol) was dissolved in 33% HBr HOAc solution (30 mL) and stirred under nitrogen for 2 h. The reaction was diluted in EtOAc (500 mL) and washed with water (3x), saturated sodium bicarbonate (1x), and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give compound 1 as a pale yellow oil in quantitative yield. The compound was used without further purification.

[0463] Compound 1 (26.34 g, 64.06 mmol) was dissolved in acetic acid (510 mL) and zinc (67.01 g, 1024 mmol) was added. The mixture was stirred vigorously. A solution of CuSO4 (2.96 g, 18.6 mmol) in aqueous NaH2PO4 (128 mL, 0.1 M, 1.53 g) was then added and the reaction was stirred for 1 h. The reaction mixture was filtered over Celite and the resulting water / AcOH mixture was evaporated to give a white solid. The white solid was dissolved in EtOAc (2x, 300 mL each), water (300 mL), and EtOAc (1x, 300 mL). The layers were separated and the organic layer was further washed with water (2x), saturated sodium bicarbonate (2x), and brine (1x). The organic solution was dried over sodium sulfate, evaporated, and purified on silica (15-25% EtOAc in hexanes) to give compound 2 in 84% yield (14.64 g, 53.76 mmol). TIFF2025509736000439.tif41159

[0464] TIFF2025509736000440.tif23128 Procedure: Compound 2 (12.0 g, 44 mmol) was dissolved in acetonitrile (250 mL) and cooled to -10 °C. In a separate nitrogen flushed flask at -10 °C, NaN3 (4.3 g, 66 mmol) and ceric ammonium nitrate (87.0 g, 158 mmol) were mixed and stirred vigorously. The acetonitrile solution of compound 2 was added dropwise via cannula and the mixture was allowed to slowly reach room temperature. The reaction mixture was stirred for a total of 12 h, then diluted with ethyl acetate (500 mL) and washed with water (3x) and brine (1x). The organic layer was dried over sodium sulfate, evaporated, and purified on silica (20-50% EtOAc in hexanes) to give compound 3 in 79% yield (13.1 g, 34.9 mmol). TIFF2025509736000441.tif49159

[0465] TIFF2025509736000442.tif23128 A sodium methoxide solution was prepared from ice-cold dry methanol (50 mL) and sodium hydride (2.296 g, 95.67 mmol, 3 equiv.) and added to a solution of compound 3 (12.00 g, 31.89 mmol) in dry methanol (100 mL). After stirring for 30 min, the reaction was determined to be neutralized by the addition of acetic acid, which was added directly to silica gel. The reaction mixture was purified over a gradient of 0-20% MeOH in DCM to give compound 4 (6.64 g, 30.3 mmol) in 95% yield. TIFF2025509736000443.tif27153

[0466] TIFF2025509736000444.tif23128 Compound 4 (5.00 g, 22.8 mmol) was dissolved in pyridine (100 mL) and stirred under nitrogen. Trimethylsilyl chloride (10.43 mL, 8.929 g, 82.18 mmol, 3.6 equiv) was added dropwise and the mixture was stirred for 6 h. The reaction was diluted in ethyl acetate and washed with water (2x) and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give the tri-TMS intermediate. Residual pyridine was removed by coevaporating with toluene (3x). The intermediate was taken up in dry MeOH (45 mL) and cooled to 0 °C before potassium carbonate (40 mg) was added. The reaction was closely monitored for 1.5 h and quenched with acetic acid (17 μL) when TLC indicated complete consumption of starting material. The product was then dry loaded onto silica and purified with a gradient of 0-50% EtOAc in hexanes to give compound 5 (6.55 g, 18.0 mmol) in 79% yield. TIFF2025509736000445.tif27158

[0467] TIFF2025509736000446.tif23128 Compound 5 (7.00 g, 19.3 mmol) was dissolved in DCM (100 mL) and stirred under nitrogen. Dess-Martin periodinane (9.82 g, 23.2 mmol, 1.2 equiv) was added and the mixture was stirred for 2 h. The reaction was diluted in DCM and washed with water (2x) and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give the intermediate aldehyde.

