Bifunctional molecules for degrading circulating proteins

Abstract

Described herein are bifunctional compounds for removal of macrophage migration inhibiting factor (MIF) or immunoglobulin G (IgG). Further described herein are pharmaceutical compositions comprising these bifunctional compounds. Further described herein are methods of treating disease states and / or conditions with the compounds or the compositions. The disease state and / or condition is mediated by MIF / IgG or wherein MIF / IgG is an onset factor for the progression and persistence of diseases and / or conditions such as autoimmune diseases and cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Application No. 17 / 695,259, filed on March 15, 2022, which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with government support under Grant GM067543 from the National Institutes of Health and Grant W81XWH-13-1-0062 from the United States Army Medical Research and Material Command. The government has certain rights in this invention.

[0005] Sequence Listing

[0006] This application contains a sequence listing, which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. The ASCII copy was created on March 12, 2023, is named 47162-7240WO2_SequenceListing.xml, and is 30.8 kilobytes in size. Background Art

[0007] MIF is a pro-inflammatory multipotent cytokine that contributes to the development and persistence of a variety of diseases. These diseases include atherosclerosis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sepsis, inflammatory bowel disease (IBD), etc. In addition, MIF has been shown to be involved in the progression of a variety of cancers, including colon cancer, prostate cancer, breast cancer, lung cancer, cervical cancer, and adenocarcinoma. In preclinical models, it has been shown that inhibition of MIF alleviates the symptoms of the above diseases and delays disease progression.

[0008] MIF and IgG greatly promote the pathological process of various diseases. MIF neutralizing antibodies and small molecule MIF inhibitors have been developed, wherein IgG is upregulated and causes adverse effects in autoimmune diseases and other diseases. Because MIF plays a role through multiple pathways, MIF inhibitors are sometimes needed to interrupt multiple protein-protein interactions (PPI), which brings challenges to the development of this application. With regard to IgG, the IgG molecules that are upregulated and cause autoimmune diseases and / or other diseases can sometimes be used to suppress and / or improve the impact of disease states. Therefore, a new method that can degrade and suppress MIF or IgG can overcome this difficulty, and more robust treatment response can be potentially provided. Encouraged by the preliminary results of bifunctional MIF and IgG degraders (degraders), the inventors decide to further test it in clinically relevant in vivo models and potentially develop it into the therapeutic agent (therapeutics) of targeting MIF or IgG in disease. They also intend to utilize this basic bifunctional molecular strategy to achieve degradation via ASGPr targeting other interested circulating proteins.

[0009] Therefore, there is a need for molecules capable of eliminating MIPs and / or IgG. The present disclosure addresses this need. Summary of the invention

[0010] 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 is intended to establish a general small molecule strategy for selective degradation of MIF or IgG that promotes the development and persistence of multiple diseases. In some embodiments, the bifunctional molecular construct comprises: a MIF binding motif, which is derived from a known small molecule ligand of MIF; or an IgG binding motif, which includes a ligand that binds IgG. These parts are collectively referred to herein as macrophage migration inhibitory factor binding moiety (macrophage migration inhibitory factor binding moiety, MIFBM) or alternatively, immunoglobulin G binding moiety (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 (asialoglycoprotein receptor, ASGPr), which is a three-branched N-acetylgalactosamine or other parts described herein. This specification sometimes refers to these parts as asialoglycoprotein receptor binding moiety (asialoglycoprotein receptor binding moiety, ASGPRBM). According to some embodiments, the motif for providing a bifunctional compound, i.e., (MIFBM or IgGBM) and (ASGPRBM) are covalently linked via a linker such as: polyethylene glycol (PEG) or other linkers with adjustable length as described herein or other linkers as described herein, which optionally include one or more linker molecules connecting the linker to MIFBM or IgGBM and / or ASGPRBM.

[0011] In some embodiments, the bifunctional compound selectively binds to MIF or IgG in the circulation and forms a protein complex. When this protein complex passes through the liver, the asialoglycoprotein receptor binding portion (ASGPRBM) of the molecule, such as a three-branched N-acetylgalactosamine or other motifs described herein, will engage the endosomal-lysosomal pathway of the hepatocytes through the ASGPr. As a result of this mechanism, MIF or IgG is eliminated from the circulation by the hepatocytes, resulting in a reduction in the level of MIF or IgG, and as a result, the corresponding disease symptoms of the patient or object to whom the compound is applied are weakened and / or eliminated. In some cases, MIF is greatly reduced or eliminated or the harmful IgG is greatly reduced, resulting in a significant reduction in symptoms, or even a cure or elimination of a disease state or condition.

[0012] Compared with the classical antibody-based strategies of the prior art targeting MIF or IgG, the methods according to the present disclosure inherently have advantages. The small molecule-based methods of the present disclosure overcome the limitations of traditional antibody-based strategies, including lack of oral bioavailability, cryogenic storage requirements, immunogenicity and high cost.

[0013] In addition, compared with conventional inhibition methods, the compounds and methods of the present disclosure are expected to have a more lasting effect because MIF or IgG is significantly reduced or eliminated by degradation inside the hepatocyte rather than simply by reversibly blocking protein-receptor interactions. The bifunctional molecular constructs according to the present disclosure are also universal, and their significance lies in that different disease states and / or conditions can be targeted by inhibiting and degrading MIF or IgG. Therefore, previously discovered non-inhibitory protein binders (currently of little value in treatment) may have potential therapeutic uses in these small molecules.

[0014] In certain embodiments, the present disclosure relates to compounds for use in removing circulating proteins associated with a disease state or condition in a patient or subject according to the following general chemical structure:

[0015]

[0016] wherein [MIFBM / IgGBM] is a MIF or IgG binding moiety that binds to circulating MIF or IgG, respectively, which is associated with a disease state and / or condition and is to be removed by the action of hepatocytes on the circulating protein (in some embodiments, the compound selectively binds to MIF or IgG in plasma);

[0017] [ASGPRBM] is a binding moiety that binds to a hepatocyte via an asialoglycoprotein receptor on the surface of a hepatocyte, such as in a patient or subject;

[0018] Each [CON] is an optional connector chemical moiety which, when present, directly connects to [MIFBM / IgGBM] or [ASGPRBM] or connects [Linker] to [MIFBM / IgGBM] or [ASGPRBM], and

[0019] [Linker] is a chemical moiety with a valency ranging from 1 to 15, such as ranging from 1 to 10, ranging from 1 to 5, or being 1, 2 or 3, which is covalently linked to one or more [ASGPRM] and / or [MIFBM / IgGBM] groups, optionally via a [CON] including a [MULTICON] group, wherein the [Linker] itself optionally comprises one or more [CON] or [MULTICON] groups;

[0020] k' is an integer ranging from 1 to 15, such as ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or being 1, 2, or 3;

[0021] j' is an integer ranging from 1 to 15, such as ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or being 1, 2, or 3;

[0022] h and h' are each independently an integer ranging from 0 to 15, such as ranging from 1 to 15, ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or 1, 2 or 3, optionally h and / or h' is at least 1;

[0023] i L is an integer ranging from 0 to 15, such as ranging from 1 to 15, ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or being 1, 2 or 3, optionally, i L is an integer ranging from 1 to 5 or 1, 2 or 3, provided that h, h' and i L At least one of is at least 1, or

[0024] Pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof.

[0025] In some embodiments, [MIFBM] is a moiety according to the following chemical structure:

[0026]

[0027] Where X M Yes-(CH 2 ) IM 、-O-(CH 2 ) IM 、S-(CH 2 ) IM NR M -(CH 2 ) IM 、C(O)-(CH 2 ) IM -, a polyethylene glycol (PEG) group containing 1 to 8 (such as 1 to 4) ethylene glycol residues, or -C(O)(CH 2 ) IM NR M Group;

[0028] R M is H or C optionally substituted by one or two hydroxy groups 1 To C 3 alkyl;

[0029] IM is 0-6, such as 1, 2, 3 or 4, such as 1.

[0030] In some embodiments, [IgGMB] is a group according to the following chemical structure:

[0031]

[0032] wherein DNP is 2,4-dinitrophenyl; or

[0033] Groups according to the following chemical structures:

[0034] Where Y' is H or NO 2 ;

[0035] X is O, CH 2 NR 1 、S(O)、S(O) 2 、-S(O) 2 O, -OS(O) 2 or OS(O) 2 O; and

[0036] R 1 It is H, C 1 To C 3 Alkyl or -C(O)(C 1 To C 3 ) group; or

[0037] Groups according to the following chemical structures:

[0038] Where R 1 Same as above; and

[0039] K" is 1 to 5 (such as 3-5, such as 4) or

[0040] A group represented by the following chemical formula:

[0041] Where X' is CH 2 , O, NR 1 'or S;

[0042] R 1’ Is H or C 1 To C 3 Alkyl; and

[0043] Z is a bond, a monosaccharide, a disaccharide, an oligosaccharide, such as a sugar radical selected from monosaccharides (including aldoses and ketoses) and disaccharides (including those described herein). The monosaccharide aldoses include monosaccharides such as aldotrose (D-glyceraldehyde, etc.), aldotroses (D-erythrose and D-threose, etc.), aldopentoses (D-ribose, D-arabinose, D-xylose, D-lyxose, etc.), aldohexoses (D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose and D-talose, etc.), and the monosaccharide ketoses include monosaccharides such as dihydroxyacetone (dihydroxyacetone, etc.), ketotetroses (D-erythrulose, etc.), ketopentose (D-ribulose and D-xylulose, etc.), ketohexoses (D-pseudofructose (D-Psicone), D-fructose, D-sorbose, D-tagatose, etc.), amino sugars (including galactosamine, sialic acid, N-acetylglucosamine, etc.) and sulfonyl sugars (including sulfoquinolose, etc.). Exemplary disaccharides useful in the present disclosure include sucrose (which may have glucose that is optionally N-acetylated), lactose (which may have galactose and / or glucose that is optionally N-acetylated), maltose (which may have one or two glucose residues that are optionally N-acetylated), trehalose (which may have one or two glucose residues that are optionally N-acetylated), cellobiose (which may have one or two glucose residues that are optionally N-acetylated), kojibiose (which may have one or two glucose residues that are optionally N-acetylated), myricose (which may have one or two glucose residues that are optionally N-acetylated), isomaltose (which may have one or two glucose residues that are optionally N-acetylated), β,β-trehalose (which may have one or two glucose residues that are optionally N-acetylated), sophorose (which may have one or two glucose residues that are optionally N-acetylated), laminaria biose (which may have one or two glucose residues that are optionally N-acetylated), sugar (which may have one or two optionally N-acetylated glucose residues), gentiobiose (which may have one or two optionally N-acetylated glucose residues), turanose (which may have optionally N-acetylated glucose residues), maltulose (which may have optionally N-acetylated glucose residues), palatinose (which may have optionally N-acetylated glucose residues), gentiobiluose (which may have optionally N-acetylated glucose residues), mannobiose, melibiose (which may have optionally N-acetylated glucose residues and / or galactose residues), melibiulose (which may have optionally N-acetylated galactose residues), rutinose (which may have optionally N-acetylated glucose residues), rutinulose and xylobiose, etc.

[0044] In some embodiments, [IgGBM] is a group according to the following chemical structure:

[0045]

[0046] Where X R O, S or NR 1 ;and

[0047] X M Yes O, NR 1 or S, and

[0048] R 1 Is H or C 1 To C 3 alkyl.

[0049] In some embodiments, [IgGBM] is a group according to the following chemical structure:

[0050]

[0051] Where X" is O, CH 2 NR 1 , S; and

[0052] R 1 It is H, C 1 To C 3 Alkyl or -C(O)(C 1 To C 3 ) group; or

[0053] Where X b is a bond, O, CH 2 or NR 1 or S; and

[0054] R 1 Same as above; or

[0055] Groups according to the following chemical structures:

[0056]

[0057] Where R N02 It is through CH 2 、S(O)、S(O) 2 、-S(O) 2 O, -OS(O) 2 or OS(O) 2 O optionally attached dinitrophenyl; or

[0058] Dinitrophenyl according to the following chemical structure:

[0059]

[0060] X is O, CH 2 NR 1 、S(O)、S(O) 2 、-S(O) 2 O, -OS(O) 2 or OS(O) 2 O; and

[0061] R 1 It is H, C 1 To C 3 Alkyl or -C(O)(C 1 To C 3 ) group.

[0062] In some embodiments, [IgGBM] is a group according to the following chemical structure:

[0063]

[0064] wherein K'" is 1 to 4 (such as 2-3, such as 3), or

[0065] According to this article Fig.67 A group of the chemical structure shown in FIG. 1 , which is covalently linked to a [CON] group, a [Linker] group or a [ASGPRBM] group through an amine group such as the following: 1 -C 3 Alkyl optionally substituted primary or secondary alkylamine groups.

[0066] In some embodiments, [IgGBM] is a peptide according to the following sequence (all cited references are incorporated herein by reference):

[0067] PAM (Fassina, et al., J. Mol. Recognit. 1996, 9, 564-569);

[0068] D-PAM (Verdoliva, et al., J. Immunol. Methods, 2002, 271, 77-88);

[0069] D-PAM-Φ (Dinon, et al. J. Mol. Recognit. 2011, 24, 1087-1094);

[0070] TWKTSRISIF (Krook, et al., J. Immunol. Methods 1998, 221, 151-157) SEQ ID NO: 1;

[0071] FGRLVSSIRY(Krook,et al.,J.Immunol.Methods 1998,221,151-157)SEQ ID NO:2;

[0072] Fc-III (DeLano, et al., Science 2000, 287, 1279-1283)

[0073] FcBP-1(Kang,et al.,J.Chromatogr.A2016,1466,105-112);

[0074] FcBP-2(Dias,et al.,J.Am.Chem.Soc.2006,128,2726-2732)

[0075] Fc-III-4c(Gong,et al.,Bioconjug.Chem.2016,27,1569-1573)

[0076] EPIHRSTLTALL(Ehrlich,et al.,J.Biochem.Biophys.Method 2001,49,443-454)

[0077] SEQ ID NO:3

[0078] APAR(Camperi,et al.,Biotechnol.Lett.2003,25,1545-1548)SEQ ID NO:4;

[0079] FcRM(Fc Receptor Mimetic,Verdoliva,et al.,ChemBioChem 2005,6,1242-1253);

[0080] HWRGWV(Yang,et al.,J.Peptide Res.2006,66,110-137)SEQ ID NO:5;

[0081] HYFKFD(Yang,et al.,J.Chromatogr.A 2009,1216,910-918)SEQ ID NO:6;

[0082] HFRRHL(Menegatti,et al.,J.Chromatogr.A 2016,1445,93-104)SEQ ID NO:7;

[0083] HWCitGWV (Menegatti, et al., J. Chromatogr. A 2016, 1445, 93 - 104) SEQ ID NO:8;

[0084] D2AAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr. A 2012, 1225, 158 - 167);

[0085] DAAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr. A 2012, 1225, 158 - 167);

[0086] Cyclo[(N - Ac)S(A)-RWHYFK - Lact - E] (Menegatti, et al., Anal. Chem. 2013, 85, 9229 - 9237)

[0087] (SEQ ID NO:9 - Lact - E);

[0088] Cyclo[(N - Ac)-Dap(A)-RWHYFK - Lact - E] (Menegatti, et al., Anal. Chem. 2013, 85, 9229 - 9237) (SEQ ID NO:10 - Lact - E);

[0089] Cyclo[Linker - M - WFRHYK] (Menegatti, et al., Biotechnol. Bioeng. 2013, 110, 857 - 870)

[0090] SEQ ID NO:11;

[0091] NKFRGKYK (Sugita, et al., Biochem. Eng. J. 2013, 79, 33 - 40) SEQ ID NO:12;

[0092] NARKFYKG (Sugita, et al., Biochem. Eng. J. 2013, 79, 33 - 40) SEQ ID NO:13;

[0093] FYWHCLDE (Zhao, et al., Biochem. Eng. J. 2014, 88, 1 - 11) SEQ ID NO:14;

[0094] FYCHWALE (Zhao, et al., J. Chromatogr. A 2014, 1355, 107-114) SEQ ID NO: 15;

[0095] FYCHTIDE (Zhao, et al., J. Chromatogr. A 2014, 1359, 100-111) SEQ ID NO: 16;

[0096] Double 1 / 3 (Zhao, et al., J. Chromatogr. A 2014, 1369, 64-72);

[0097] RRGW (Tsai, et al., Anal. Chem. 2014, 86, 2931-2938) SEQ ID NO: 17;

[0098] KHRFNKD (Yoo and Choi, BioChip J. 2015, 10, 88-94) SEQ ID NO: 18;

[0099] In some embodiments, [ASGPRBM] is a group according to the following chemical structure:

[0100]

[0101] Where X is 1-4 atoms in length and includes O, S, N (R N1 ) or C(R N1 )(R N1 ) group makes

[0102] When X is 1 atom in length, X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[0103] When X is 2 atoms long, no more than one atom in X is O, S, or N (R N1 ),

[0104] When X is 3 or 4 atoms in length, no more than 2 atoms in X are O, S, or N (R N1 );

[0105] Where R N1 is H or C optionally substituted by 1-3 halo groups (such as F) 1 -C 3 Alkyl (in some embodiments, R N1 is H or methyl);

[0106] R1 and R 3 are independently H, -(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br or I) 1 -C 4 Alkyl, -(CH 2 ) K Vinyl, O-(CH 2 ) K Vinyl, -(CH 2 ) K Alkynyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or

[0107] R 1 and R 3 Each independently is A group, which is optionally substituted by: up to three (such as 1) halo groups (such as F); C 1 -C 4 alkyl, each of which is optionally substituted by one to three halo groups (such as F), or one or two hydroxy groups; or OC 1 -C 4 alkyl, wherein each alkyl is optionally substituted by one to three halo groups (such as F), or one or two hydroxy groups, and K is independently an integer ranging from 0 to 4 (such as 0, 1, 2, 3 or 4), or

[0108] R 1 and R 3 Each is independently a group according to the following chemical structure:

[0109] Where R 7 It's OC 1 -C 4alkyl, which is optionally substituted by 1 to 3 halo groups (such as F) and 1 or 2 hydroxy groups, or R 7 yes

[0110] -NR N3 R N4 Group or

[0111] or R 1 and R 3 Each is independently a group according to the following structure:

[0112]

[0113] Group,

[0114] wherein CYC is a ring selected from the group consisting of:

[0115] and C 3 -C 8 Saturated carbon ring, where the linker X, R C and -(CH 2 ) K - Each of them is connected to the open price in CYC, including NH;

[0116] R C is absent, is H, is C optionally substituted by 1-3 halo (such as F) or 1-2 hydroxyl 1 -C 4 Alkyl or a group according to the following structure:

[0117]

[0118] Where R 4 , R 5 and R 6 are independently H, halogen (F, Cl, Br, I), CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br, I) 1 -C 3 alkyl, -OC optionally substituted by 1-3 halo groups (such as F) 1 -C 3 -alkyl, -(CH 2) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or

[0119] R C yes

[0120]

[0121] Where R N , R N1 and R N2 are each independently H or C optionally substituted with one to three halo groups (such as F) or one or two hydroxy groups 1 -C 3 alkyl;

[0122] K is independently an integer ranging from 0-4 (0, 1, 2, 3 or 4);

[0123] K' is an integer ranging from 1 to 4 (such as 1);

[0124] R N3 is H or C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl; and

[0125] R N4 is H, C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl, or R N4 yes group, wherein K is sometimes 1;

[0126] is a linker group comprising at least one [MIFBM / IgGBM] group and connecting the [MIFBM / IgGBM] group to [ASGPRBM] via one or more optional [CON] groups, or

[0127] is a linker group comprising at least one or more functional groups that can be used to covalently bind the linker group to at least one [MIFBM / IgGBM] group or an optional [CON] group;

[0128] R 2 yes Group, where R N1 and K are the same as above;

[0129] R AM is H, C optionally substituted with up to 3 halo groups (such as F) and one or two hydroxy groups 1 -C 4 Alkyl, -(CH 2 ) K COOH group, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, -(CH 2 ) K -NR N3 R N4 Group, where R N3 is H or C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl; and

[0130] R N4 is H, C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl, or R N4 yes A group (K is sometimes 1), or

[0131] R 2 yes Group,

[0132] Where R TA H, CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br or I) 1 -C4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or R TA It is C 3 -C 10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of which is optionally substituted by up to three (such as 1) of the following groups: CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1 to 3 halogens (F, Cl, Br or I) or 1 or 2 hydroxyl groups 1 -C 3 alkyl, -OC optionally substituted by 1-3 halo groups (such as F) 1 -C 3 -alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl or -(CH 2 ) K C(O)-C 1 -C 4 Alkyl, or

[0133] R TA yes

[0134] or

[0135] R TA yes group, which is composed of up to three (such as 1) C 1 -C 3 The alkyl group is optionally substituted, C 1 -C 3 The alkyl group is optionally substituted with up to three halo groups (such as F), or R TA yes Group,

[0136] Where R N , R N1 and R N2 are each independently H or C optionally substituted with one to three halo groups (such as F) or one or two hydroxy groups 1 -C 3 Alkyl, and

[0137] Each of these -(CH 2 ) K The group is 1-4 (such as 1 or 2) C 1 -C 3 The alkyl group is optionally substituted, C 1 -C 3 The alkyl group is optionally substituted with 1-3 fluoro groups or 1-2 hydroxy groups;

[0138] And K is independently 0-4 (0, 1, 2, 3 or 4).