[0468] Compound 6 was dissolved in molecular sieve dried EtOH (100 mL). Paraformaldehyde (36.50 g, 384.9 mmol, 20 equiv.) and 21% sodium ethoxide solution (14.5 mL, 38.5 mmol, 2 equiv.) were added and the reaction was stirred for 8 h. The solvent was evaporated and the product was adsorbed onto silica. The product was purified using a gradient of 0-25% MeOH in DCM to give compound 7 (2.981 g, 11.97 mmol) in 62% yield. TIFF2025509736000447.tif5128

[0469] TIFF2025509736000448.tif23128L6-7 (500 mg, 2.00 mmol) was dissolved in water (4.5 mL) and sulfuric acid (0.5 mL). The reaction was sealed in a microwave vial and heated at 100 °C for 40 min. The reaction was cooled to 0 °C, then diluted with MeOH (10 mL) and neutralized by addition of concentrated ammonia solution. The salts were filtered off and washed several times with methanol. The filtrate was adsorbed onto silica and purified with a gradient of 0-15% MeOH in DCM to give compound L6-8 (347 mg, 1.60 mmol) in 80% yield. TIFF2025509736000449.tif5134

[0470] Example 2-9. Bicyclic ASGPR ligand CF3 (Figure 21) TIFF2025509736000450.tif23128 Compound (400 mg, 1.84 mmol) was dissolved in methanol (30 mL) and the reaction flask was purged with nitrogen. Lindlar's catalyst (40.0 mg, 10 wt%) was then added and the reaction mixture was stirred under 1 atm hydrogen atmosphere (balloon) for 6 h. The reaction was filtered over Celite and evaporated to give compound 10 (351 mg, 1.84 mmol) in quantitative yield, which was used in the next reaction without further purification.

[0471] Compound (351 mg, 1.84 mmol) was dissolved in pyridine (15 mL) and treated with trifluoroacetic anhydride (1.24 mL, 1.85 g, 8.83 mmol, 4.8 equiv). The reaction was stirred for 6 h, then diluted in ethyl acetate and washed with 1M HCl (1x), saturated sodium bicarbonate (1x), and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give compound 11 (1.01 g, 1.75 mmol) in 95% yield, which was used in the next step without purification.

[0472] Compound 11 (1.01 g, 1.75 mmol) was dissolved in methanol (25 mL) and dry sodium methoxide (86.2 mg, 1.60 mmol, 4 equiv.) was added. The reaction was stirred at room temperature for 1 h, then neutralized with acetic acid and evaporated onto silica. The crude mixture was purified on silica (0-15% MeOH in DCM) to give compound 12 (482 mg, 1.68 mmol) in 96% yield. TIFF2025509736000451.tif41156

[0473] TIFF2025509736000452.tif27128 Compound 12 (110 mg, 0.383 mmol) was dissolved in DMF (8 mL) and dimethoxypropane (236 μL, 200 mg, 1.92 mmol, 5 equiv.) and camphorsulfonic acid (45 mg, 0.192 mmol, 0.5 equiv.) was added. The reaction was stirred at 70 °C overnight and then the DMF was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate (1x) and brine (1x), then evaporated onto silica and purified (0-5% MeOH in DCM) to give compound 13 (99.1 mg, 0.303 mmol) in 79% yield. TIFF2025509736000453.tif49155

[0474] TIFF2025509736000454.tif31128 Compound 13 (99.1 mg, 0.303 mmol) was dissolved in DMF (5 mL) and treated with sodium hydride (8.7 mg, 0.364 mmol, 1.2 equiv.) and then stirred under nitrogen for 15 min. Compound 18 (108 mg, 0.364 mmol, 1.2 equiv.) was then added and the reaction was stirred for 1 h. The reaction was neutralized by dropwise addition of acetic acid. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and washed with brine (4x), the organic layer was dried over sodium sulfate and evaporated onto silica. The crude mixture was purified on silica (50-100% EtOAc in hexanes) to give compound 14 (131 mg, 0.248 mmol) in 82% yield. TIFF2025509736000455.tif20157

[0475] TIFF2025509736000456.tif31128 Compound 14 (131 mg, 0.240 mmol) was dissolved in methanol (10 mL) and stirred under a nitrogen atmosphere. Lindlar's catalyst (13.1 mg, 10 wt%) was then added and the reaction was stirred under a H2 atmosphere (1 atm) for 6 h. The reaction was then filtered over Celite and the solvent was evaporated to give compound 15 (120 mg, 0.240 mmol) in quantitative yield, which was used without further purification. TIFF2025509736000457.tif5128

[0476] Example 2-10. Divalent MIF binding (Figure 23) TIFF2025509736000458.tif14128 Serinol (2.00 g, 22.0 mmol) was dissolved in dichloromethane (40 mL) and trimethylamine (10 mL). Di-tert-butyl dicarbonate (5.76 g, 26.4 mmol, 1.2 equiv) was then added and the reaction was stirred for 4 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic fraction was washed with water (1x), 1M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), then dried over sodium sulfate and evaporated to give compound 23 (3.99 g, 20.9 mmol) in 95% yield, which was used without purification in the further step.

[0477] TIFF2025509736000459.tif26128 Compound 23 (3.99 g, 20.9 mmol) was dissolved in a mixture of dioxane (12 mL) and aqueous KOH (1.63 g, 29 mmol, 2.4 mL). Acrylonitrile (3.02 mL, 2.44 g, 46.0 mmol, 2.2 equiv) was then added dropwise over 2.5 h and the reaction was stirred under nitrogen for 24 h. The reaction was neutralized by addition of 2M HCl (16 mL) and partitioned between DCM and water. The organic layer was washed with water (2x) and brine (1x), dried over sodium sulfate and evaporated. The crude mixture was purified on silica (20-100% EtOAc in hexanes) to give compound 20 (4.96 g, 16.7 mmol) in 80% yield. TIFF2025509736000460.tif27156

[0478] TIFF2025509736000461.tif26128 Compound 24 (4.96 g, 16.7 mmol) was dissolved in methanol (40 mL) and concentrated sulfuric acid (10 mL) was added. The mixture was heated at reflux under nitrogen for 24 h and then cooled to room temperature. Excess sodium bicarbonate was then added followed by di-tert-butyl dicarbonate (4.37 g, 20.04 mmol, 1.2 equiv.) and the reaction was stirred at room temperature for 6 h. The cloudy mixture was partitioned between water and ethyl acetate and the organic fraction was washed with water (1x), 0.5 M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), dried over sodium sulfate, and evaporated. Compound 20 was purified on silica over a gradient of 0-10% MeOH in DCM and recovered in 74% yield (4.50 g, 12.4 mmol). TIFF2025509736000462.tif27153

[0479] TIFF2025509736000463.tif34128 Compound 25 (1.00 g, 2.75 mmol) was dissolved in dry MeOH (10 mL) and TFA (1 mL) and stirred for 15 min. Volatiles were evaporated under reduced pressure to give compound 26 as a TFA salt (1.04 g) in quantitative yield.

[0480] TIFF2025509736000464.tif37128 Compound 34 (50.0 mg, 0.123 mmol) was dissolved in DMF (5 mL) and DIPEA (214 μL, 159 mg, 1.23 mmol, 10 equiv) and stirred under nitrogen. HBTU (102.4 mg, 0.270 mmol, 2.2 equiv) was then added and the reaction was stirred for 15 min. A solution of compound 26 (102 mg, 0.270 mmol, 2.2 equiv) in DMF (1 mL) was then added dropwise and the reaction was stirred for 1 h. The mixture was diluted in ethyl acetate and washed with 1M HCl (2x) and brine (5x). The organic layer was evaporated to give a gummy residue which was purified by reverse phase HPLC (35-45% MeCN in water, 0.1% TFA) to give compound 40 (62.6 mg, 0.0959 mmol) in 78% yield. TIFF2025509736000465.tif4128

[0481] Compound 40 (62.6 mg, 0.0959 mmol) was dissolved in dioxane (1.8 mL) and 1M NaOH (0.2 mL) was added. The solution was stirred at room temperature for 2 h, then acidified (pH 3) and evaporated. The residue was resuspended in EtOAc, washed with 1M HCl, and dried over sodium sulfate. The organic layer was evaporated to give compound 41 as an oil (57.6 mg, 0.0921 mmol) in 96% yield, which was used without further purification.