[0139] In some embodiments, [CON] is a linker moiety as described elsewhere herein (including [MULTICON]).

[0140] In some embodiments, [Linker] is a linking moiety as described elsewhere herein, which links [MIFBM / IgGBM] to an [ASGPRBM] group and optionally comprises one or more linker moieties (which optionally link more than one chemical moiety to provide the linking moiety or which links the linking moiety to the [MIFBM / IgGBM] group or the [ASGPRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0141] In some embodiments, when X is 2 atoms in length, 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(RN1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 ),

[0142] When the length of X is 3 atoms, X is -O-C(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(R N1 )(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

[0143] When X is 4 atoms long, 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(RN1 )(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 Same as above. In some embodiments, R N1 It's H.

[0144] In an embodiment, X is OCH 2 or CH 2 O. In some embodiments, R N1 It's H.

[0145] In an embodiment, the [ASGPRBM] group is a group according to the following chemical structure:

[0146]

[0147] Where R 1 , R 2 and R 3 Same as above, or

[0148] Pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof.

[0149] In some embodiments, the [ASGPRBM] group is a group according to the following chemical structure:

[0150]

[0151] Where R A It is C 1-C 3 Alkyl, which is optionally substituted with 1 to 5 halo groups (such as F) (in some embodiments, R A is methyl or ethyl, which is optionally substituted by 1 to 3 fluoro groups);

[0152] Z A Yes-(CH 2 ) IM 、-O-(CH 2 ) IM 、S-(CH 2 ) IM NR M -(CH 2 ) IM 、C(O)-(CH 2 ) IM -, a PEG group containing 1 to 8 (such as 1 to 4) ethylene glycol residues or -C(O)(CH 2 ) IM NR M A group (in some embodiments, a PEG-containing group comprising 1 to 8 ethylene glycol residues (such as 2-4 ethylene glycol residues), wherein IM and R M Same as above; and

[0153] Z B Does not exist, is (CH 2 ) IM , is C(O)-(CH 2 ) IM - or C(O)-(CH 2 ) IM -NR M , where IM and R M Same as above.

[0154] In some embodiments, R 1 and R 3 Each is independently often a group according to the following chemical structure:

[0155] Where R C , and K are the same as above.

[0156] In some embodiments, in the above compounds,

[0157]

[0158] yes

[0159]

[0160] Where R C , and K are the same as above.

[0161] In some embodiments, the compound comprises Figure 1 , Figure 7 and Fig.13 In some embodiments, the additional compound is present in Figure 16-Figure 66 and including the final compounds listed therein and the intermediates used to prepare the final compounds according to the present disclosure.

[0162] In some embodiments, R of the [ASGPRBM] group 1 and R 3 Including this article Fig.68 In some embodiments, the R 2 Including this article Fig.69 Those parts presented in .

[0163] In some embodiments, the IgGBM group is a FCIII group according to the following chemical structure: It can be expressed as (SEQ ID NO:19)

[0164] or an FcIII-4c peptide, which can be represented as (SEQ ID NO:20).

[0165] In some aspects, the present disclosure relates to pharmaceutical compositions comprising an effective amount of a compound according to the present disclosure in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional biologically active agent.

[0166] In some aspects, the disclosure relates to methods for treating disease states or conditions, wherein MIF is related to, or promotes, disease states and / or conditions or symptoms associated with disease states or conditions. These disease states and / or conditions include autoimmune diseases and various inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer's disease, atherosclerosis, heart disease, stroke, and cancer (including leukemia), etc. In some embodiments, the method of treatment includes administering an effective amount of at least one compound according to the present disclosure to a patient or object in need of treatment, optionally in combination with another bioactive agent, to reduce the likelihood of a disease state or condition, inhibit and / or treat a disease state or condition by removing MIF associated with a disease state and / or condition from the circulation of the patient or object.

[0167] In the experiment, the bifunctional molecule MIF-GN disclosed in the present invention3 Able to induce degradation of human MIF injected into mice. Additional work focuses on evaluating MIF-GN in autoimmune disease models. 3 , and seek to optimize bifunctional MIF degraders using different MIF and ASGPr ligands. IgG targeting molecules can recapitulate our results using MIF in cell culture and mediate the removal of IgG from mouse serum. Therefore, the present disclosure provides a useful platform for developing new therapies for these critical diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0168] Figure 1 Representative compounds according to some embodiments are shown. It should be noted that the figure discloses compound 3w (MIF inhibition negative control), MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1, MIF-AcF3-2 and MIF-AcF3-3. It should be noted that n in the PEG linker sometimes ranges from 1-12, such as 1 to 10, 2 to 8, 2 to 6, 2 to 5 or 1, 2, 3 or 4.

[0169] Figure 2 Fluorescence polarization data of MIF-FITC binding to human MIF according to some embodiments is shown, indicating that our MIF binding moiety binds to MIF. The bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3 and NVS-PEG3-GN3 competitively bind to MIF-FITC, indicating that the bifunctional molecules maintain the ability to bind to human MIF.

[0170] Figure 3 It was shown that the bifunctional molecules according to some embodiments are capable of depleting human MIF from the supernatant of cultured HepG2 cells.

[0171] Figure 4 It was shown that MIF internalized by HepG2 cells according to some embodiments is trafficked to lysosomes.

[0172] Figure 5 It is shown that MIF-GN3 mediates injected human MIF depletion from mice according to some embodiments.

[0173] Figure 6 It was shown that MIF-GN3 according to some embodiments can delay tumor growth in a mouse model of prostate cancer.

[0174] Figure 7 Shown are molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind anti-DNP IgG and ASGPR, according to some embodiments.

[0175] Figure 8 It is shown that DNP-GN3 and DNP-AcF3-3 mediate the formation of a ternary complex between HepG2 cells and anti-DNP according to some embodiments.

[0176] Fig. 9 It is shown that DNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa 488-labeled anti-DNP by HepG2 cells according to some embodiments.

[0177] Fig.10 It is shown that DNP-GN3 and DNP-AcF3-3 mediate the localization of alexa 568-labeled anti-DNP to late endosomes and lysosomes according to some embodiments.

[0178] Fig.11 It is shown that DNP-AcF3-3 mediates the degradation of alexa 488-labeled anti-DNP in HepG2 cells according to some embodiments.

[0179] Fig.12 It is shown that DNP-GN3 mediates depletion of anti-DNP from mouse serum according to some embodiments.

[0180] Fig.13 Shown are the structures of IgG degradation molecules IBA-GN3, Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3 according to some embodiments.

[0181] Fig.14 It is shown that FcIII-GN3 mediates uptake of human IgG into HepG2 cells according to some embodiments. The experiments were performed as described above.

[0182] Fig.15 It is shown that FcIII-GN3 mediates localization of IgG to late endosomes in HepG2 cells according to some embodiments. The experiments were performed as described above.

[0183] Figure 16-Figure 18 Shown are the syntheses of PEG linkers used in several molecules according to some embodiments.

[0184] Figure 19-21 Shown are the syntheses of ASGPR binding precursors and ligands used in several molecules according to some embodiments.

[0185] Figure 22-Figure 26 Shown are the syntheses of valency linkers used in several molecules according to some embodiments.

[0186] Figure 27-Figure 28 Shown are the syntheses of MIF ligands used in several bifunctional molecules according to some embodiments.

[0187] Fig.29 The synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3 according to some embodiments is described.

[0188] Fig.30 The synthesis of the bifunctional molecules MIF-GN3 and MIF-PEGn-GN3 according to some embodiments is described.

[0189] Fig.31 Described is the synthesis of a bifunctional molecule targeting MIF and ASGPR comprising a bicyclic ASGPR AcF3 ligand according to some embodiments.

[0190] Fig.32 The synthesis of a bifunctional molecule targeting MIF and ASGPR comprising two bicyclic ASGPr AcF3 ligands according to some embodiments is described.

[0191] Fig.33 The synthesis of bifunctional molecules targeting MIF and ASGPR comprising three bicyclic ASGPR ligands according to some embodiments is described.

[0192] Fig.34 Shown is the synthesis of DNP-GN3 according to some embodiments.

[0193] Fig.35 Shown is the synthesis of DNP-AcF3-3 according to some embodiments.

[0194] Fig.36 Shown is a synthetic scheme for obtaining IBA-GN3 according to some embodiments.

[0195] Fig.37 Shown is the synthesis of triazine-GN3 according to some embodiments.

[0196] Fig.38 Shown is a synthetic scheme for obtaining FcIII-GN3 according to some embodiments.

[0197] Fig.39 A synthetic scheme for obtaining FcIII-4c-GN3 according to some embodiments is shown.

[0198] Figure 40-Figure 43 The synthesis of a bifunctional molecule targeting MIF and ASGPr comprising three bicyclic ASGPR ligands with different substitutions on the 2-amine of the sugar according to some embodiments is described.

[0199] Fig.44 Shown is the synthesis of compound MIF-18-3 according to some embodiments.

[0200] Fig.45 Shown is the synthesis of compound MIF-31-3 according to some embodiments.

[0201] Fig.46 Shown is the synthesis of compound MIF-15-3 according to some embodiments.

[0202] Fig.47 Shown is the synthesis of compound MIF-19-3 according to some embodiments.

[0203] Fig.48 Shown is the synthesis of compound MIF-16-3 according to some embodiments.

[0204] Fig.49 Shown is the synthesis of compound MIF-20-3 according to some embodiments.

[0205] Fig.50 Shown is the synthesis of compound MIF-14-3 according to some embodiments.

[0206] Fig.51 Shown is the synthesis of compound MIF-21-3 according to some embodiments.

[0207] Figure 52-Figure 66 Shown is the synthesis of multiple MIF-binding compounds with various ASGPRBM moieties according to some embodiments.

[0208] Fig.67 Exemplary IgGBM groups according to some embodiments are shown, each of which is covalently linked to a [CON] group, a [Linker] group, or a [ASGPRBM] group through an amine group such as the following: 1 -C 3 Alkyl optionally substituted primary or secondary alkylamine groups.

[0209] Fig.68 shows exemplary R on the ASGPRBM group according to some embodiments 1 and R 3 Substituent.

[0210] Fig.69 shows exemplary R on the ASGPRBM group according to some embodiments 2 Substituent. DETAILED DESCRIPTION

[0211] In some aspects, the present disclosure provides bifunctional molecules that utilize the endosome-lysosome machinery (machinery) in the liver to eliminate MIF and / or IgG. In some embodiments, the present disclosure utilizes bifunctional molecules to target MIF or IgG, and is modular and universal. This provides convenience for applying pharmaceutical chemistry optimization molecules. For example, in preliminary experiments, it has been shown that incorporating more optimized ASGPr binding motifs can enhance external MIF or IgG degradation. Because bifunctional molecules can degrade MIF or IgG, it is not required that MIF binding motif (MIFBM) or IgG binding moiety (IgGBM) be inhibitors, but in practice, many of these binding agents will play the role of MIF or IgG inhibitors. The reality of this dual inhibitory effect provides opportunities for the development of powerful MIF or IgG binding agents, which may have been overlooked in the past because they could not suppress various PPIs. Compared with monoclonal antibodies, the small molecule method of the present disclosure can achieve simpler, cheaper and more consistent manufacturing practices, and provides a method for treating potential immune side effects less.

[0212] In some aspects, the disclosure relates to bifunctional compounds, which are used as medicaments in the treatment of disease states and / or conditions mediated by macrophage migration inhibitory factor (MIF) or immunoglobulin G (IgG). In some aspects, the disclosure relates to pharmaceutical compositions including these bifunctional compounds and methods for treating disease states and / or conditions, disease states and / or conditions are mediated by MIF or IgG, or MIF and IgG are precipitating factors for the development and sustained size of diseases and / or conditions (especially including autoimmune diseases and cancer, etc.). In some aspects, the disclosure provides molecular strategies for reducing plasma MIF levels or IgG levels in patients with autoimmune diseases or certain types of cancer and other diseases. Bifunctional molecular constructs are composed of MIF targeting motifs derived from small molecule MIF ligands or IgG binding motifs in combination with IgG and ASGPr targeting motifs in combination with hepatocyte asialoglycoprotein receptor (ASGPr). These compounds selectively bind to MIF or IgG in plasma, and then engage the endosome-lysosome pathway of hepatocytes through ASGPr. Thus, MIF or IgG is internalized and degraded by hepatocytes, thereby resulting in potential reduction of corresponding disease symptoms mediated by MIF and / or IgG.

[0213] According to some embodiments, conventional chemical synthesis and pharmaceutical formulation methods as well as pharmacology, molecular biology, microbiology and recombinant DNA techniques within the skill of the art are used. These techniques are well known and otherwise fully described in the literature.

[0214] Where a range of values ​​is provided, it is understood that unless the context clearly indicates otherwise (such as in the case of a group comprising a plurality of carbon atoms), each intermediate value between the upper and lower limits of the range, up to one tenth of the unit of the lower limit, and any other stated or intermediate values ​​within this stated range are encompassed within the disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limitations within the stated range. When a stated range includes one or both of the limits, ranges excluding either of the two included limits are also encompassed within the disclosure.

[0215] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, some exemplary methods and materials are now described.

[0216] It should be noted that as used herein and in the appended claims, the singular forms "a," "an," "and," and "the" include plural referents unless the context clearly dictates otherwise.

[0217] In addition, the following terms shall have the definitions set forth below. It should be understood that, where a particular term is not defined below, that term shall have the meaning within its ordinary usage within the context as understood by one of ordinary skill in the art.

[0218] definition

[0219] Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein, and includes tautomers, regioisomers, geometric isomers, stereoisomers, and, where appropriate, optical isomers (enantiomers), and pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When used in context, the term compound generally refers to a single compound, but may also include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers in context to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. It is noted that in describing the present compounds, a variety of substituents, linkers and linker molecules and variables associated therewith, etc. are described. The use of a bond represented by ----- indicates the presence or absence of a single bond, depending on the context of the chemistry being described, including the connection of the bond to another moiety. The use of a bond represented by ----- indicates that a single bond or a double bond is intended to depend on the context of the chemistry being described. It will be appreciated by those of ordinary skill in the art that the molecules described herein are stable compounds, as generally described below.

[0220] The term "patient" or "subject" is used throughout the specification to describe an animal, typically a mammal, such as a human, that is treated with a composition according to the present disclosure, including prophylactic treatment (prevention, particularly including when the term is used to reduce the likelihood of metastasis of an existing cancer). For treatment of those infections, conditions or disease states that are specific to a particular animal, such as a human patient, or a patient of a particular sex, such as a human male or female patient, the term "patient" refers to that particular animal. The compounds according to the present disclosure are useful for treating a variety of disease states, including autoimmune disease states and / or conditions and inflammatory disease states and / or conditions, as well as cancer, particularly including for reducing the likelihood of cancer metastasis or recurrence.

[0221] Unless otherwise indicated, the term "effective" is used herein to describe the amount of a compound or composition used to produce or achieve a desired result in the context of an environment, whether the result involves inhibiting the effects of a disease state (e.g., autoimmune diseases (such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE)), atherosclerosis, heart disease or stroke, or cancer (including leukemia)) on a subject or treating or preventing a secondary condition, disease state, or manifestation of a disease state as described elsewhere herein. This term includes all other effective amount or effective concentration terms (including the term "therapeutically effective") described elsewhere in this application.

[0222] As used herein, the terms "treat", "treating" and "treatment" refer to any of the following effects: providing a benefit to a patient at risk of a disease state or condition that may require removal of MIF protein (such as autoimmune diseases (including rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE)), atherosclerosis, heart disease, stroke and cancer (including leukemia) - including recurrence and / or metastasis of cancer), improving the condition by alleviating or inhibiting at least one symptom of the disease state or condition, inhibiting one or more manifestations of the disease state (e.g., plaque formation, heart disease, cancer growth, reduction of cancer cells or tissue), preventing, reducing the likelihood of or delaying the progression of a disease state or condition or manifestation (especially including 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 cancer, etc.), preventing or delaying the onset of a disease state or condition secondary to a disease state or condition (including recurrence or metastasis of cancer, etc.). Treatment as used herein encompasses both prophylactic and therapeutic treatment, depending on the context of the treatment. When the term "prophylactic" is used, it refers to reducing the likelihood of occurrence or the severity of occurrence in the context of treatment of a disease state or condition, as described elsewhere above.