[0482] Example 2-11. Trivalent MIF binding (Figure 23) TIFF2025509736000466.tif41128 Compound 34 (50.0 mg, 0.123 mmol) was dissolved in DMF (5 mL) and DIPEA (214 μL, 159 mg, 1.23 mmol, 10 equiv) and stirred under nitrogen. HBTU (154 mg, 0.405 mmol, 3.3 equiv) was then added and the reaction was stirred for 15 min. A solution of compound 29 (200 mg, 0.405 mmol, 3.3 equiv) in DMF (1 mL) was then added dropwise and the reaction was stirred for 1 h. The mixture was diluted in ethyl acetate and washed with 1M HCl (2x) and brine (5x). The organic layer was evaporated to give a gummy residue which was purified by reverse phase HPLC (35-50% MeCN in water, 0.1% TFA) to give compound 44 (79.3 mg, 0.103 mmol) in 84% yield. TIFF2025509736000467.tif5128

[0483] Compound 44 (79.3 mg, 0.103 mmol) was dissolved in dioxane (1.8 mL) and 1M NaOH (0.2 mL) was added. The solution was stirred at room temperature for 2 h, then acidified (pH 3) and evaporated. The residue was resuspended in EtOAc, washed with 1M HCl, and dried over sodium sulfate. The organic layer was evaporated to give compound 41 as an oil (68.9 mg, 0.0948 mmol) in 92% yield, which was used without further purification.

[0484] Example 2-12. MIF-AcF3-2 (Figure 24) TIFF2025509736000468.tif55163 Compound 41 (57.6 mg, 0.0921 mmol) was dissolved in DMF (1.8 mL) and DIPEA (0.2 mL). HBTU (84.0 mg, 0.222 mmol, 2.4 equiv) was then added and the reaction was stirred for 15 min, after which compound 15 (111 mg, 0.222 mmol, 2.4 equiv) was added. The reaction was stirred for 1 h and then evaporated to give a red residue which was used in the next reaction without purification.

[0485] Compound 42 (crude product, 0.0921 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 h. The reaction was directly purified by HPLC (20-40% MeCN in HO, +3% TFA) to give compound 43 (44.66 mg, 0.0295 mmol) in 32% yield. TIFF2025509736000469.tif4128

[0486] Example 2-13. MIF-AcF3-3 (Figure 25) TIFF2025509736000470.tif77163 Compound 45 (68.9 mg, 0.0948 mmol) was dissolved in DMF (1.8 mL) and DIPEA (0.2 mL). HBTU (126 mg, 0.333 mmol, 3.6 equiv) was then added and the reaction was stirred for 15 min, after which compound 15 (167 mg, 0.333 mmol, 3.6 equiv) was added. The reaction was stirred for 1 h and then evaporated to give a reddish residue which was used in the next reaction without purification.

[0487] Compound 38 (crude product, 0.0948 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 h. The reaction was directly purified by HPLC (20-40% MeCN in HO, +3% TFA) to give compound 39 (78.1 mg, 0.0379 mmol) in 40% yield. TIFF2025509736000471.tif4128

[0488] Example 2-14. Synthesis of MIF-AcF2-3, MIF-Ac-3, and MIF-Et-3 The chemical synthesis of MIF-AcF2-3, MIF-Ac-3, MIF-Et-3, and MIF-EtF3-3, which were produced using methods similar to those described above with minor modifications, are described in Figures 26-29.

[0489] The above outlines the features of some embodiments so that those skilled in the art can better understand aspects of the present disclosure. Those skilled in the art should recognize that they can easily use this disclosure as a basis for designing or modifying other processes and structures to perform the same purpose and / or achieve the same advantages as the embodiments introduced herein. Those skilled in the art should also understand that these equivalent configurations do not depart from the spirit and scope of the present disclosure, and that those skilled in the art can make various changes, substitutions, and alterations to the present specification without departing from the spirit and scope of the present disclosure.