[0223] As used in this application, the terms "about" and "approximately" are used as equivalents. Any numeral used in this application with or without about / approximately is intended to cover any normal fluctuations in the value as understood by one of ordinary skill in the relevant art.

[0224] The term "macrophage migration inhibitory factor binding moiety" or "MIFBM" refers to a chemical moiety on one end of a bifunctional compound according to the present disclosure that is capable of binding to a circulating MIF protein associated with or contributing to a disease state or condition described in other aspects of the present invention. In the present disclosure, MIFBM is capable of binding to circulating MIF protein, forming a complex with the present compound, and delivering the bound protein to hepatocytes, whereby the other end of the bifunctional molecule comprises an asialoglycoprotein receptor binding moiety (ASGPRBM) and is capable of binding to the surface of hepatocytes, respectively. Once attached to hepatocytes, the bifunctional molecule bound to the circulating protein is internalized by the hepatocytes through an endocytic mechanism, whereby the cell will destroy the protein through lysosomal degradation or other degradation 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 the bifunctional molecule according to the present disclosure to ultimately be destroyed in hepatocytes. In certain cases of describing the present disclosure, the terms MIFBM and IgGBM are used synonymously.

[0225] Exemplary MIFBMs included in bifunctional compounds according to the present disclosure include those present in the presence of Figure 1 In some embodiments, MIFBM includes a moiety according to the following chemical structure:

[0226]

[0227]

[0228] Where X M Yes-(CH 2 ) IM 、-O-(CH 2 ) IM 、S-(CH 2 ) IM NR M -(CH 2 ) IM 、C(O)-(CH 2 ) IM -, a PEG group containing 1 to 8 (such as 1 to 4) ethylene glycol residues or -C(O)(CH 2 ) IM NR M Group;

[0229] R M is H or C optionally substituted by one or two hydroxy groups 1 -C 3 Alkyl; and

[0230] IM is 0-6, such as 1, 2, 3 or 4.

[0231] The term "asialoglycoprotein receptor binding moiety" ("ASGPRBM") refers to a binding moiety that binds to the hepatocyte asialoglycoprotein receptor. This binding moiety is also the component of the presently claimed bifunctional compound that is bound to the MIHBM moiety via a linker. The ASGPRBM selectively binds to the hepatocyte asialoglycoprotein receptor on the surface of hepatocytes. It is through this moiety that the bifunctional compound complexed with the circulating protein binds to the hepatocyte. Once bound to the hepatocyte, the circulating MIF protein is taken up into the hepatocyte via a phagocytic mechanism, where the circulating protein is degraded by lysosomal degradation.

[0232] Exemplary ASGPRBM groups for compounds according to the present disclosure include, among others, moieties according to the following chemical structures:

[0233]

[0234] Where X is 1-4 atoms in length and includes O, S, N (R N1 ) or C(RN1 )(R N1 ) group makes

[0235] When X is 1 atom in length, X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[0236] When X is 2 atoms long, no more than one atom in X is O, S, or N (R N1 ),

[0237] When X is 3 or 4 atoms in length, no more than 2 atoms in X are O, S, or N (R N1 );

[0238] Where R N1 is H or C optionally substituted by 1-3 halo groups (such as F) 1 -C 3 Alkyl (in some embodiments, R N1 is H or methyl);

[0239] R 1 and R 3 are independently H, -(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br or I) 1 -C 4 Alkyl, -(CH 2 ) K Vinyl, O-(CH 2 ) K Vinyl, -(CH 2 ) K Alkynyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or

[0240] R 1 and R 3 Each independently is A group, which is optionally substituted by: up to three (such as 1) halo groups (such as F); C 1 -C 4 alkyl, each of which is optionally substituted by one to three halo groups (such as F), or one or two hydroxy groups; or OC 1 -C 4 alkyl, wherein each alkyl is optionally substituted by one to three halo groups (such as F), or one or two hydroxy groups, and K is independently an integer ranging from 0 to 4 (0, 1, 2, 3 or 4), or

[0241] R 1 and R 3 Each is independently a group according to the following chemical structure:

[0242] Where R 7 It's OC 1 -C 4 alkyl, which is optionally substituted by 1 to 3 halo groups (such as F) and 1 or 2 hydroxy groups, or R 7 yes

[0243] -NR N3 R N4 Group or

[0244] or R 1 and R 3 Each is independently a group according to the following structure:

[0245]

[0246] Group,

[0247] wherein CYC is a ring selected from the group consisting of:

[0248] and C 3 -C 8 Saturated carbon ring, where the linker X, R C and (CH 2 ) K - Each of them is connected to the open price in CYC, including NH;

[0249] R C is absent, is H, is C optionally substituted by 1-3 halo (such as F) or 1-2 hydroxyl 1 -C 4 Alkyl or a group according to the following structure:

[0250]

[0251] Where R 4 , R 5 and R 6 are independently H, halogen (F, Cl, Br, I), CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br, I) 1 -C 3 alkyl, -OC optionally substituted by 1-3 halo groups (such as F) 1 -C 3 -alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or

[0252] R C yes

[0253]

[0254] Where R N , R N1 and R N2 are each independently H or C optionally substituted with one to three halo groups (such as F) or one or two hydroxy groups 1 -C 3 alkyl;

[0255] K is independently an integer ranging from 0-4 (0, 1, 2, 3 or 4);

[0256] K' is an integer in the range of 1-4 (such as 1);

[0257] R N3is H or C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl; and

[0258] R N4 is H, C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl, or R N4 yes group, wherein K is sometimes 1;

[0259] is a linker group comprising at least one [MIFBM / IgGBM] group and connecting the [MIFBM / IgGBM] group to [ASGPRBM] via one or more optional [CON] groups, or

[0260] is a linker group comprising at least one or more functional groups that can be used to covalently bind the linker group to at least one [MIFBM / IgGBM] group or an optional [CON] group;

[0261] R 2 yes Group, where R N1 and K are the same as above;

[0262] R AM is H, C optionally substituted with up to 3 halo groups (such as F) and one or two hydroxy groups 1 -C 4 Alkyl, -(CH 2 ) K COOH group, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, -(CH 2 ) K -NR N3 R N4 Group, where R N3 is H or C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl; and

[0263] R N4 is H, C optionally substituted by 1-3 halo (such as F) or 1 or 2 hydroxyl groups 1 -C 3 Alkyl, or R N4 yes A group (K is sometimes 1), or

[0264] R 2 yes Group,

[0265] Where R TA H, CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1-3 halogens (F, Cl, Br or I) 1 -C 4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl, -C(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 Alkyl, or R TA It is C 3 -C 10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of which is optionally substituted by up to three (such as 1) of the following groups: CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K OC 1 -C 4 alkyl, C optionally substituted by 1 to 3 halogens (F, Cl, Br or I) or 1 or 2 hydroxyl groups 1 -C 3alkyl, -OC optionally substituted by 1-3 halo groups (such as F) 1 -C 3 -alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)OC 1 -C 4 alkyl, OC(O)-C optionally substituted by 1-3 halo groups (such as F) 1 -C 4 alkyl or -(CH 2 ) K C(O)-C 1 -C 4 Alkyl, or R TA yes

[0266] (In some embodiments, R TA yes group, which is composed of up to three (such as 1) C 1 -C 3 The alkyl group is optionally substituted, C 1 -C 3 The alkyl group is optionally substituted with up to three halo groups (such as F), or R TA yes Group, )

[0267] Where R N , R N1 and R N2 are each independently H or C optionally substituted with one to three halo groups (such as F) or one or two hydroxy groups 1 -C 3 Alkyl, and

[0268] Each of these -(CH 2 ) K The group is 1-4 (such as 1 or 2) C 1 -C 3 The alkyl group is optionally substituted, C 1 -C 3 The alkyl group is optionally substituted with 1-3 fluoro groups or 1-2 hydroxy groups;

[0269] And K is independently 0-4 (0, 1, 2, 3 or 4).

[0270] In some embodiments, [CON] is a linker moiety as described elsewhere herein (including [MULTICON]).

[0271] In some embodiments, [Linker] is a linking moiety as described elsewhere herein, which links [MIFBM / IgGBM] to an [ASGPRBM] group and optionally comprises one or more linker moieties (which optionally link more than one chemical moiety to provide the linking moiety or which links the linking moiety to the [MIFBM / IgGBM] group or the [ASGPRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0272] In some embodiments, when X is 2 atoms in length, 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 ),

[0273] When X is 3 atoms long, 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 )(RN1 )-、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

[0274] When X is 4 atoms long, 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 )(RN1 )-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 Same as above. Most commonly, R N1 It's H.

[0275] In some embodiments, X is OCH 2 or CH 2 O. In some embodiments, R N1It's H.

[0276] In an embodiment, the [ASGPRBM] group is a group according to the following chemical structure:

[0277]

[0278] Where R 1 , R 2 and R 3 Same as above, or

[0279] Pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof.

[0280] In an embodiment, the [ASGPRBM] group is a group according to the following chemical structure:

[0281]

[0282]

[0283] Where R A It is C 1 -C 3 Alkyl, which is optionally substituted with 1-5 halo (such as F) (in some embodiments, R A is methyl or ethyl, which is optionally substituted by 1 to 3 fluoro groups);

[0284] Z A Yes-(CH 2 ) IM 、-O-(CH 2 ) IM 、S-(CH 2 ) IM NR M -(CH 2 ) IM 、C(O)-(CH 2 ) IM -, a polyethylene glycol (PEG) group containing 1 to 8 (such as 1-4) ethylene glycol residues, or -C(O)(CH 2 ) IM NR M A group such as a PEG-containing group containing 1 to 8 ethylene glycol residues such as 2-4 ethylene glycol residues, wherein IM and R M Same as above; and

[0285] Z B Does not exist, is (CH 2 ) IM , is C(O)-(CH 2 ) IM - or C(O)-(CH2 ) IM -NR M , where IM and R M Same as above.

[0286] In some embodiments, the ASPGRM group as described above is represented as follows:

[0287]

[0288] Throughout the specification, the term "neoplasmogenesis" or "cancer" is used to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors, that is, abnormal tissues that grow by cell proliferation, usually faster than normal, and continue to grow after the stimulus that triggers new growth stops. Malignant tumors show partial or complete lack of structural organization and functional coordination with normal tissues, and most of them invade surrounding tissues, metastasize to several sites, and are likely to recur and cause patient death after attempted removal unless adequate treatment is performed. As used herein, the term neoplasia is used to describe all cancerous disease states and pathological processes associated with malignant hematopoiesis, ascites and solid tumors. Compared with normal proliferation in the same type of tissue, tumors include but are not limited to irregular morphology of cells in the subject or host tissue and pathological proliferation of cells in the subject tissue. In addition, tumors include invasive or non-invasive benign tumors and malignant tumors (e.g., colon tumors). The difference between malignant tumors (cancer) and benign tumors is that the former shows a greater degree of degeneration, or cell differentiation and directional loss, and has invasive and metastatic properties. Examples of tumors or neoplasias derived from the disclosed target cells include, but are not limited to, carcinomas (e.g., squamous cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those 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., glial cell carcinoma, myeloma, and sarcoma); tumours (e.g., ovarian, ovarian, testicular, thyroid, astrocytoma, esophageal, pancreatic, gastric, hepatic, colon and melanoma); mixed types of neoplasia, particularly carcinosarcoma and Hodgkin's disease; and tumours of mixed origin, such as Wilms' tumour 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 tumors can be treated using the compounds according to the present disclosure.

[0289] Representative common cancers to be treated with compounds according to 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, kidney cancer, brain / CNS cancer, head and neck cancer, throat 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, kidney cancer and lymphoma, etc., which can be treated by one or more compounds according to the present disclosure. Due to the activity of the present compounds, the present disclosure is generally applicable to the treatment of almost any cancer in any tissue, and therefore, the compounds, compositions and methods of the present disclosure are generally applicable to the treatment of cancer and reduce the possibility of cancer development and / or metastasis of existing cancers.

[0290] In some specific aspects of the present disclosure, the cancer treated is a metastatic cancer, a recurrent cancer or a resistant cancer, particularly including a resistant cancer. Respectively, metastatic cancers may be found in almost all tissues of cancer patients in the late stages of the disease, generally in the lymphatic system / lymph nodes (lymphoma), bones, lungs, bladder tissues, kidney tissues, liver tissues and almost any tissue, including the brain (brain cancer / tumor). Therefore, the present disclosure is generally applicable and can be used to treat any cancer in any tissue, regardless of etiology.

[0291] The term "tumor" is used to describe a growth or enlargement, whether malignant or benign.

[0292] The term "autoimmune disease" refers to a disease or condition that occurs when body tissue is attacked by the autoimmune system. The immune system is a complex organization in the body, usually designed to "seek and destroy" invaders of the body, including infectious pathogens. In diseases described as autoimmune diseases, MIF levels usually increase. The disclosure seeks to suppress or reduce the MIF levels that increase in autoimmune disease (and inflammatory diseases and conditions and cancer) patients and improve the various symptoms and secondary effects of these disease states and conditions by reducing MIF levels. Examples of autoimmune diseases that usually show high MIF expression levels include, for example, systemic lupus erythematosus, Sjogren's syndrome (Sjogrensyndrome), Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis and multiple other diseases such as pulmonary fibrosis.

[0293] A more complete list of autoimmune diseases that can be treated by the compounds and pharmaceutical compositions according to the present disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, leuk ... cryoglulinemia, Evans syndrome, pernicious anemia, pure red cell dysplasia, thrombocytopenia, obesity dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, esosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry Romberg syndrome syndrome), Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, 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, Balo's concentric sclerosis, Bickerstaff's encephalitisencephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, primary inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis type II, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Syndenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Moore's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome syndrome), optic neuritis, scleritis, Susac syndrome, sympathetic eye disease, Tolman-Henrich syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytic destructive vasculitis, lupus vasculitis, rheumatoid 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, etc.

[0294] The term "inflammatory disease" is used to describe diseases or conditions that have acute but more often chronic inflammation as a primary manifestation of the disease or condition. Inflammatory diseases include: neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias), diseases in which the immune response is impaired and causes inflammation (e.g., disorders of T cell maturation, B cell and T cell homeostasis, counters damaging inflammation, The invention relates to the treatment of various diseases including chronic inflammatory diseases (e.g., inflammatory bowel disease, including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjögren's syndrome); hyperglycemia, diabetes (I and II), effects on lipid metabolism, pancreatic islet function and / or structure, pancreatic beta cell death and associated hyperglycemia, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, leprechaun syndrome and lipoatrophic diabetes); and dyslipidemia (e.g., hyperlipidemia, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome expressed in obese subjects). Syndrome), liver disease, kidney disease (plaque cell apoptosis, glomerular disease), cardiovascular disease (especially including infarction, ischemia, stroke, pressure overload and complications during reperfusion), muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, such as cardiac and neurological (both central and peripheral) clinical manifestations, including stroke, age-related dementia and occasional Alzheimer's disease and psychiatric disorders (including depression), stroke and spinal cord injury, arteriosclerosis, etc. In these diseases, MIF is often observed to be elevated, making these disease states and / or conditions responsive to therapy using compounds and / or pharmaceutical compositions according to the present disclosure. It should be noted that there is some overlap between certain autoimmune diseases and inflammatory diseases as described herein.

[0295] The term "linker" refers to a chemical entity comprising a composite linker that connects a macrophage migration inhibitory factor binding moiety (MIFBM) to an asialoglycoprotein receptor binding moiety (ASGPRBM) by covalent bonds, optionally through at least one (such as one or two) linker moieties [CON] in a compound according to the present disclosure. The length of the linker between the two active moieties of the molecule (i.e., MIFBM and ASGPRBM) ranges from about to about or longer, approx. to about about to about about to about about to about about to about about to about about to about about to about about to about about to about about to about Etc. Can be used for the joint of ethylene glycol unit and length between 2 to 15 ethylene glycol units, between 1 to 8 ethylene glycol units, length is 1,2,3,4,5 and 6 ethylene glycol units, although the length of some joints may be much longer.By having the joint of certain length as disclosed in other aspects herein, MIFBM group and ASGPRBM group can be positioned to advantageously utilize the biological activity of the compound according to the present disclosure, according to the compound of the present disclosure, bind to the asialoglycoprotein receptor on the hepatocyte, cause the MIF circulating protein to be selectively and targetedly degraded in the lysosomal degradation mechanism or other degradation mechanism of the hepatocyte.The selection of joint component is based on its recorded biocompatibility, solubility in aqueous medium and organic medium and low immunogenicity / antigenicity and other characteristics. Although a variety of 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 to 100, about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 1 to 8, 1 to 3, 1 to 4, 2 to 6, 1 to 5, etc.) can be advantageous as linkers due to the chemical and biological properties of these molecules. Polyethylene glycol (PEG) linkages of 2 to 15 ethylene glycol units are sometimes used. When describing a linker according to the present disclosure (including a polyethylene glycol linker or other linker), one or more additional groups (e.g., a methylene group, an amide group, a keto group, an amine group, etc.) may be covalently attached to either end of the linker group, thereby connecting to an ASGPRBM group, a [CON] group, other linker groups, or a CPBM group.

[0296] Optional linkers can include, for example, polyamino acid linkers of up to 100 amino acids (of any type, such as D-amino acids or L-amino acids, such as naturally occurring L-amino acids) in length (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, about 1 to 3, etc. in length), optionally including one or more linking groups (such as 1 or 2 linking groups at one or both ends of the polyamino acid linker).

[0297] Exemplary linkers include linkers according to the following chemical structures:

[0298]

[0299] or polypropylene glycol or polypropylene-co-polyethylene glycol linkers having 1 to 100 alkylene glycol units, such as 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, about 1 to 3;

[0300] Where R a It is H, C 1 -C 3 Alkyl or alkanol or with R 3 Cyclic (proline), and R 3 is a side chain derived from the following D-amino acids or L-amino acids (such as naturally occurring L-amino acids), such as selected from alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (acetic acid), cysteine ​​(thiol, reduced or oxidized dithiol), glutamine (ethylcarboxamide), glutamic acid (propionic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethyl sulfide), phenylalanine (benzyl), proline hydroxyproline (R 3 With R aand adjacent nitrogen groups to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylenephenol), or valine (isopropyl);

[0301] m (in the context of this use) is an integer ranging from 1 to 100, such as 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.

[0302] Other exemplary linkers include polyethylene glycol linkers comprising 1 to 1 to 100, such as 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 ethylene glycol units, with a lysine group or other amino acid moiety attached to one or both ends of the linker (which may consist of 1 to 10 amino acids that can bind to MIFBM and / or ASGPRBM groups). Still other linkers include amino acid residues (D or L) attached to the MIFBM and / or ASGPRBM moiety. ), as described in other aspects herein. In another embodiment, as described in other aspects herein, when providing a linker with a MIFBM and / or ASGPRBM group, the amino acid has 1-15 methylene groups separating the amino group from the acid group (acyl), wherein the linker comprises 1 to 100, 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 amino acid groups linked together by peptide bonds to form a linker. This linker is represented by the following chemical structure:

[0303]

[0304] Where R am is H or C optionally substituted by one or two hydroxy groups 1 -C 3 alkyl;

[0305] na is an integer ranging from 1 to 15, such as 1-12, 1-10, 1-8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0306] m is an integer ranging from 1 to 100, such as 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 51 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.

[0307] or other linkers according to the following formula:

[0308]

[0309] wherein Z and Z' are each independently a bond, -(CH 2 ) i -O、-(CH 2 ) i -S, -(CH 2 ) i -NR,

[0310] Wherein the -(CH 2 ) i The group, if present in Z or Z', is bound to a linker (CON), MIFBM or ASGPRBM;

[0311] Each R is H or C 1 -C 3 an alkyl or alkanol group;

[0312] Every R 2 independently H or C 1 -C 3 alkyl;

[0313] each Y is independently a bond, O, S or NR;

[0314] each i is independently an integer ranging from 0 to 100, such as 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;

[0315] D is

[0316]

[0317] -(CH 2 ) m '-;

[0318] or

[0319] a bond, provided that Z, Z' and D are not each a bond at the same time;

[0320] j is an integer ranging from 1 to 100, such as 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;

[0321] m' is an integer ranging from 1 to 100, such as 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;

[0322] n is an integer ranging from 1 to 100, such as 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;

[0323] X 1 is O, S or NR; and

[0324] R is H or C 1 -C 3 An alkyl or alkanol group, or a pharmaceutical salt thereof.

[0325] Other linkers included herein include linkers according to the following chemical structures:

[0326]

[0327] wherein each n and n' is independently an integer ranging from 1 to 25, such as 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, and 2 to 3, or is 1, 2, 3, 4, 5, 6, 7 or 8; and

[0328] Each n" is independently an integer ranging from 0 to 8, such as 1 to 7, or 1, 2, 3, 4, 5 or 6.

[0329] The linker may also include two or more linker segments (based on the linkers described above) that are directly linked to each other or linked through a [CON] group to form a composite linker. Certain linkers that include a [CON] group (especially a diamide [CON] group as described elsewhere herein) that connects a first and a second (PEG) linker group include the following structures:

[0330]

[0331] wherein each n and n' is independently an integer ranging from 1 to 25, such as 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, and 2 to 3, or is 1, 2, 3, 4, 5, 6, 7 or 8; and

[0332] Each n" is independently an integer ranging from 0 to 8, such as 1 to 7 or 1, 2, 3, 4, 5 or 6. It is noted that each of these linkers may also contain an alkylene group, with 1 to 4 methylene groups at the distal end of each linker group to facilitate the attachment of the linker group.

[0333] Other linkers including the linker group [CON] include groups represented by the following chemical formula

[0334] PEG-[CON]-PEG

[0335] wherein each PEG is independently a polyethylene glycol group comprising 1-12 ethylene glycol residues and [CON] is a linker group as described elsewhere herein, such as

[0336] Triazolyl

[0337] The term "linker", represented by "CON" or [CON] in the general formula, is used to describe a chemical moiety that is optionally included in the bifunctional compound according to the present disclosure, which is formed from the reaction product of an activated linker and a MIFBM portion (which is sometimes also activated to covalently bind the linker to the portion) or an ASGPRBM group and an activated linker. The linker group is typically formed from the resulting portion of the facile condensation of two or more separate chemical fragments, which contain reactive groups that can provide linker groups as described in other aspects, thereby producing bifunctional or multifunctional compounds according to the present disclosure. It should be noted that the linker can be distinguishable from the linker because the linker is the result of a specific chemistry used to provide a bifunctional compound according to the present disclosure, wherein the reaction product of these groups produces an identifiable linker group or a portion of a linker group that can be distinguished from the linker group, but in some cases, the linker group is incorporated into the linker group as described in other aspects herein and is integrated with it. It is also noted that the linker group can be attached to multiple linkers to provide multifunctionality within the same molecule (i.e., more than one CPBM moiety and / or more than one ASGPRBM / FCRNBM moiety). It is noted that there may be some overlap between the descriptions of the linker group and the linker group such that the linker group is actually incorporated into the linker or forms part of the linker, especially for more common linker groups such as the following: amide, oxygen (ether), sulfur (thioether) or amine bond linkages, urea or carbonate -OC(O)O- groups or as described elsewhere herein. It is also noted that the linker (or linker) can be attached to the MIFBM, ASGPRBM or linker at the position represented by the following symbols for attachment to other groups

[0338]

[0339] When two or more such groups are present in a linker or connector, any of the ASGPRBM, linker or MIFBM may be bound to such groups. When the symbol is not used, the linker may be located at one or more positions of a moiety.

[0340] Common linker groups for use in the present disclosure include the following chemical groups:

[0341]

[0342] wait

[0343] Where R CON1 and R CON2 are each independently H, methyl or a bond (for connection to another moiety); or

[0344] A diamide group according to the following structure:

[0345]

[0346] Where X 2 Yes CH 2 , O, S, NR 4 、C(O), S(O), S(O) 2 、-S(O) 2 O, -OS(O) 2 or OS(O) 2 O;

[0347] X 3 O, S, NR 4 ;

[0348] R 4 It is H, C 1 -C 3 Alkyl or alkanol group or -C(O)(C 1 -C 3 ) group;

[0349] R 1 Is H or C 1 -C 3 Alkyl; and

[0350] n" is independently an integer ranging from 0 to 8, such as 1 to 7 or 1, 2, 3, 4, 5 or 6;

[0351] Or a linker group [CON] is a group according to the following chemical structure:

[0352]

[0353] Where R 1CON , R 2CON and R 3CON are independently H, -(CH 2 ) MC1 、-(CH 2 ) MC1a C(O) XA (NR 4 ) XA -(CH 2 ) MC1a 、-(CH 2 ) MC1a (NR 4 ) XA C(O) XA -(CH 2 ) MC1a or -(CH 2 ) MC1a O-(CH 2 ) MC1 -C(O)NR4 -, provided that R 1CON , R 2CON and R 3CON Not at the same time H;

[0354] Each MC1 is independently an integer ranging from 1 to 4, such as 1 or 2;

[0355] Each MC1a is independently an integer ranging from 0 to 4, such as 0, 1 or 2; and

[0356] R 4 It is H, C 1 -C 3 Alkyl or alkanol group or -C(O)(C 1 -C 3 ) group.

[0357] The above triazole group is an exemplary linker group. Other exemplary linker groups are

[0358]

[0359] It is linked to at least one MIFBM and / or at least one ASPRGBM (such as 3 ASPRGBM moieties). This linker group can be used to form GN3.

[0360] It is noted that each linker may be extended with one or more methylene groups to facilitate attachment to linker groups, other CON groups, MIFBM groups or ASGPRBM. It is noted that in certain circumstances in the context, the diamide group may also independently function as a linker group.

[0361] Additional galactosyl and talosyl ASGPR binding moieties

[0362] In certain embodiments, the present disclosure relates to compounds for use in removing circulating proteins associated with a disease state or condition in a patient or subject according to the general chemical structure of Formula II:

[0363]

[0364] The term "extracellular protein targeting ligand" as used herein is used interchangeably with the term CPBM (cellular protein binding moiety). The term "ASGPR ligand" as used herein is used interchangeably with asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0365] In the compounds of Formula II, each [CON] is an optional linker chemical moiety which, when present, directly links to [CPBM] or [CRBM] or links [Linker-2] to [CPBM] or [CRBM].

[0366] In the compound of formula II:

[0367] [Linker-2] is a chemical moiety with a valence of 1 to 15, which is covalently linked to one or more [CRBM] and / or [CPBM] groups, optionally via a [CON] including a [MULTICON] group, wherein the [Linker-2] optionally itself comprises one or more [CON] or [MULTICON] groups;

[0368] k' is an integer from 1 to 15;

[0369] j' is an integer from 1 to 15;

[0370] h and h' are each independently an integer from 0 to 15;

[0371] i L is an integer from 0 to 15;

[0372] The premise is h, h' and i L At least one of the compounds is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0373] The [MULTICON] group may connect one or more of [CRBM] or [CPBM] to one or more of [Linker-2]. In various embodiments, [Linker-2] has a valence of 1 to 10. In various embodiments, [Linker-2] has a valence of 1 to 5. In various embodiments, [Linker-2] has a valence of 1, 2, or 3. In various embodiments, in the compounds of Formula II, [Linker-2] comprises a linker as defined herein A , Connectors B , Connectors C , Connectors D and / or one or more of their combinations.

[0374] In the compound 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.

[0375] In the 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.

[0376] In the 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.

[0377] In the compound of formula II, X 1 are independently selected from O, S, N(R 6 ) and C(R 4 )(R 4 ) of 1 to 5 consecutive atoms, where if X 1 is 1 atom, then X 1 O, S, N (R 6 ) or C(R 4 )(R 4 ), if X 1 is 2 atoms, then X 1 No more than one atom in the 6 ), if X 1 is 3, 4 or 5 atoms, then X 1 No more than 2 atoms are O, S or N (R 6 );

[0378] R 3 Each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF 3 , -CHF 2 、-CH 2 F, -CH 2 CF 3 、-CH 2 CH 2 F and -CF 2 CF 3 ), aralkyl, heteroaralkyl, alkenyl, alkynyl and heteroaryl, heterocycle, -OR 8 and -NR 8 R 9 ;

[0379] R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 ,

[0380] R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, 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) 2 R 3 ;

[0381] R 8 and R 9 and alkyl. Each occurrence of is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0382] A. Galactosyl ASGPR Binding Cell Receptor Binding Portion of Formula II

[0383] In certain embodiments, the compound of formula II is selected from:

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] In certain embodiments, the compound of Formula II has one of the following structures:

[0403]

[0404]

[0405] In various embodiments, the ASGPR ligand is linked to C 1 or C 5 (R 1 or R 5 ) position to form a degradation compound. In various embodiments, the ASGPR ligand is linked to C 6 For example, when the ASGPR ligand is

[0406] hour,

[0407] Non-limiting examples of ASGPR binding compounds of Formula II include:

[0408]

[0409] or a di- or tri-substituted version thereof, or a pharmaceutically acceptable salt thereof, wherein the di- or tri-substituted version refers to the number of additional galactose derivatives attached to the linker moiety.

[0410] In any embodiment drawn herein where an ASGPR ligand is used in a degrader, the ASGPR ligand is generally present in C 5 bit (eg, it may refer to an adjacent C 6 The linker is connected to the extracellular protein targeting ligand through the C hydroxyl group or other functional parts that can be used for the purpose of connection. 1 When attachment is made at a carbon position, the carbon is appropriately functionalized for attachment, such as with a hydroxyl, amino, allyl, alkynyl or hydroxy-allyl group.

[0411] In various embodiments, the ASGPR ligand is not attached to the C 3 or C 4 In certain embodiments, the ASGPR ligands for incorporation into the compounds of Formula II are selected from:

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423] In certain embodiments, the compound of formula II is selected from:

[0424]

[0425]

[0426]

[0427]

[0428] B. Talose ASGPR Binding Cell Receptor Binding Moiety of Formula II

[0429] In certain embodiments, the compound of formula II is selected from:

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471] In certain embodiments, the compound of formula II is an extracellular protein degradation compound, wherein the ASGPR ligand is a ligand as described herein.

[0472]

[0473] In certain embodiments, in the compound of Formula II, the ASGPR ligand is linked to C1 or C5 (R 1 or R 5 ) position to form a degradation compound. In certain embodiments, in the compound of Formula II, the ASGPR ligand is attached at C6. In various embodiments, when the ASGPR ligand is

[0474] hour

[0475] Non-limiting examples of ASGPR binding compounds of Formula II include:

[0476]

[0477] or a disubstituted or trisubstituted form thereof or a pharmaceutically acceptable salt thereof, wherein the disubstituted or trisubstituted refers to the number of additional galactose derivatives attached to the linker moiety. In certain embodiments, the compound of formula II is selected from:

[0478]

[0479] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0480] In certain embodiments, the compound of formula II is selected from:

[0481]

[0482]

[0483] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0484] In certain embodiments, the compound of formula II is selected from:

[0485]

[0486]

[0487] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0488] In certain embodiments, the compound of formula II is selected from:

[0489]

[0490]

[0491] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0492] In certain embodiments, the compound of formula II is selected from:

[0493]

[0494]

[0495] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0496] In certain embodiments, the compound of formula II is selected from:

[0497]

[0498]

[0499] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0500] In certain embodiments, the compound of formula II is selected from:

[0501]

[0502]

[0503] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6-(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0504] In certain embodiments, the compound of formula II is selected from:

[0505]

[0506]

[0507] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0508] In certain embodiments, the compound of formula II is selected from:

[0509]

[0510]

[0511] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0512] In certain embodiments, the compound of formula II is selected from:

[0513]

[0514]

[0515]

[0516] Wherein in certain embodiments, R 2 Selected from -NR6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0517] In certain embodiments, the compound of formula II is selected from:

[0518]

[0519]

[0520] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0521] In certain embodiments, the compound of formula II is selected from:

[0522]

[0523]

[0524] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0525] In certain embodiments, the compound of formula II is selected from:

[0526]

[0527]

[0528] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0529] In certain embodiments, the compound of formula II is selected from:

[0530]

[0531]

[0532] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups is optionally substituted with 1, 2, 3 or 4 independent substituents as described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0533] In certain embodiments, the compound of formula II is selected from:

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545] In certain embodiments, the ASGPR ligand for incorporation into the compound of Formula II is selected from:

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557] C. ASGPR Ligand / Binding Moiety in Compounds of Formula II

[0558] In certain embodiments, in the compound of Formula II, R 1 It's hydrogen.

[0559] In certain embodiments, in the compound of Formula II, R 1 yes

[0560] In certain embodiments, in the compound of Formula II, R 1 yes

[0561] In certain embodiments, in the compound of Formula II, R 1 yes

[0562] In certain embodiments, in the compound of Formula II, R 1 yes

[0563] In certain embodiments, in the compound of Formula II, R 1 yes

[0564] In certain embodiments, in the compound of Formula II, R 1 yes

[0565] In certain embodiments, in the compound of Formula II, R 1 is C optionally substituted by 1, 2, 3 or 4 substituents 0 -C 6 Alkyl-cyano.

[0566] In certain embodiments, in the compound of Formula II, R 1 is alkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0567] In certain embodiments, in the compound of Formula II, R 1 is an alkenyl group optionally substituted with 1, 2, 3 or 4 substituents. 1 is an alkynyl group optionally substituted with 1, 2, 3 or 4 substituents. 1 is a haloalkyl group optionally substituted with 1, 2, 3 or 4 substituents. 1 It's F.

[0568] In certain embodiments, in the compound of Formula II, R 1 It is Cl.

[0569] In certain embodiments, in the compound of Formula II, R 1 It's Br.

[0570] In certain embodiments, in the compound of Formula II, R 1 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0571] In certain embodiments, in the compound of Formula II, R 1 is aralkyl optionally substituted by 1, 2, 3 or 4 substituents.

[0572] In certain embodiments, in the compound of Formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0573] In certain embodiments, in the compound of Formula II, R 1 is heteroaralkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0574] In certain embodiments, in the compound of Formula II, R 1 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0575] In certain embodiments, in the compound of Formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0576] In certain embodiments, in the compound of Formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3 or 4 substituents.

[0577] In certain embodiments, in the compound of Formula II, R 1 is -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-OC(O)R 3 , C 0 -C 6 Alkyl-OS(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 or C 0 -C 6 Alkyl-OS(O) 2 R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents.

[0578] In certain embodiments, in the compound of Formula II, R 2 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0579] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0580] In certain embodiments, in the compound of Formula II, R 2 is a heteroaryl group comprising 1 or 2 heteroatoms independently selected from N, O and S, optionally substituted with 1, 2, 3 or 4 substituents.

[0581] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0582]

[0583] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0584] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)-R 3 .

[0585] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -C(S)-R 3 .

[0586] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)(NR6 )-R 3 .

[0587] In certain embodiments, in the compound of Formula II, R 2 is -N=S(O)(R 3 ) 2 .

[0588] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 C(O)NR 9 S(O) 2 R 3 .

[0589] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O) 2 -R 10 .

[0590] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -C(NR 6 )-R 3 .

[0591] In certain embodiments, in the compound of Formula II, R 2 It's hydrogen.

[0592] In certain embodiments, in the compound of Formula II, R 2 YesR 10 .

[0593] In certain embodiments, in the compound of Formula II, R 2 is alkyl-C(O)-R 3 .

[0594] In certain embodiments, in the compound of Formula II, R 2 Yes-C(O)-R 3 .

[0595] In certain embodiments, in the compound of Formula II, R 2 It is an alkyl group.

[0596] In certain embodiments, in the compound of Formula II, R 2 It is a haloalkyl group.

[0597] In certain embodiments, in the compound of Formula II, R 2 Yes-OC(O)R 3 .

[0598] In certain embodiments, in the compound of Formula II, R 2 Yes - NR 8 -C(O)R 10 .

[0599] In certain embodiments, in the compound of Formula II, R 2 is alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0600] In certain embodiments of alkenyl groups, in the compound of formula II, R 2 is allyl optionally substituted with 1, 2, 3 or 4 substituents.

[0601] In certain embodiments, in the compound of Formula II, R 2 is alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0602] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkenyl.

[0603] In certain embodiments, in the compound of Formula II, R 2 is -O-alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0604] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkynyl.

[0605] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -heteroaryl.

[0606] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -Aryl.

[0607] In certain embodiments, in the compound of Formula II, R 2 is -O-heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0608] In certain embodiments, in the compound of Formula II, R2 is -O-aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0609] In certain embodiments, in the compound of Formula II, R 2 is -O-alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0610] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0611] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0612] In certain embodiments, in the compound of Formula II, R 2 Selected from wherein R is an optional substituent as defined herein.

[0613] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0614]

[0615] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0616] wherein R is an optional substituent as defined herein.