Claims

1. Chemical structure below: A difunctional compound thereof, or a salt, stereoisomer, or solvate thereof, During the ceremony, [MIFBM / IgGBM] is an MIF-binding or IgG-binding moiety that binds to circulating MIF or circulating IgG, respectively, and each of these circulating MIF or circulating IgGs is associated with a pathological condition and / or state and should be removed by the action of hepatocytes on circulating proteins; [ASGPRBM] is a binding site that, preferably in a patient or subject, binds to hepatocytes via asialoglycoprotein receptors on the surface of hepatocytes; Each [CON] is an optional connector chemical part, which, if present, is directly connected to [MIFBM / IgGBM] or [ASGPRBM], or connects the [linker] to [MIFBM / IgGBM] or [ASGPRBM]. [Linker] is a chemical moiety having a valency of 1 to 15, more frequently 1 to 10, more frequently 1 to 5, or 1, 2, or 3, which optionally contains one or more [CON] or [MULTICON] groups, wherein the linker itself may contain one or more [CON] or [MULTICON] groups; k' is 1-15, 1-10, 1-5, 1-3, or 1, 2, or 3; j' is 1-15, 1-10, 1-5, 1-3, or 1, 2, or 3; h and h' are each independently between 0 and 15; i L is 0 to 15, frequently 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1, 2, or 3, preferably i L is 1 to 5, or 1, 2, or 3, except h, h', and i L At least one of these is preferably at least one, Here, the compound in question is as follows: Selected from the group consisting of, During the ceremony, An extracellular protein targeting ligand is an MIF-binding or IgG-binding moiety that binds to circulating MIF or circulating IgG, respectively, in the target, and each of these circulating MIFs or IgGs is associated with a pathological condition or state and should be removed by the action of the target hepatocytes or other cells; X 1 is one to five groups independently selected from O, S, N(R 6 ), and C(R 4 )(R<00000!07>), where when X 1 is one group, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ), and when X 1 is two groups, at most one group of X 1 is O, S, or N(R 6 ), and when X 1 is three, four, or five groups, at most two groups of X 1 are O, S, or N(R 6 ); R 2 teeth (i) Heteroaryls comprising an aryl, a heterocyclic, and one or two heteroatoms independently selected from N, O, and S, where each of the aryl, heterocyclic, and heteroaryl may be substituted with one, two, three, or four substituents; (ii) ; (iii) Each may be substituted with one, two, three, or four substituents, -NR 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 ) 2 , -NR 8 C(O)NR 9 S(O) 2 R 3 , -NR 8 -S(O) 2 -R 10 , and -NR 8 -C(NR 6 )-R 3 ; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 More selected; R 10 These are aryl, alkyl-NR 8 -C(O)R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 Alkyl-NR 6 R 8 , NR 8 -NR 6 -C(O)R 3 , NR 8 -S(O) 2 R 3 , alkenyl, allyl, alkinyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, the R 10 Each of these may be substituted with one, two, three, or four substituents; R 1 and R 5 are independently hydrogen, heteroalkyl, C 0 -C 6 -alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-SR 6 , C 0 -C 6 -alkyl-NR 6 R 7 , C 0 -C 6 -alkyl-C(O)R 3 , C 0 -C 6 -alkyl-S(O)R 3 , C 0 -C 6 -alkyl-C(S)R 3 , C 0 -C 6 -alkyl-S(O) 2 R 3 , C 0 -C 6 -alkyl-N(R 8 )-C(O)R 3 , C 0 -C 6 -alkyl-N(R 8 )-S(O)R 3 , C 0 -C 6 -alkyl-N(R 8 )-C(S)R 3 , C 0 -C 6 -alkyl-N(R 8 )-S(O) 2 R 3 , C 0 -C 6 -alkyl-O-C(O)R 3 , C 0 -C 6 -alkyl-O-S(O)R 3 , C 0 ~C 6 Alkyl-OC(S)R 3 -N=S(O)(R 3 ) 2 , C 0 ~C 6 Alkyl N 3 , and C 0 ~C 6 Alkyl-OS(O) 2 R 3 More are selected, each of which may be substituted with one, two, three, or four substituents; R 3 Each instance independently produces hydrogen, alkyl, heteroalkyl, and haloalkyl (-CF) atoms. 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 F and -CF 2 CF 3 (including), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 8 , and -NR 8 R 9 More selected; R 4 These independently appear as hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 6 and R 7 These independently appear as hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 8 and R 9 Each element is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic elements at each occurrence; The ring is a 3- to 8-membered fused cyclic group which may be substituted with one, two, three, or four substituents; Each linker A This is either binding to or linking the ASGPR ligand. B It is the part that is covalently connected to it; Linker B is a link or a combination. A This is the portion that covalently links to an extracellular protein targeting ligand; Linker C Each linker A It is a chemical group that links to an extracellular protein targeting ligand; Linker D Each linker A It is a chemical group that links to an extracellular protein targeting ligand; Here, R 2 NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O) 2 -Alkenyl, -NR 8 -S(O) 2 -alkynyl, -NR 6 -heteroaryl, or -NR 6 - If it is an aryl ligand, the extracellular protein targeting ligand does not contain an oligonucleotide; Optional substituents may be alkyl, alkenyl, alkynyl, haloalkyl, or -OR, as long as their valence allows for a stable compound. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , More selected The aforementioned bifunctional compound, or its salt, stereoisomer, or solvate.