[0617] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0618]

[0619] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0620]

[0621] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0622]

[0623] In certain embodiments, in the compound of Formula II, R 2 Selected from In certain embodiments, in the compound of Formula II, R 2 Selected from

[0624] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0625]

[0626] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0627]

[0628] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0629]

[0630] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0631]

[0632] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0633]

[0634] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0635] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0636]

[0637] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0638]

[0639] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0640]

[0641] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0642]

[0643] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0644]

[0645] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0646]

[0647] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0648]

[0649] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0650]

[0651] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0652]

[0653] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0654]

[0655] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0656]

[0657] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0658]

[0659] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0660]

[0661] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0662]

[0663] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0664]

[0665] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0666]

[0667] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0668]

[0669] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0670]

[0671] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0672]

[0673] In certain embodiments, in the compound of Formula II, R 2 or R 2A Selected from

[0674]

[0675]

[0676] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0677]

[0678] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0679]

[0680] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0681]

[0682] In certain embodiments, in the compound of Formula II, R 2Selected from

[0683]

[0684] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0685] In certain embodiments, in the compound of Formula II, R 2 is a spirocyclic heterocycle, for example, and without limitation,

[0686] In certain embodiments, in the compound of Formula II, R 2 is a silicon-containing heterocycle, for example, and without limitation,

[0687] In certain embodiments, in the compound of Formula II, R 2 By SF 5 Replace, for example, and without limitation,

[0688] In certain embodiments, in the compound of Formula II, R 2 is substituted with a sulfoxime, for example, and without limitation,

[0689] In certain embodiments, in the compound of Formula II, R 10 is selected from bicyclic heterocycles.

[0690] In certain embodiments, in the compound of Formula II, R 10 is selected from spiro heterocycles.

[0691] In certain embodiments, in the compound of Formula II, R 10 Selected from -NR 6 -Heterocyclic ring.

[0692] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0693]

[0694] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0695]

[0696] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0697]

[0698] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0699]

[0700] In certain embodiments, in the compound of formula II, the ring is selected from

[0701]

[0702] In certain embodiments, in the compound of Formula II, R 30 Selected from:

[0703]

[0704] In certain embodiments, in the compound of Formula II, R 200 yes

[0705] In certain embodiments, in the compound of Formula II, R 200 yes

[0706] In certain embodiments, in the compound of Formula II, R 200 yes

[0707] In certain embodiments, in the compound of Formula II, R 200 yes

[0708] In certain embodiments, in the compound of Formula II, R 200 yes

[0709] In certain embodiments, in the compound of Formula II, R 200 yes

[0710] In certain embodiments, in the compound of Formula II, R 200 yes

[0711] In certain embodiments, in the compound of Formula II, R 200 yes

[0712] In certain embodiments, in the compound of Formula II, R 200 yes

[0713] In certain embodiments, in the compound of Formula II, R 200 yes

[0714] In certain embodiments, in the compound of Formula II, R 200 yes

[0715] In certain embodiments, in the compound of Formula II, R 200 yes

[0716] Connectors

[0717] In a non-limiting embodiment, in the compound of formula II, the linker A and connectors B Independently selected from:

[0718]

[0719] in:

[0720] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -、-S(O)-、-C(S)-、-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 )-, divalent residues of natural or unnatural amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, heterocyclic, heteroaryl, -CH 2 CH 2 -[O-(CH 2 ) 2 ] n -O-、CH 2 CH 2 -[O-(CH 2 ) 2 ] n -NR 6 -、-CH 2 CH 2 -[O-(CH 2 ) 2 ] n-、-[-(CH 2 ) 2 -O-] n -、-[O-(CH 2 ) 2 ] n -、-[O-CH(CH 3 )C(O)] n -、-[C(O)-CH(CH 3 )-O] n -、-[O-CH 2 C(O)] n -、-[C(O)-CH 2 -O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated monocarboxylic acid or a dicarboxylic acid; each of which is independently selected from R 21 The substituents are optionally substituted;

[0721] n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0722] R 21 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxy, alkoxy, azide, amino, cyano, -NR 6 R 7 、-NR 8 SO 2 R 3 、-NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl and heterocyclic;

[0723] The remaining variables are as defined in this article.

[0724] In certain embodiments, in the compound of formula II, the linker A Is the key and the connector B yes

[0725]

[0726] In certain embodiments, in the compound of formula II, the linker B Is the key and the connector A yes

[0727]

[0728] In certain embodiments, in the compound of formula II, the divalent amino acid residue is selected from

[0729]

[0730]

[0731] Therein the amino acids may be oriented in either orientation and wherein the amino acids may be in the L- or D-form or a mixture thereof.

[0732] In certain embodiments, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated by a nucleophilic addition reaction:

[0733]

[0734] Non-limiting embodiments of the divalent residue of a dicarboxylic acid generated by a nucleophilic addition reaction include:

[0735]

[0736] In certain embodiments, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated by the condensation reaction:

[0737]

[0738] Non-limiting embodiments of the divalent residue of the dicarboxylic acid produced by the condensation include:

[0739]

[0740] Non-limiting embodiments of the divalent residue of a saturated dicarboxylic acid include:

[0741]

[0742] Non-limiting embodiments of the divalent residue of a saturated dicarboxylic acid include:

[0743]

[0744] A non-limiting embodiment of the divalent residue of a saturated monocarboxylic acid is selected from butyric acid (-OC(O)(CH 2 ) 2 CH 2 -), hexanoic acid (-OC(O)(CH 2 ) 4 CH 2 -), octanoic acid (-OC(O)(CH 2 ) 5 CH 2 -), decanoic acid (-OC(O)(CH 2 ) 8 CH 2 -), lauric acid (-OC(O)(CH 2 ) 10 CH 2-), myristic acid (-OC(O)(CH 2 ) 12 CH 2 -), pentadecanoic acid (-OC(O)(CH 2 ) 13 CH 2 -), palmitic acid (-OC(O)(CH 2 ) 14 CH 2 -), stearic acid (-OC(O)(CH 2 ) 16 CH 2 -), behenic acid (-OC(O)(CH 2 ) 20 CH 2 -) and lignoceric acid (-OC(O)(CH 2 ) 22 CH 2 -);

[0745] Non-limiting embodiments of divalent residues of fatty acids include residues selected from the group consisting of linoleic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid:

[0746]

[0747] A non-limiting embodiment of the divalent fatty acid residue is selected from linoleic acid (-C(O)(CH 2 ) 7 (CH) 2 CH 2 (CH) 2 (CH 2 ) 4 CH 2 -), docosahexaenoic acid (-C(O)(CH 2 ) 2 (CHCHCH 2 ) 6 CH 2 -), eicosapentaenoic acid (-C(O)(CH 2 ) 3 (CHCHCH 2 ) 5 CH 2 -), α-linolenic acid (-C(O)(CH 2 ) 7 (CHCHCH 2 ) 3 CH 2 -), octadecatetraenoic acid (-C(O)(CH 2 )4 (CHCHCH 2 ) 4 CH 2 -), y-linolenic acid (-C(O)(CH 2 ) 4 (CHCHCH 2 ) 3 (CH 2 ) 3 CH 2 -), arachidonic acid (-C(O)(CH 2 ) 3 ,(CHCHCH 2 ) 4 (CH 2 ) 4 CH 2 -), docosahexaenoic acid (-C(O)(CH 2 ) 5 (CHCHCH 2 ) 4 (CH 2 ) 4 CH 2 -), palmitoleic acid (-C(O)(CH 2 ) 7 CHCH(CH 2 ) 5 CH 2 -), vaccenic acid (-C(O)(CH 2 ) 9 CHCH(CH 2 ) 5 CH 2 -), eicosenoic acid (-C(O)(CH 2 ) 11 CHCH(CH 2 ) 5 CH 2 -), oleic acid (-C(O)(CH 2 ) 7 CHCH(CH 2 ) 7 CH 2 -), elaidic acid (-C(O)(CH 2 ) 7 CHCH(CH 2 ) 7 CH 2 -), gondoic acid (-C(O)(CH 2 ) 9 CHCH(CH 2 ) 7 CH 2 -), gadoleic acid (-C(O)(CH2 ) 7 CHCH(CH 2 ) 9 CH 2 -), neuraminic acid (-C(O)(CH 2 ) 13 CHCH(CH 2 ) 3 CH 2 -), mead acid (-C(O)(CH 2 ) 3 (CHCHCH 2 ) 3 (CH 2 ) 6 CH 2 -), myristoleic acid (-C(O)(CH 2 ) 7 CHCH(CH 2 ) 3 CH 2 -) and erucic acid (-C(O)(CH 2 ) 11 CHCH(CH 2 ) 7 CH 2 -).

[0748] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0749]

[0750] in:

[0751] R 22 is independently selected at each occurrence from alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 )N-, alkenyl, haloalkyl, aryl, heterocyclic and heteroaryl, each of which is independently selected from R 21 The substituents are optionally substituted;

[0752] The remaining variables are as defined in this article.

[0753] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0754]

[0755] in:

[0756] R 32 is independently selected at each occurrence from alkyl, N + X-, -C-, alkenyl, haloalkyl, aryl, heterocyclic and heteroaryl, each of which is independently selected from R 21 The substituents are optionally substituted;

[0757] X- is an anionic group, such as Br- or Cl-; and

[0758] All other variables are as defined herein.

[0759] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0760]

[0761] Wherein each heteroaryl, heterocycle, cycloalkyl and aryl may be optionally substituted with 1, 2, 3 or 4 of any combination of halogen, alkyl, haloalkyl and heteroaryl, heterocycle or cycloalkyl as long as the valence permits.

[0762] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0763]

[0764] Wherein each heteroaryl, heterocycle, cycloalkyl and may be optionally substituted with 1, 2, 3 or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl as long as valence permits.

[0765] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0766]

[0767] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0768]

[0769] In certain embodiments, in the compound of formula II, the linker B , Connectors C or connector D Selected from:

[0770]

[0771] wherein tt is independently selected from 1, 2 or 3 and ss is 3 minus tt (3-tt).

[0772] In certain embodiments, in the compound of formula II, the linker B , Connectors C or connector D Selected from:

[0773]

[0774] wherein tt and ss are as defined herein.

[0775] In certain embodiments, in the compound of formula II, the linker B , Connectors C or connector D Selected from:

[0776]

[0777]

[0778]

[0779]

[0780] wherein each heteroaryl, heterocycle, cycloalkyl and aryl may be optionally substituted with 1, 2, 3 or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl as valence permits; and tt and ss are as defined herein.

[0781] In certain embodiments, in the compound of formula II, the linker B , Connectors C or connector D Selected from:

[0782]

[0783]

[0784] wherein each heteroaryl, heterocycle, cycloalkyl and aryl may be optionally substituted with 1, 2, 3 or 4 of any combination of halogen, alkyl, haloalkyl and heteroaryl, heterocycle or cycloalkyl as valence permits: and tt and ss are as defined herein.

[0785] In certain embodiments, in the compound of formula II, the linker B , Connectors C or connector D Selected from:

[0786]

[0787] wherein each heteroaryl and aryl may be optionally substituted with 1, 2, 3 or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl as valence permits: and tt and ss are as defined herein.

[0788] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0789]

[0790] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0791]

[0792] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0793]

[0794] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0795]

[0796] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0797]

[0798] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0799]

[0800] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0801]

[0802]

[0803] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0804]

[0805]

[0806] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0807]

[0808] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0809]

[0810] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0811]

[0812] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0813]

[0814] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0815]

[0816] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0817]

[0818] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0819]

[0820] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0821]

[0822] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0823]

[0824] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0825]

[0826]

[0827] In certain embodiments, in the compound of formula II, the linker D is selected from:

[0828]

[0829] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0830]

[0831] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0832]

[0833] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0834]

[0835] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0836]

[0837] In certain embodiments, in the compound of formula II, the linker A Selected from

[0838]

[0839] In certain embodiments, in the compound of formula II, the linker A Selected from

[0840]

[0841] In certain embodiments, in the compound of formula II, the linker A Selected from

[0842]

[0843] In certain embodiments, the linker A Selected from

[0844]

[0845]

[0846] Each of which is selected from 1, 2, 3 or 4 21The substituents are optionally substituted. In certain embodiments, in the compound of formula II, the linker A Selected from:

[0847]

[0848] In certain embodiments, in the compound of formula II, the linker A Selected from

[0849]

[0850] In certain embodiments, in the compound of formula II, the linker A Selected from

[0851]

[0852] In certain embodiments, in the compound of formula II, the linker A Selected from

[0853]

[0854] In certain embodiments, in the compound of formula II, the linker A Selected from

[0855]

[0856] In certain embodiments, in the compound of formula II, the linker A Selected from

[0857]

[0858] In certain embodiments, in the compound of formula II, the linker A In certain embodiments, in the compound of formula II, the linker A Selected from

[0859]

[0860]

[0861] In certain embodiments, in the compound of formula II, the linker A Selected from

[0862]

[0863]

[0864] In certain embodiments, in the compound of formula II, the linker A Selected from

[0865]

[0866] In certain embodiments, in the compound of formula II, the linker A Selected from

[0867]

[0868] In certain embodiments, in the compound of formula II, the linker A Selected from

[0869]

[0870] In certain embodiments, in the compound of formula II, the linker A Selected from

[0871]

[0872] In certain embodiments, in the compound of formula II, the linker A Selected from

[0873]

[0874] In certain embodiments, in the compound of formula II, the linker A Selected from

[0875]

[0876] In certain embodiments, in the compound of formula II, the linker B Selected from

[0877]

[0878] In certain embodiments, in the compound of formula II, the linker B Selected from

[0879]

[0880] In certain embodiments, in the compound of formula II, the linker B Selected from

[0881]

[0882] In certain embodiments, in the compound of formula II, the linker B Selected from each of which is 1, 2, 3 or 4 selected from R 21 The substituents are optionally substituted.

[0883] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0884]

[0885] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0886]

[0887] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0888]

[0889] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0890]

[0891] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0892]

[0893] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0894]

[0895] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0896]

[0897] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0898]

[0899] In certain embodiments, in the compound of formula II, the linker B -Connectors A Selected from:

[0900]

[0901] In certain embodiments, in the compound of formula II, the linker B -Connectors A Selected from:

[0902]

[0903] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0904]

[0905] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0906]

[0907] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0908]

[0909] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0910]

[0911] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0912]

[0913] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0914]

[0915] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0916]

[0917]

[0918]

[0919] In certain embodiments, in the compound of formula II, the linker C Selected from: Each of which is selected from 1, 2, 3 or 4 R 21 The substituents are optionally substituted.

[0920] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0921]

[0922] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0923]

[0924] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0925]

[0926] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0927]

[0928] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0929]

[0930] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0931]

[0932] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0933]

[0934] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0935]

[0936] In certain embodiments, in the compound of formula II, the linker C -(Connector A ) 2 Selected from:

[0937]

[0938] In certain embodiments, in the compound of formula II, the linker C -(Connector A ) 2 Selected from:

[0939]

[0940] In certain embodiments, in the compound of formula II, the linker C -(Connector A ) 2 Selected from:

[0941]

[0942] In certain embodiments, in the compound of formula II, the linker C -(Connector A ) 2 Selected from:

[0943]

[0944] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0945]

[0946] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0947]

[0948] Each of which is selected from 1, 2, 3 or 4 21 The substituents are optionally substituted.

[0949] In certain embodiments, in the compound of formula II, the linker B -(Connector A )

[0950]

[0951] In certain embodiments, in the compound of formula II, the linker C -(Connector A )

[0952]

[0953] In certain embodiments, in the compound of formula II, the linker D -(Connector A )

[0954]

[0955] In various embodiments, R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O) 2 R3 .

[0956] In various embodiments, in the compound of formula II, R 5 are independently selected from hydrogen, heteroalkyl, C 0 -C 6 Alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, 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-OC(O)R 3 , C 0 -C 6 Alkyl-OS(O)R 3 , C 0 -C 6Alkyl-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 , each of which is optionally substituted with 1, 2, 3 or 4 substituents.

[0957] In various embodiments, in the compound of formula II, R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, 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) 2 R 3 .

[0958] In various embodiments, in the compound of formula II, R 8 and R 9 and alkyl. Each occurrence of is independently selected from the group consisting of hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0959] In various embodiments, the compound of Formula II has the structure of Formula II-A. In various embodiments, in the compound of Formula II-A, [MIFBM] and [IgGBM] are as defined herein.

[0960] The compound of formula II-A has the following structure:

[0961]

[0962] in:

[0963] [MIFBM / IgGBM] is a MIF or IgG binding moiety that binds to circulating MIF or IgG, respectively, in a subject, each of which is associated with a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject;

[0964] [ASGPBM] is an asialoglycoprotein receptor binding moiety having a structure selected from the group consisting of:

[0965]

[0966]

[0967] Each [CON] is an optional linker chemical moiety which, when present, links [LIN] to [CPBM] or to [ASGPBM];

[0968] [LIN] is [Linker] or [Linker-2], each of which is a chemical moiety with a valence of 1 to 15, which is covalently linked to one or more [ASGPBM] or [CPBM] groups, optionally via [CON], wherein [LIN] optionally itself comprises one or more [CON] groups;

[0969] Z B Does not exist, is (CH 2 ) IM 、C(O)-(CH 2 ) IM - or C(O)-(CH 2 ) IM -NR M ;

[0970] R M is H or C optionally substituted by one or two hydroxy groups 1 -C 3 alkyl;

[0971] R 2 yes

[0972] Where R AM is H, C optionally substituted with up to 3 halo and one or two hydroxyl groups 1 -C 4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)O-(C 1 -C 4 alkyl), -OC(O)-(C 1 -C 4 alkyl), -C(O)-(C 1 -C 4 alkyl) or -(CH 2 ) K -NR N3 R N4 ,or

[0973] R 2 yes

[0974] in

[0975] R TA H, CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K O(C 1 -C 4 alkyl), C optionally substituted by 1 to 3 halogen groups 1 -C 4 Alkyl, -(CH 2 ) K COOH, -(CH 2 ) K C(O)O-(C 1 -C 4 alkyl), -OC(O)-(C 1 -C 4 alkyl) or -C(O)-(C 1 -C 4 alkyl), or

[0976] R TA It is C 3 -C 10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of which is optionally substituted by up to three of the following groups: CN, NR N1 R N2 、-(CH 2 ) K OH, -(CH 2 ) K O(C 1 -C 4 alkyl), C optionally substituted by 1-3 halogen or 1-2 hydroxyl groups 1 -C 3 alkyl, -O-(C 1 -C 3 -alkyl), -(CH 2 ) K COOH, -(CH 2 ) K C(O)O-(C 1 -C 4alkyl), OC(O)-(C 1 -C 4 alkyl) or -(CH 2 ) K C(O)-(C 1 -C 4 alkyl), or

[0977] R TA yes It is raised to the three Cs 1 -C 3 The alkyl group is optionally substituted, C 1 -C 3 Alkyl is optionally substituted with up to three halo groups; or

[0978] R TA yes

[0979] D. Other ASGPR binding sites

[0980] In some embodiments, the ASGPR binding moiety can be any of the moieties described in the following literature: 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; 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., "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., "EnhancedBinding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," BioconjugateChem, 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 illustrative and not intended to be limiting. .

[0981] 1. GalNAc-tyrosine moiety

[0982] In some embodiments, the ASGPR binding moiety can be a moiety having a 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, the compound of Formula I or the compound of Formula II can have one, two or three ASGPR binding moieties having a structure of M1, M2, M3 or M4.

[0983]

[0984] In various embodiments, the ASGPR binding moieties M1 to M4 can be conjugated to any suitable [CON], [Linker] or [Linker-2] as described herein and described 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.

[0985] 2. Trivalent triazole moiety

[0986] In some embodiments, the ASGPR binding moiety can be a moiety having the structure of M5:

[0987]

[0988] In the structure of M5, each R is independently R at each occurrence. 1 or R 2 ,

[0989]

[0990] In various embodiments, the compound of Formula I or Formula II comprises an ASGPR binding portion having a structure of M5. In various embodiments, each R in M5 is R 1 In various embodiments, each R in M5 is R 2 .

[0991] In various embodiments, the ASGPR binding moiety M5 can be conjugated / bound to any suitable [CON], [Linker] or [Linker-2] as described herein and described 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.

[0992] 3. Galactose-derivatized behenate moiety and agarose-derivatized behenate moiety

[0993] In various embodiments, the ASGPR binding moiety can be a galactosylbehenate derived moiety M7:

[0994]

[0995] In the structure of M7, Y is OH or NHAc.

[0996] In various embodiments, the ASGPR binding moiety can be an agarose behenate-derivatized moiety M8:

[0997]

[0998] 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 described in Dhawan, V., et al., “Polysaccharide conjugatessurpass 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.

[0999] 4. Other small molecule ASGPR binding moieties

[1000] In various embodiments, the ASGPR binding moiety can be any one of the following compounds 2-18:

[1001]

[1002]

[1003] In various embodiments, in compounds 15 and 16, R is CH 2 OAc, COOH or CH 2OH. Compounds 2-18 can be conjugated / bound to any suitable [CON], [Linker] or [Linker-2] as described herein and in 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., "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 onglycoconjugated natural triterpenoids,” Russian Chemical Bulletin, International Edition, Vol.68, No.12, pp.2331-2338, December 2019. Compound 2-18 can be linked via any suitable reactive group contained therein. Without limitation, compound 2-13 can be linked to [CON], [Linker] or [Linker-2] by or through reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone or aromatic halogen contained in compound 2-18. Suitable reaction modes for linking compound 2-18 to [CON], [Linker] or [Linker-2] as described herein include, but are not limited to, substitution (e.g., alkylation of OH or NH groups), esterification (ester formation), amidation (amide formation), transesterification (exchanging one ester for another ester), transamidation (exchanging one amide for another amide), azide-alkyne cycloaddition, and other reactions capable of forming CC, NC or OC bonds with vinyl and alkynyl groups, such as cycloaddition, amidation, oxidation, alkylation, rearrangement reactions (e.g., Claisen, Cope, etc.), and the like.

[1004] The term "pharmaceutically acceptable salt" or "salt" is used throughout the specification to describe one or more salt forms of the compositions herein, which are proposed to increase the solubility of the compound in saline for parenteral delivery or in the gastric juice of the gastrointestinal tract of the patient to promote the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include: salts derived from alkali metals such as potassium and sodium; salts derived from alkaline earth metals such as calcium and magnesium; and ammonium salts, as well as salts derived from a variety of other acids known in the pharmaceutical field. In some embodiments, sodium salts and potassium salts are used as neutralized salts of compositions containing carboxylic acids and free acid phosphates according to the present disclosure. The term "salt" shall refer to any salt consistent with the use of the compounds according to the present disclosure. In the case where the compound is used in a pharmaceutical indication (including the treatment of prostate cancer (including metastatic prostate cancer)), the term "salt" shall refer to a pharmaceutically acceptable salt, consistent with the use of the compound as a medicament.

[1005] The term "co-administration" shall mean that at least two compounds or compositions are administered to a patient simultaneously, such that an effective amount or concentration of each of the two or more compounds may be present in the patient's body at a given time point. Although compounds according to the present disclosure may be co-administered to a patient simultaneously, the term encompasses the administration of two or more agents simultaneously or at different times, provided that effective concentrations of all co-administered compounds or compositions are present in the subject's body at a given time. Chimeric antibody-recruiting compounds according to the present disclosure may be administered together with one or more additional anticancer agents or other agents for treating or ameliorating symptoms of cancer, particularly prostate cancer, including metastatic prostate cancer.

[1006] The term "anticancer agent" or "additional anticancer agent" refers to a compound other than a chimeric compound according to the present disclosure, which can be used in combination with a compound according to the present disclosure to treat cancer. Exemplary anticancer agents that can be co-administered in combination with one or more chimeric compounds according to the present disclosure include, for example, antimetabolites, inhibitors of topoisomerases I and II, alkylating agents, and microtubule inhibitors (e.g., taxol), among others.Exemplary anticancer compounds for use in the present disclosure may 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 decoy antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, Lo Nolatrexed, AZD2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, cottonpol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR. 1KRX-0402, Lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, cerevisiae Seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate citrate), anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6,Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2 Acetate of acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X, wherein x = 1 to 2.4], goserelin acetate, leuprolideacetate, triptorelin pamoate pamoate), medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acidacid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, Cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib b), leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer ), procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil nitrogen mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside,arabinoside), 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox), gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and cetuximab (erbitux), paclitaxel without Cremophor, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxy 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD184352, 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, zolendronate, prednisone, cetuximab cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomabtiuxetan), androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunomycin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoprolol metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa alfa) and darbepoetin alfa, vemurafenib, etc., including immunotherapeutic agents such as IDO inhibitors (inhibitors of the indoleamine 2,3-dioxygenase (IDO) pathway) such as Indoximod (NLG-8187), Navoximod (GDC-0919) and NLG802, PDL1 inhibitors (inhibitors of programmed death ligand 1), including, for example, nivolumab, durvalumab and atezolizumab, PD1 inhibitors such as pembrolizumab (Merck) and CTLA-4 inhibitors (inhibitors of cytotoxic T lymphocyte-associated protein 4 / cluster of differentiation 152), including ipilimumab and tremelimumab, etc.

[1007] In addition to anticancer agents, a variety of other agents may also be co-administered with the chimeric compounds according to the present disclosure in the treatment of cancer. These agents include active agents, minerals, vitamins and nutritional supplements that show certain efficacy in inhibiting cancer tissue or its growth, or can be used to treat cancer in other aspects. For example, dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids and phytoestrogens (including β-sitosterol) can be used in combination with the present compounds to treat cancer.

[1008] Without being limited by theory, the compounds according to the present disclosure comprising a MIF binding portion (MIFBM) or an antibody binding portion and an ASGPR binding portion selectively bind to hepatocytes and, through this binding, promote the introduction of the MIFBM group into hepatocytes that selectively bind to the ASGPRBM, wherein the MIF protein within the hepatocytes is degraded and removed from the circulation. Thus, the compounds according to the present disclosure both bind to the MIF protein and remove the MIF protein from the circulation, thereby producing a dual effect, which is particularly effective for treating disease states and conditions.

[1009] Pharmaceutical compositions comprising an effective amount of at least one compound disclosed herein, typically a bifunctional chimeric compound according to the disclosure (comprising at least one MIFBM group or antibody binding portion and at least one ASGPRBM) and a combination of one or more of the compounds described herein in other aspects, all of which are combined in effective amounts with a pharmaceutically effective amount of a carrier, additive or excipient represent further aspects of the disclosure. These compounds may be used in combination with at least one additional, optional anticancer agent as disclosed herein in other aspects.

[1010] The compositions of the present disclosure can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in the form of controlled release formulations. Pharmaceutically acceptable carriers that can be used for these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene glycol-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[1011] In some embodiments, the compositions of the present disclosure are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, etc. 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 compositions are administered orally (including via cannula through the mouth or nose into the stomach), intraperitoneally, or intravenously.

[1012] The sterile injectable form of the composition of the present disclosure can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil (especially its polyoxyethylated form). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[1013] The pharmaceutical composition of the present disclosure can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are generally added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient is mixed with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavoring agents or coloring agents may also be added.

[1014] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions 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 will therefore melt in the rectum to release the drug. These materials include cocoa butter, beeswax, and polyethylene glycol.

[1015] Pharmaceutical compositions of the present disclosure may also be applied topically, particularly for the treatment of skin cancer, psoriasis or other diseases occurring in or on the skin. Suitable topical formulations are readily prepared for each of these regions or organs. Topical application to the lower intestinal tract may be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically acceptable transdermal patches may also be used.

[1016] For topical application, the pharmaceutical composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, paraffin oil, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[1017] Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream comprising the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[1018] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated in an ointment such as petrolatum.

[1019] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[1020] The amount of compound that can be combined with the carrier material to produce a single dosage form in the pharmaceutical compositions of the present disclosure will vary depending on the host and disease being treated, the particular mode of administration, etc. In some embodiments, the composition is formulated to contain from about 0.05 mg to about 1.5 g, 0.1 mg to 1 g, 0.5 mg to 750 mg, more typically from about 1 mg to about 600 mg, and even more typically from about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one additional compound useful for treating cancer, prostate cancer or metastatic prostate cancer, or secondary effects or conditions thereof.

[1021] Methods for treating a patient or object in need of a specific disease state or condition (especially cancer) as described elsewhere herein include administering an effective amount of a pharmaceutical composition comprising a therapeutic amount of one or more novel compounds described herein and optionally at least one additional biologically active (e.g., anticancer, anti-inflammatory) agent. The amount of active ingredient (one or more) used in the treatment methods disclosed herein that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated, the specific mode of administration. For example, the composition can be formulated so that the novel compound is between 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 patient / day, or in some embodiments, greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg / kg patient / day Therapeutic effective doses can be administered to patients receiving these compositions.

[1022] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, 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 specific disease or condition being treated.

[1023] Patients or subjects (e.g., humans) suffering from autoimmune diseases, inflammatory diseases, or cancer can be treated by administering to the patient (subject) an effective amount of a chimeric / bifunctional compound according to the present disclosure, including a pharmaceutically acceptable salt, solvate, or polymorph thereof (optionally in a pharmaceutically acceptable carrier or diluent), alone or in combination with other known agents, exemplary agents capable of adjuvant treatment of autoimmune diseases and / or inflammatory diseases or cancer (including metastatic cancer or recurrent cancer) or amelioration of secondary effects and / or symptoms associated with these disease states and / or conditions. Such treatment can also be administered in combination with other conventional therapies such as radiation therapy or cancer surgery.

[1024] The present compounds, alone or in combination with other agents described herein, can be administered by any suitable route (eg, oral, parenteral, intravenous, intradermal, subcutaneous or topical), in liquid, cream, gel or solid form or by aerosol form.

[1025] The amount of active compound included in the pharmaceutically acceptable carrier or diluent is sufficient to deliver a therapeutically effective amount for the desired indication to the patient without causing severe toxic effects in the treated patient. Exemplary dosages of active compounds for all conditions mentioned herein range from about 10 ng / kg to 300 mg / kg per day, such as 0.1 to 100 mg / kg per day, such as 0.5 to about 25 mg / kg per day of the recipient / patient's body weight. Some exemplary dosages will range from about 0.01-3% wt / wt in a suitable carrier.

[1026] The compound is conveniently administered in any suitable unit dosage form, including but not limited to those containing less than 1 mg, 1 mg to 3000 mg, such as 5 to 500 mg, of active ingredient per unit dosage form. An oral dosage of about 25-500 mg is generally convenient.

[1027] Sometimes the active ingredient is administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, such as 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 as a bolus of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[1028] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation and excretion rate of the drug and other factors known to those skilled in the art. It should be noted that the dosage value will also vary with the severity of the condition to be alleviated. It should be further understood that for any specific object, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the personnel who administer or supervise the administration of the composition, and the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once or divided into multiple smaller doses administered at different time intervals.

[1029] Oral compositions will typically include an inert diluent or edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be incorporated via an excipient and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and / or auxiliary materials may be included as part of the composition.

[1030] Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, 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 flavoring agents such as mint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the types described above, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.

[1031] The active compound or its pharmaceutically acceptable salt may 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, colorings, and flavors.

[1032] The active compound or its pharmaceutically acceptable salt may also be mixed with other active substances that do not impair the desired effect or with substances that supplement the desired effect such as other anticancer agents, anti-inflammatory agents, immunosuppressants, antibiotics, antifungal agents or antiviral compounds. In certain aspects of the present disclosure, one or more chimeric / bifunctional MIF binding compounds according to the present disclosure are co-administered with another anticancer agent and / or another bioactive agent, as described herein in other aspects.

[1033] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical application may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. The parental preparation may be packaged into ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[1034] If administered intravenously, the carrier is sometimes physiological saline or phosphate buffered saline (PBS).

[1035] In certain embodiments, the compound is prepared with a carrier that will prevent the active compound from being rapidly eliminated from the body, such as a controlled and / or sustained release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such preparations will be apparent to those skilled in the art.

[1036] Liposomal suspensions or cholestosomes can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, the method described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations can be prepared by dissolving appropriate lipids (one or more) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, then evaporating, thereby leaving a thin film of dried lipids on the container surface. Then the aqueous solution of the active compound is introduced into the container. The container is then rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposomal suspension.

[1037] Chemical synthesis

[1038] Attached to this article Figure 1 , Figure 7 and Fig.13 Identified exemplary compounds according to the present disclosure that exhibit activity in binding and reducing and / or eliminating unwanted circulating proteins for therapeutic and / or diagnostic purposes. These compounds are based on MIF, anti-DNP IgG or IgG binding moieties, ASPGR groups such as GN 3 Or the AcF3-3 group is covalently linked to these binding moieties via a linker comprising 1 to 100 ethylene glycol groups, more typically 1 to 15 ethylene glycol groups, 1 to 10 ethylene glycol groups, and typically 2 to 10 ethylene glycol groups, which are optionally linked via a [CON] group (such as 1,2,3-triazole or other [CON] groups as described herein).

[1039] Fig.16 The synthesis of an azide / amide carboxylic acid terminated PEG linker intermediate is shown, which can be condensed to an alkynyl precursor (e.g., Figure 5 NVS alkyne precursor) to provide a carboxylic acid terminated intermediate, which can be used to provide a bifunctional molecule.

[1040] Fig.17 A general method for converting PEG molecules to hydroxy azides is described. The PEG compound is tosylated (TsCl, DCM, in the presence of a base) at reduced temperatures and further reacted with sodium azide in a non-nucleophilic solvent at elevated temperatures. The final azido alcohol is used in the following figure.

[1041] Fig.18 The same synthetic steps are described for the synthesis of mesylated azides from the starting PEG molecule to give the intermediate azido alcohol, which is then treated with MsCl in pyridine to give the final compound.

[1042] Fig.19 The synthesis of a GalNAc ASGPR ligand attached to a terminal amine via PEG is shown. Pentaacetyl galactosamine is reacted with TMSOTf in DCE at elevated temperatures to form a bicyclic intermediate, which is then reacted with azido alcohol to give the azido intermediate (TMSOTf, DCE). This molecule is then subjected to a Staudinger reduction to give the amine, which is used in the following figure.

[1043] Fig. 20 The synthesis of a high affinity bicyclic ASGPR ligand is shown. Treatment of galactose pentaacetate with HBr / AcOH affords a bromide intermediate, which is then treated with Zn and CuSO4 (water / AcOH) to afford the galactaldehyde. Treatment with ceric ammonium nitrate and sodium azide at reduced temperature (MeCN) affords the disubstituted intermediate compound. This is then treated with a strong base (NaOH / MeOH) to afford the triol azide intermediate. This compound is fully silylated (TMSCl / pyr), followed by primary alcohol deprotection (potassium carbonate, MeOH, reduced temperature) and oxidation (Dess-Martin periodinane, DCM). Treatment with a strong base (NaOEt / HOEt) and paraformaldehyde affords the tetraol intermediate, which is then cyclized in a strong acid (H2SO4 / water) to afford the bicyclic azide ligand.

[1044] Fig.21 The synthesis of trifluoroacetate derivatives of bicyclic ASGPR ligands is shown. Triol azides are reduced (Pd / C, MeOH) to give intermediate amines, which are then peracylated with trifluoroacetic anhydride. These esters are hydrolyzed with strong base (NaOMe / HOMe) to give intermediate amides, which are protected with dimethoxypropane in the presence of camphorsulfonic acid in DMF at elevated temperatures. They are then reacted with mesylated azido alcohols in the presence of strong base (NaH / DMF) to give intermediate azides, which are then reduced (Lindella's catalyst, MeOH) to give the final amines.

[1045] Fig. 22 The synthesis of the MIF targeting linker as a monovalent linker is shown, which is synthesized by a method similar to that described in the previous figure. The boc-protected methyl ester is deprotected with TFA in DCM and then coupled with a MIF targeting carboxylic acid (HBTU, DIPEA, DMF). The MIF targeting carboxylic acid is then hydrolyzed with a strong base (NaOH / dioxane / H2O) to obtain the MIF targeting carboxylic acid.

[1046] Fig.23 Shown is the synthesis of the dicarboxylic acid MIF targeting motif, which was synthesized as described in the previous figure.

[1047] Fig.24 The synthesis of a tris base derived trivalent linker is shown. Treatment of the tris base with di-tert-butyl dicarbonate in the presence of a base gives a boc protected triol, which then reacts with acrylonitrile in the presence of a base (dioxane / H2O) to give a trinitrile intermediate. This is then converted to the methyl ester by treatment with a strong acid in methanol. The amine then reacts with Cbz-glycine via DCC mediated amide formation and deprotection gives the tricarboxylic acid, which is used in the following figure.

[1048] Fig.25 The synthesis of ASGPR targeting moieties using three GalNAc ASGPR ligands is described. A tricarboxylic acid is reacted with an amine-terminated protected GalNAc (amide bond formation in the presence of HBTU and DIPEA) followed by deprotection by reduction (Pd / C, solvent) and treatment with a strong base (NaOMe / MeOH).

[1049] Fig.26 Shown is the synthesis of the tricarboxylic acid MIF targeting motif, which was synthesized as described in the previous figure.

[1050] Fig. 27 Shown is the synthesis of a MIF NVS alkyne precursor, which can be reacted with a carboxylic acid-containing azido reactant (as illustrated in the following figure) to provide a MIF-NVS-carboxylic acid terminated reactant, thereby producing a bifunctional compound.

[1051] Fig.28 The synthesis of a carboxylic acid-terminated MIF targeting moiety is shown. 2-Chloroquinolin-6-ol was reacted with ethyl 4-bromobutyrate in the presence of a base (DMF, elevated temperature) to give the aryl chloride, which was then Sonogashira coupled with ethynyltrimethylsilane at elevated temperature. The intermediate silylated compound was deprotected with TBAF (DCM / THF). A click reaction then formed a triazole between the alkyne intermediate and in situ synthesized 4-azido-2-fluorophenol to give the ethyl ester intermediate, which was then hydrolyzed with a strong base (NaOH / dioxane) to give the carboxylic acid, which was used in the following figure.