2. A bifunctional compound according to claim 1, selected from the group consisting of the following.

3. A bifunctional compound according to claim 1, selected from the group consisting of the above.

4. R 1 The bifunctional compound according to claim 1, wherein is H.

5. R 2 R 10 The bifunctional compound according to claim 1.

6. R 10 ga-NR 6 - The bifunctional compound according to claim 1, wherein it is a heteroaryl compound.

7. R 6 The bifunctional compound according to claim 1, wherein is H.

8. -NR 6 -heteroaryl A bifunctional compound according to claim 1, selected from the group consisting of the following.

9. The bifunctional compound according to claim 1, wherein the extracellular protein targeting ligand is the MIF binding site.

10. The bifunctional compound according to claim 1, wherein the extracellular protein targeting ligand is an IgG binding site.

11. Linker A but A bifunctional compound according to claim 1, selected from the group consisting of the following.

12. A pharmaceutical composition comprising, in combination with a pharmaceutically acceptable carrier, additive, or excipient, a therapeutically effective amount of the bifunctional compound according to any one of claims 1 to 11, and optionally further comprising an additional bioactive agent effective for treating, relieving, and / or preventing cancer, autoimmune disease, or inflammatory disease in a patient or subject, or cancer, autoimmune disease, or inflammatory disease associated with upregulation of MIF or IgG in a patient or subject.

13. The aforementioned additional bioactive agents include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batablin, ofatumumab (Arzerra), zanorimumab, edtecarin, tetrandrin, rubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Jaimatecan, IL13-PE38QQR, INO 1001, IPdR 1 KRX-0402, Lucanton, LY 317615, Neurab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-L-glutamate disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, batalanib, AG-013736, AVE-0005, acetate of [D-Ser(But)6,Azgly10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH 2 Acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X (wherein x = 1 to 2.4 in the formula), goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifanib; Amifostin, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, clado Livin, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleebec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisol, lomustine, mechloretamine, melphalan, 6-mercaptoprazole Phosphorus, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-cis-retinoic acid, Phenyl Alanine mustard, uracil mustard, estramustine, altoretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimasut, COL-3, neovastat, BMS-275291, squalamine, endostatin,SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxyfene, Spironolactone, Finasteride, Cimetidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezomib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vi Norelbine, Bevacizumab, Erbitux, Cremohol-free Paclitaxel, Epotilon B, BMS-247550, BMS-310705, Doroxifene, 4-Hydroxytamoxifene, Pipendoxifene, ERA-923, Alzoxifene, Fulvestrant, Acorbifen, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte colony-stimulating factor, Zoledronate, Prednisone, Cetuximab, Granulocyte-macrophage colony-stimulating factor, Histrelin, Pegylated interferon α-2a, Interferon α-2a, Pegylated interferon α-2b, Interferon α-2b, Azaciti Zin, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor antagonist, palonosetron,The pharmaceutical composition according to claim 12, selected from the group consisting of aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, PD-L1 checkpoint inhibitor, PD-1 checkpoint inhibitor, or CTLA-4 checkpoint inhibitor.

14. A pharmaceutical composition for removing excess circulating MIF or circulating IgG in a patient or subject, comprising a therapeutically effective amount of the bifunctional compound according to any one of claims 1 to 11.

15. A pharmaceutical composition for treating, relieving, and / or preventing a pathological condition or state associated with the upregulation of MIF or IgG in a patient or subject, comprising a therapeutically effective amount of the bifunctional compound according to any one of claims 1 to 11.

16. The pharmaceutical composition according to claim 15, wherein the aforementioned pathological condition or state is cancer, an autoimmune disease, or an inflammatory disease.

17. A pharmaceutical composition for treating, relieving, or preventing cancer, autoimmune disease, or inflammatory disease in a subject or patient, comprising a therapeutically effective amount of the bifunctional compound according to any one of claims 1 to 11.

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