[1052] Fig.29 The synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3 by HBTU-mediated coupling of ASPGR targeting amine with MIF targeting carboxylic acid in DMF is described, which is prepared by first condensing the reactant azido PEG-carboxylic acid onto the MIF portion containing an alkyne-terminated PEG group to form the MIF targeting carboxylic acid.

[1053] Fig.30The synthesis of the bifunctional molecules MIF-GN3 and MIF-PEGn-GN3 by HATU-mediated coupling of ASGPR-targeting amines with MIF-targeting carboxylic acids (DMF, DIPEA) is described.

[1054] Fig.31 The synthesis of a bifunctional molecule targeting MIF and ASGPR containing a bicyclic ASGPR AcF3 ligand is described. The monocarboxylic acid bound to MIF was treated with HBTU, DIPEA, an amine-terminated ligand, and DMF to give an amide, which was then deprotected with 1 M HCl to give the final compound.

[1055] Fig.32 The synthesis of a bifunctional molecule targeting MIF and ASGPR is described, which contains two bicyclic ASGPr ligands. It was synthesized as described above.

[1056] Fig.33 The synthesis of a bifunctional molecule targeting MIF and ASGPR is described, which contains three bicyclic ASGPr ligands. It was synthesized as described above.

[1057] Fig.34 The synthesis of DNP-GN3 is shown. Treatment of 2,4-dinitrochlorobenzene with an aminocarboxylic acid in the presence of a weak base affords the di-nitro analine carboxylic acid intermediate. Further steps were performed as described for the previous molecule.

[1058] Fig.35 The synthesis of DNP-AcF3-3 is shown and was performed in a similar manner to the previous compounds.

[1059] Fig.36 A synthetic scheme for obtaining IBA-GN3 is shown. Pentaethylene glycol is treated with p-toluenesulfonyl chloride in the presence of a base to give the monotosylated alcohol, which is then treated with sodium azide at elevated temperatures to give the azido alcohol. This compound is then oxidized using Jones reagent and then reduced with palladium on carbon under a hydrogen atmosphere to give the carboxylic acid-amine. Indolebutyric acid is treated with N-hydroxysuccinimide, EDC, and DIPEA, respectively, to give the NHS-ester indole, which is then reacted with the above carboxylic acid-amine. This product is reacted again with N-hydroxysuccinimide, EDC, and DIPEA to give the NHS ester. This NHS ester is reacted with NH2-GN3 prepared as described above. The subsequent amide is deprotected with NaOMe in MeOH to give compound IBA-GN3.

[1060] Fig.37The synthesis of triazine-GN3 is shown. Treatment of cyanuric chloride with (4-(methoxycarbonyl)phenyl)methanaminium and diisopropylethylamine in THF at -78°C affords the monosubstituted product. This is then treated with cyclohexylmethylamine at room temperature to afford the second substitution. The final substitution is accomplished with (1S,2S,4R)-bicyclo[2.2.1]heptane-2-amine at elevated temperatures to afford the trisubstituted triazine. Deprotection with lithium hydroxide followed by amide coupling with a monoprotected diamine affords the Boc protected derivative, which is then deprotected and reacted with glutaric anhydride to afford the carboxylic acid, which is converted to the NHS ester using standard coupling conditions. This is reacted with NH2-GN3 to afford the final product.

[1061] Fig.38 The synthetic scheme for obtaining FcIII-GN3 is shown. The acetylenic peptide is prepared using standard solid phase peptide synthesis techniques. The peptide is removed from the Rink resin using reagent L and then oxidized with ammonium bicarbonate buffer (pH 8-9) in MeOH under air to obtain the cyclic peptide. As previously described, the peptide is reacted with GN3-azide to obtain the product triazole FcIII-GN3.

[1062] Fig.39 Shown is a synthetic scheme to obtain FcIII-4c-GN3, which was accomplished using the methods described above.

[1063] Figure 40-Figure 43 Described is the synthesis of bifunctional molecules targeting MIF and ASGPr, which contain three bicyclic ASGPR ligands with different substitutions on the 2-amine of the sugar. They were synthesized by similar methods as described above, as illustrated in the accompanying figures.

[1064] Fig.44 The synthesis of compound MIF-18-3 is shown. The triacylgalactaldehyde is deprotected with ammonia in methanol, and then the tribenzyl group is protected with benzyl bromide in the presence of a base. The olefin is hydrolyzed overnight with HCl in THF / H2O, and then oxidized with PCC to give the aldehyde. Sodium azide α is then added to the carbonyl group with KHMDS and TIBSN3 at a reduced temperature. The intermediate is then treated with p-OMePhMgBr in THF and toluene to give the intermediate alcohol, which is then reduced using Et3SiH at a reduced temperature in the presence of BF3-Et2O. The resulting azide is then reduced with Lindela's catalyst under a hydrogen atmosphere to give the corresponding amine, which is then acylated with trifluoroacetic acid in pyridine. The benzyl group is then removed with carbon-supported Pd(OH2) in MeOH at reflux, and the resulting triol is protected as an acetal with dimethoxypropane and camphorsulfonic acid at an elevated temperature. The remainder of the synthesis is performed as described for the previous molecule.

[1065] Fig.45 The synthesis of compound MIF-31-3 is shown. Galactosamine hydrochloride is fully protected with acetic anhydride and then treated with allyl alcohol in the presence of BF3 ehtrate to give the allyl intermediate. Treatment with pivaloyl chloride in pyridine gives the di-Piv protected intermediate, which is then treated with trifluoromethanesulfonic anhydride and then hydrolyzed in water at elevated temperatures. Treatment with NaOMe in MeOH to remove the pivaloyl group gives the allyl triol intermediate. Subsequent steps are performed as described for the previous molecule.

[1066] Fig.46 Shown is the synthesis of compound MIF-15-3, which was synthesized using a similar method to the above compounds.

[1067] Fig.47 The synthesis of compound MIF-19-3 is shown. This molecule was synthesized by a late triazole-forming click reaction between triazide and propiolic acid in methanol in the presence of THPTA, copper sulfate, water, and sodium ascorbate. All other reactions were performed as described above.

[1068] Fig.48 Shown is the synthesis of compound MIF-16-3, which was synthesized using a similar procedure to the above compounds.

[1069] Fig.49 Shown is the synthesis of compound MIF-20-3, which was synthesized using a similar procedure to the above compounds.

[1070] Fig.50 Shown is the synthesis of compound MIF-14-3, which was synthesized using a similar procedure to the above compounds.

[1071] Fig.51 Shown is the synthesis of compound MIF-21-3, which was synthesized using a similar procedure to the above compounds.

[1072] Figure 52-Figure 66 The synthesis of a number of MIF binding compounds containing various ASGPRBM moieties is shown. These compounds were synthesized by methods similar to those described above.

[1073] Example

[1074] This specification is further described in detail by reference to the following experimental examples. The purpose of providing these examples is only to illustrate, and unless otherwise specified, these examples are not intended to be limiting. Therefore, this specification should never be interpreted as being limited to the following examples, but should be interpreted as covering any and all variations that become apparent due to the teachings provided herein.

[1075] Proper protein secretion and turnover are essential processes for maintaining 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 terminal with 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 asialoglycoprotein receptors (ASGPRs) on the surface of hepatocytes (3-5).

[1076] ASGPR is a C-type lectin that removes aged circulating proteins containing exposed GalNAc residues from the circulation by trafficking them to lysosomes. Multiple galactose or GalNAc residues displayed on the protein surface are required for high-affinity binding to ASGPR and subsequent endocytosis (6,7). Once these proteins are endocytosed, they are released from ASGPR by depletion of endosomal calcium and changes in the protonation of amino acids at the binding site due to a decrease in pH (12); this allows ASGPR to recycle back to the hepatocyte surface (13). The endocytosed proteins are trafficked to late endosomes, which then fuse with lysosomes. Lysosomal proteases then degrade the endocytosed proteins, permanently removing them from the circulation (14).

[1077] Nonglycosylated proteins are not known to be natural targets of ASGPR. One such protein is macrophage inhibitory factor (MIF), a 12.5 kDa protein that may have catalytic activity (15). Genetic depletion or antibody neutralization of MIF has been shown to have positive results in models of sepsis (16), multiple sclerosis (17), rheumatoid arthritis (18), and burn recovery (21). A bifunctional molecule has been proposed for the degradation of circulating MIF that utilizes ASGPR as a portal for the protein to enter the endosomal-lysosomal degradation pathway. The bicyclic ASGPR binding molecules in MIF-AcF2 and MIF-AcF3 have previously been reported as high-affinity binders of ASGPR (22,23).

[1078] Example 1: Biological Data

[1079] In Example 1, exemplary compounds according to some embodiments were tested to determine their biological activity. The active compounds are shown in Figure 1 , Figure 7 and Fig.13 The results of the biological experiments are described below.

[1080] Figure 1Exemplary compounds according to the present disclosure are shown. Note that 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 in the figure. Note that n in the PEG linker sometimes ranges from 1-12, such as 1 to 10, 2 to 8, 2 to 6, 2 to 5, or is 1, 2, 3, or 4.

[1081] The results are shown in Figure 2 In the experiment, A. Fluorescence polarization data of MIF-FITC binding to human MIF showed that the MIF binding moiety of the present disclosure binds to MIF. B. The bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3 and NVS-PEG3-GN3 competitively bind to MIF-FITC, indicating that the bifunctional molecules maintain the ability to bind to human MIF.

[1082] The results are shown in Figure 3 In the experiment, the bifunctional molecules were able to deplete human MIF from the supernatant of cultured HepG2 cells. Briefly, human MIF (100 nM) was added to the cell culture medium in the presence of a negative control MIF inhibitor for 3 w 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 used known MIF binding ligands. In 96-well plates (surface area approximately .3 cm 2 ) were tested. HepG2 cells were grown to 90% confluence in RPMI culture medium, then washed with PBS (2x) and treated with serum-free medium (optimem + .1% BSA, + ​​Pen / Strep) containing 100nM huMIF (Cayman Chemical) and compounds (where applicable). Compounds were diluted with 1mM stock solution in DMSO. After 24 hours, supernatant samples (2uL) were collected, diluted 1:100, and analyzed by sandwich ELISA for MIF content (and incubated for 24 hours in the presence or absence of compounds). The remaining MIF levels were determined by sandwich ELISA (biolegend monoclonal anti-MIF antibody and biotinylated anti-MIF antibody). Data represent the mean value of at least 3 biological replicates, and error bars represent standard deviations. After 24 hours, up to 95.3% of MIF was depleted from cell culture medium (in the case of MIF-AcF3-3).

[1083] Figure 4Shown is the result of the experiment of whether MIF internalized by HepG2 cells is transported to lysosome.In this experiment, cells were incubated with rhuMIF (Cayman) of 100nM and MIF-GN3 of 200nM with concentration.After 12 hours, cells were fixed with formaldehyde, permeabilized, and detected with anti-Lamp2 antibody (mouse monoclonal antibody, Abcam), anti-MIF antibody of polyclonal rabbit (Thermo) and anti-mouse antibody of Alexa-488 labelling and anti-rabbit antibody of Alexa 568 labelling, proving internalization in lysosome.

[1084] Figure 5 MIF-GN3 was shown to mediate the depletion of injected human MIF from mice. The half-life of human MIF in mice is approximately 40 minutes. In this experiment, human recombinant MIF (Cayman chemical) was co-injected into mice with anti-DNP IgG used as an injection positive control. Specifically, nude mice were injected with 5 μg of recombinant human MIF and 200 μg of anti-DNP IgG ( Figure 4 ). Then MIF-GN was injected at the indicated concentrations. 3 Blood was drawn every 20 minutes over the course of 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). There were no significant differences in the levels of injected IgG between the test groups. 3 In mice treated with MIF-GN, moderate increases in huMIF levels were observed, up to 20 ng / ml, while in mice injected with PBS negative control, serum levels up to 150 ng / ml were observed, demonstrating that administration of MIF-GN 3 After that, the huMIF level dropped significantly.

[1085] Figure 6 MIF-GN3 was shown to slow tumor growth in a prostate cancer mouse model. In this experiment, nude mice were implanted with PC3 human prostate cancer cells. The treatment with a non-bifunctional MIF inhibitor (3w), anti-MIF antibody or MIF-GN3 was then immediately initiated. Throughout the experimental process, MIF-GN3 was shown to slow tumor growth, comparable to a MIF neutralizing antibody. 3w did not inhibit tumor growth, verifying the necessity of degrading MIF for therapeutic efficacy.

[1086] Figure 7 Shown are the molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind anti-DNP IgG and ASGPR. These compounds were used in several experiments as described below.

[1087] Figure 8DNP-GN3 and DNP-AcF3-3 were shown to mediate the formation of a ternary complex between HepG2 cells and anti-DNP, thus validating the bifunctional nature of these molecules. In this experiment, HepG2 cells expressing ASGPR were incubated with the bifunctional molecules and anti-DNP labeled with Alexa-488 (Thermo). The readout was the mean fluorescence intensity of the cell population. Fluorescence was measured using a flow cytometer.

[1088] In another experiment, the results are shown in Fig. 9 In, it shows 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 is the same as described above for MIF uptake. The readout is the percentage of Alexa 488 positive cells after 6 hours. Fluorescence is measured using a flow cytometer.

[1089] Fig.10 DNP-GN3 and DNP-AcF3-3 were shown to mediate the localization of alexa 568-labeled anti-DNP to late endosomes and lysosomes. This experiment was performed as described above for the MIF co-localization study.

[1090] These experimental results are shown in Fig.11 In, show that DNP-AcF3-3 mediates the degradation of the anti-DNP of alexa 488 labeling in HepG2 cells.In this experiment, cells are incubated with 1uM anti-DNP (Thermo) labeled with alexa 488 and 200nM DNP-AcF3-3.Cells are lysed at a given time (RIPA in PBS, containing protease inhibitors) and measured by SDS-PAGE gel.Reading is the fluorescence of protein fragments.

[1091] These results are shown in Fig.12 In this study, we demonstrated that DNP-GN3 mediates the depletion of anti-DNP from mouse serum. Mice were injected with anti-DNP on day 0 and then treated daily with the given compound for 6 days. Serum IgG levels were measured by ELISA. DNP-(OH) 3 Used as a non-bifunctional control molecule.

[1092] Fig.13 The structures of IgG-degrading molecules IBA-GN3, triazine-GN3, FcIII-GN3, and FcIII-4c-GN3 are shown.

[1093] Fig.14 FcIII-GN3 was shown to mediate the uptake of human IgG into HepG2 cells. This experiment was performed as described above.

[1094] Fig.15FcIII-GN3 was shown to mediate IgG localization to late endosomes in HepG2 cells. The experiments were performed as described above.

[1095] Example 2: Experimental Chemistry

[1096] In Example 2, the synthesis and characterization of exemplary compounds according to some embodiments will be described.

[1097] Example 2-1. MIF binding molecules ( Fig.13 )

[1098] Example 2-1-1: MIF-1

[1099]

[1100] 2-Chloroquinolin-6-ol (1.00 g, 5.57 mmol) and K 2 CO 3 (1.53 g, 11.1 mmol, 2.0 eq) was dissolved in DMF (20 mL). Ethyl bromobutyrate (1.63 g, 1.2 mL, 8.35 mmol, 1.5 eq) was then added and the mixture was stirred at 80 ° for 12 hours. The reaction solution was diluted into 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.

[1101] 1 H NMR (400 MHz, chloroform-d) δ7.98 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.40-

[1102] 7.32(m,2H),7.07(d,J=2.7Hz,1H),4.20-4.09(m,5H),2.56(t,J=7.2Hz,2H),2.19(t,J=6.7Hz,2H),1.26(t,J=7.1Hz,4H).

[1103] 13 C NMR (101MHz, cdcl 3 )δ173.24,157.46,148.18,143.87,137.83,130.05,128.06,123.40,12 2.67,106.20,77.48,77.16,76.84,67.30,60.69,30.87,24.63,14.39.

[1104] HRMS:[M+H] + Expected value 294.090, measured value 294.11

[1105] Example 2-1-2: MIF-2

[1106]

[1107] Compound 30 (1.52 g, 5.17 mmol) was dissolved in THF (20 mL) and triethylamine (2.88 mL, 20.7 mmol, 4 eq). Then copper (I) iodide (49.0 mg, .258 mmol, .05 eq), Pd (PPh 3 ) 2 Cl 2 (181 mg, .258 mmol, .05 eq) and TMS-acetylene (1.07 mL, 762 mg, 7.75 mmol, 1.5 eq) were added and the reaction was stirred at 65° under pressure for 16 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, and evaporated. The residue was purified on silica (50% ethyl acetate in hexane) to give compound 31.

[1108] 1 H NMR (500 MHz, chloroform-d) δ 8.00 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.43-

[1109] 7.33(m,1H),7.04(d,J=2.2Hz,1H),4.15(dt,J=12.7,6.5Hz,4H),2.56(t,J=7.2Hz,2H),2.24-2.13(m,2H),1.26(t,J=7.1Hz,3H),0.30(s,9H).

[1110] 13 C NMR (151MHz, cdcl 3 )δ173.07,124.73,105.65,67.11,60.51,30.67,24.42,14.21,-0.27.

[1111] HRMS:[M+H] + Expected value 356.168, measured value 356.505

[1112] Example 2-1-3: MIF-3

[1113]

[1114] program

[1115] 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 eq) was added dropwise. After stirring for 1 minute, 10% citric acid (50 mL) was added and the reaction was stirred for 30 minutes. 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.

[1116] 1 H NMR (600MHz, chloroform-d) δ8.11-8.00(m,1H),7.51(d,J=8.4Hz,1H),7.38(dd,J=9.3,2.3Hz,1H),7.05(d,J=2.4Hz,1H),4.15(p,J=6.6,6.0Hz,3H),3.4 3-3.36(m,1H),2.56(t,J=7.2Hz,1H),2.22-2.14(m,1H),1.73-1.64(m, 1H), 1.47 (q, J = 7.4Hz, 1H), 1.26 (t, J = 7.1Hz, 2H), 1.02 (t, J = 7.3Hz, 1H).

[1117] CNMR: 13 C NMR (151MHz, cdcl 3 )δ173.06,137.60,129.91,128.64,124.50,123.18,122.48,105.99,105.58,77. 20,76.99,76.77,67.12,60.51,59.14,30.67,24.42,24.22,19.80,14.21,13.69.

[1118] HRMS:[M+H] + Expected value 284.129, measured value 284.327

[1119] Example 2-1-4: MIF-4

[1120]

[1121] 2-Fluoro-4-iodophenol (126 mg, .529 mmol) and sodium azide (38 mg, .528 mmol, 1.0 eq) were dissolved in DMSO (2.5 mL) and stirred at 70° for 2 hours. Compound 32 (150 mg, .529 mmol, 1 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (11 mg, .079 mmol, .15 eq), sodium ascorbate (10 mg, .053 mmol, .1 eq), copper (I) iodide (15 mg, .079 mmol, .15 eq) and H were then added. 2 O (2.5 mL), and the mixture was stirred at 70° overnight. The reaction was diluted with ethyl acetate and H 2 The organic layer was dried over sodium sulfate, evaporated, and purified on silica (DCM / EtOAc) to give compound 33.

[1122] 1 H NMR (600 MHz, DMSO-d 6 )δ10.46(s,1H),9.32(s,1H),8.39(d,J=8.6Hz,1H),8.23(d,J=8.5Hz,1H),7.95(d d,J=11.6,2.6Hz,2H),7.77-7.71(m,1H),7.43(dd,J=4.8,2.0Hz,2H),7.16(t,J=9 .0Hz,1H),4.17(d,J=6.3Hz,2H),4.13-4.07(m,3H),3.17(d,J=5.2Hz,3H),2.53(d ,J=7.3Hz,3H),2.07(t,J=6.8Hz,2H),1.19(d,J=7.1Hz,3H),0.94(d,J=7.3Hz,1H).

[1123] 13 C NMR(151MHz,dmso)δ172.96,156.95,151.95,150.34,148.62,145.98,143.82,136.47,130.40,129.01,123.19,121.83,119.06,118.62,117. 31,109.87,109.72,107.12,67.43,60.35,49.03,40.48,40.36,40.22, 40.09,39.95,39.81,39.67,39.53,30.61,24.58,23.48,14.56,13.93.

[1124] HRMS: expected value 437.163, measured value 437.164

[1125] Example 2-1-5: MIF-5

[1126]

[1127] Compound 33 (90 mg, .206 mmol) was dissolved in dioxane (6 mL) and 2M NaOH (3 mL). The reaction was stirred at room temperature for 2.5 hours, at which time the reaction was diluted with water and the pH was adjusted to 3-4 with 1M HCl. The mixture was cooled to 4° and filtered to give compound 34, which was used without further purification.

[1128] Example 2-2. GaINAc spacer ( Fig.14 )

[1129]

[1130] Triethylene glycol (17.5 mL, 19.7 g, 131.13 mmol, 5 eq) was dissolved in DCM (150 mL) and trimethylamine (5.48 mL, 3.98 g, 1.5 eq) and cooled to 0 °. TsCl (5.00 g, 26.23 mmol, 1 eq) was then added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted into DCM and washed with water (3x) and brine (1x). The organic layer was dried over sodium sulfate and concentrated in vacuo. 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.

[1131] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.80 (d, J = 8.3 Hz, 2H), 7.38-7.30 (m, 2H), 4.23-4.14 (m, 2H), 3.71 (td, J = 5.3, 4.3 Hz, 4H), 3.66-3.55 (m, 6H), 2.45 (s, 3H).

[1132] 13 C NMR (101MHz, cdcl 3 )δ144.98,133.09,129.95,128.09,72.58,70.91,70.44,69.28,68.84,61.88,21.76.

[1133]

[1134] Compound 64 (2.00 g, 6.57 mmol) and sodium azide (.470 g, 7.23 mmol, 1.1 eq) were dissolved in DMF (40 mL) and stirred overnight at 60 °. 25 mL of DMF was then removed by rotary evaporation, and the resulting mixture was diluted into 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.

[1135] Example 2-3. GaINAc ASGPR ligand ( Fig.15 )

[1136]

[1137] Galactosamine pentaacetate (100 mg, .257 mmol) was dissolved in dichloroethane (1 mL) and stirred at room temperature before adding TMSOTf (70 uL, 86.0 mg, .387 mmol, 1.5 eq). The reaction was stirred at 50° for 90 minutes, then cooled to room temperature and stirred for an additional 12 hours. 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 (.236 mmol, 77.7 mmol, 92%) as a dark gum which was used without further purification.

[1138] 1 H NMR (400MHz, chloroform-d) δ5.98(d,J=6.8Hz,1H),5.45(t,J=3.0Hz,1H),4.90(dd,J=7.4,3.3Hz,1H),4.29-4.20(m,1H),4 .17(d,J=6.9Hz,1H),4.10(dd,J=11.1,5.7Hz,1H),3.99(td,J=7.1,1.4Hz,1H),2.11(s,3H),2.05(m,J=7.6Hz,6H).

[1139] 13 C NMR (101MHz, cdcl 3 )δ170.46,170.13,169.78,166.35,121.82,118.64,101.41,71.76,69.4 4,65.25,63.53,61.56,46.82,20.77,20.68,20.54,14.41,8.64,-0.06.

[1140]

[1141] Compound 66 (200 mg, .607 mmol) and compound 65 (160 mg, .913 mmol, 1.5 eq) were dissolved in 1,2-dichloroethane (5 mL). Then, Molecular sieves, and the reaction was stirred for 30 minutes. TMSOTf (55uL, 67.5mg, .304mmol, .5eq) was then added to the mixture, and the reaction was stirred overnight. The mixture was diluted into DCM, washed with 1M sodium bicarbonate (1x) and water (1x), then dried over magnesium concentrate and concentrated. The crude oil was purified on silica gel (50-100% EtoAc in DCM) to give compound 67 (245mg, .486mmol) in 80.1% yield.

[1142] 1 H NMR (400MHz, chloroform-d) δ6.13(d,J=9.3Hz,1H),5.31(dd,J=3.4,1.1Hz,1H),5.05(dd,J=11.2,3.4Hz,1H),4.77(d,J=8.6Hz,1H),4.28- 4.04(m,3H),3.93-3.79(m,3H),3.78-3.58(m,8H),3.43(dt,J=28.2,4.9Hz,4H),2.15(s,3H),2.04(s,3H)1.98(s,3H),1.97(s,3H)

[1143] 13 C NMR (101MHz, cdcl 3 )δ170.24,170.09,169.99,101.84,72.06,71.27,70.50,70.29,70.27,70.20,70.00,69 .98,69.67,69.37,68.18,66.30,61.38,61.17,50.32,50.26,50.11,22.80,20.37,20.31

[1144] HRMS:[M+Na] + 527.207 Measured value 527.203

[1145]

[1146] 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 uL, 14.28 mmol, 4 eq) were then added and the reaction was stirred at room temperature under nitrogen for 36 hours. The solvent was removed and the crude product was used in the next step without further purification.

[1147] Example 2-4. Trivalent Glycine ( Fig.16 )

[1148]

[1149] 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 eq) was then added and the reaction was stirred for 4 hours. The mixture was evaporated and the residue was portioned 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 in other steps without purification.

[1150]

[1151] 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 eq) was then added dropwise over 2.5 hours, and the reaction was stirred for 24 hours under nitrogen. 2M HCl (30 mL) was added to neutralize the reaction 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 hexane) to give compound 20 (7.87 g, 20.7 mmol) in 59% yield.

[1152] HNMR: 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.84 (s, 1H), 3.73 (s, 6H), 3.65 (t, J = 6.1 Hz, 6H), 2.57 (t, J = 6.1 Hz, 6H), 1.35 (s, 9H).

[1153]

[1154] 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 hours and then neutralized with sodium bicarbonate. The 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.

[1155] HNMR: 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.79-3.64 (m, 15H), 3.32 (s, 6H), 2.56 (t, J = 6.3 Hz, 6H).

[1156] CNMR: 13 C NMR (101MHz, cdcl 3 )δ172.03,72.52,66.77,56.10,51.62,34.80.

[1157]

[1158] Compound 70 (723 mg, 1.90 mmol) was dissolved in MeCN (25 mL). HOBT (291 mg, 1.90 mmol, 1 eq), Cbz-glycine (397 mg, 1.90 mmol, 1 eq) and DCC (392 mg, 1.90 mmol, 1 eq) were then added and the reaction was stirred overnight. MeCN was then evaporated and the residue was adsorbed on silica and purified with a gradient of 0-75% EtOAc in hexane. Compound 71 (866 mg, 1.52 mmol) was recovered with a yield of 80%.

[1159] 1 H NMR (600 MHz, CHLOROFORM-d) δ 7.33 (dd, J = 24.9, 4.4 Hz, 5H), 6.33 (s, 1H), 5.55 (s, 1H), 5.12 (s, 2H), 3.86 (d, J = 5.1 Hz, 2H), 3.68 (t, J = 5.5 Hz, 21H), 3.49 (s, 1H), 2.53 (t, J = 6.1 Hz, 6H).

[1160] 13 C NMR (151MHz, cdcl 3)δ172.14,168.67,156.32,136.41,128.45,128.05,127.98,69.04,66.85,66.71,59.83,51.69,44.55,34.64.

[1161] Expected value: [M+H] + 571.250, measured value 571.243

[1162]

[1163] Compound 71 (100 mg, .175 mmol) was dissolved in dioxane (2 mL) and 2M NaOH (2 mL). The reaction was stirred for 3 hours, 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 other steps without purification.

[1164] Example 2-5. GaINAc trivalent ( Fig.17 )

[1165]

[1166] Compound 72 (372 mg, .704 mmol, 1 eq) was dissolved in DMF (40 mL) and DIPEA (981 uL, 728 mg, 5.632 mmol, 8 eq). HBTU (1.01 g, 2.67 mmol, 3.8 eq) was then added and the reaction was stirred at room temperature for 10 minutes before compound 68 (1.28 g, 2.67 mmol, 3.8 eq) was added. The reaction was stirred for 2 hours before being diluted into DCM and washed with H3PO4 (1 M, 1x), NaHCO3 (1 M, 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, .436 mmol) in 62% yield.

[1167] 1 H NMR (500 MHz, DMSO-d 6)δ7.91(t,J=5.7Hz,3H),7.80(d,J=9.2Hz,3H),7.39-7.28(m,6H),7.12(s,1H),5.21(d,J= 3.4Hz,3H),5.02(s,2H),4.97(dd,J=11.2,3.4Hz,3H),4.55(d,J=8.5Hz,3H),4.10-3.99(m ,9H),3.92-3.84(m,3H),3.81-3.75(m,3H),3.62-3.46(m,35H),3.39(t,J=6.1Hz,6H),3.2 3-3.16(m,6H),2.30(t,J=6.4Hz,6H),2.10(s,9H),1.99(s,9H),1.89(s,9H),1.77(s,9H).

[1168] 13 C NMR(126MHz,dmso)δ170.40,170.16,170.09,169.79,169.48,169.04,156.60,137.23,128.50,127.94,127.84,101.12,72.50,70.65,70.07, 69.93,69.86,69.77,69.59,69.29,68.50,67.51,66.89,65.59,61.63, 60.38,59.84,49.50,43.77,38.68,36.01,22.95,20.68,20.62,20.60.

[1169]

[1170] Compound 73 (710 mg, .372 mmol) was dissolved in dry methanol (90 mL) and cooled to 0° under nitrogen. Pd / C (71.0 mg, 10% w / w) was then added and the reaction was stirred for 16 hours at 0° under hydrogen (1 atm). After the reaction was complete, compound 74 (657 mg, .370 mmol) was obtained by filtration through celite and evaporation of methanol with a yield of 99.5% and was used without further purification.

[1171] Compound 74 (441 mg, .248 mmol) was dissolved in methanol (15 mL) and cooled to 0°. Sodium methoxide solution (400 uL, 5.4 M in MeOH) was then added and the reaction was stirred for 30 minutes. Dowex 50WX8 was then added until the solution was weakly acidic. The resin was filtered out and washed thoroughly with methanol. The combined methanol fractions were evaporated under reduced pressure to give compound 75 (274 mg, .196 mmol) with a yield of 79%. Compound 75 was used in other steps without purification.

[1172] Example 2-6. MIF-GN3 ( Fig.18 )

[1173]

[1174] Compound 34 (23.5 mg, .0575 mmol, 1.1 eq) and HATU (20.0 mg, .0522 mmol, 1 eq) were dissolved in dry DMF (5 mL) and DIPEA (23.3 uL, 16.9 mg, .131 mmol, 2.5 eq) and stirred at room temperature for 10 minutes. Compound 75 (73.0 mg, .0522 mmol) was then added and the reaction was stirred for 30 minutes. The mixture was directly loaded onto HPLC and purified (20-30% MeCN, 3% TFA in water) to give compound 76 (12 mg, .0067 mmol) with a yield of 12.8%.

[1175] Expected value [M+H] + 1787.801, measured value 1787.823

[1176] Example 2-7. Bicyclic ASGPR Spacer ( Fig.19 )

[1177]

[1178] Tetraethylene glycol (50.0 g, 258 mmol) was dissolved in THF (1 mL), cooled to 0° and stirred. NaOH (1.65 g, 41.3 mmol, 1.6 eq) in water (1 mL) was then added, followed by dropwise addition of p-toluenesulfonyl chloride (4.92 g, 25.8 mmol, 1 eq) in THF (3 mL). The reaction mixture was stirred at 0° for 4 hours and then diluted into DCM. The organic layer was washed with 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 other steps without purification.

[1179]

[1180] 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 eq) was added. The reaction was heated to reflux for 16 hours and then cooled to room temperature, after which 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 a yellow oil compound 17 (4.82 g, 22.1 mmol) with a yield of 87%.

[1181] HNMR: 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.69-3.64 (m, 2H), 3.61 (m, J = 4.2 Hz, 10H), 3.57-3.51 (m, 2H), 3.33 (td, J = 5.0, 2.3 Hz, 2H), 2.81 (s, 1H).

[1182] CNMR: 13 C NMR (101MHz, cdcl 3 )δ72.47,70.65,70.63,70.59,70.52,70.28,69.99,61.60,50.59.

[1183]

[1184] Compound 17 (5.00 g, 22.8 mmol) was dissolved in pyridine (50 mL). Methanesulfonyl chloride (3.14 g, 27.4 mmol, 1.2 eq) was then added and the reaction was stirred under nitrogen for 6 hours. The mixture was then diluted into ethyl acetate, washed with water (3x), .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.

[1185] HNMR: 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.41-4.33 (m, 2H), 3.81-3.72 (m, 2H), 3.70-3.59 (m, 10H), 3.38 (t, J=5.0 Hz, 2H), 3.06 (s, 3H).

[1186] CNMR: 13 C NMR (101MHz, cdcl 3 )δ70.79,70.75,70.71,70.15,69.39,69.11,50.77,37.78.

[1187] HRMS: expected value 298.107, measured value 298.105

[1188] Example 2-8. Bicyclic ASGPR Precursor ( Fig. 20 )

[1189]

[1190] Pentaacetylgalactose (25.0 g, 64.0 mmol) was dissolved in 33% HBr in HOAc (30 mL) and stirred under nitrogen for 2 hours. The reaction was diluted into 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 a light yellow oil compound 1 in quantitative yield. The compound was used without further purification.

[1191] 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. Then a solution of CuSO4 (2.96 g, 18.6 mmol) in aqueous NaH2PO4 (128 mL, .1 M, 1.53 g) was added and the reaction was stirred for 1 hour. The reaction mixture was filtered through a 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 (14.64 g, 53.76 mmol) in 84% yield.

[1192] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (dd, J = 6.3, 1.8 Hz, 1H), 5.54 (qd, J = 2.8, 1.2 Hz, 1H), 5.41 (dt, J = 4.7, 1.7 Hz, 1H), 4.71 (ddd, J = 6.3, 2.7, 1.5 Hz, 1H), 4.33 (ddt, J = 7.0, 5.6, 1.4 Hz, 1H), 4.29-4.15 (m, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H).

[1193] 13C NMR (101 MHz, chloroform-d) δ 170.33,, 170.06, 169.97, 145.30, 98.80, 72.69, 63.82, 63.59, 61.85, 20.66, 20.64, 20.58.

[1194] HRMS:[M+Na] + Expected value 295.079, measured value 295.078

[1195]

[1196] Procedure: Compound 2 (12.0 g, 44 mmol) was dissolved in acetonitrile (250 mL) and cooled to -10°. In a separate -10° flask flushed with nitrogen, NaN 3 (4.3g, 66mmol) and cerium ammonium nitrate (87.0g, 158mmol) were mixed and stirred vigorously. A solution of compound 2 in acetonitrile was added dropwise via a cannula, and the mixture was slowly brought to room temperature. The reaction mixture was stirred for a total of 12 hours, then diluted with ethyl acetate (500mL) 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 hexane) to obtain compound 3 (13.1g, 34.9mmol) with a yield of 79%.

[1197] 1 H NMR (400MHz, chloroform-d) δ6.31(d,J=4.1Hz,1H),5.60(d,J=8.8Hz,1H),5.43(dd,J=3.4,1.3Hz,1H),5.32(t,J=3.3Hz,1H),5.16(dt,J=11.6,3.4Hz,1H ),4.96(dd,J=10.6,3.3Hz,1H),4.39-4.28(m,1H),4.14-4.00(m,5H),3. 76(ddd,J=13.5,9.6,4.7Hz,1H),2.19-2.05(m,6H),2.05-1.88(m,12H).

[1198] 13 C NMR (101MHz, cdcl 3 )δ170.15-169.06,97.91,97.79,96.91,71.68,71.45,69.35,68.42,66.9 8,66.53,65.85,64.75,61.07,60.84,57.38,55.82,55.08,20.31-20.20.

[1199] HRMS:[M+Na] + Expected value 399.076, measured value 399.073

[1200]

[1201] Sodium methoxide solution was prepared from ice-cold dry methanol (50 mL) and sodium hydride (2.296 g, 95.67 mmol) (3 eq) and added to a solution of compound 3 (12.00 g, 31.89 mmol) in dry methanol (100 mL). After stirring for 30 minutes, the reaction was neutralized by adding acetic acid and loaded directly onto silica gel. The reaction mixture was purified under a gradient of 0-20% MeOH in DCM to give compound 4 (6.64 g, 30.3 mmol) with a yield of 95%.

[1202] CNMR: 13 C NMR (101MHz, cd 3 od)δ102.60,100.87,98.59,75.65,74.62,71.43,70.41,68.82,67.81,67. 69,67.47,67.37,63.73,62.96,60.75,60.43,59.54,55.42,53.69,45.94.

[1203] HRMS:[M+Na] + Expected value 242.075, measured value 242.072

[1204]

[1205] Compound 4 (5.00 g, 22.8 mmol) was dissolved in pyridine (100 mL) and stirred under nitrogen. Trimethylchlorosilane (10.43 mL, 8.929 g, 82.18 mmol, 3.6 eq) was added dropwise and the mixture was stirred for 6 hours. The reaction was diluted into ethyl acetate and washed with water (2x) and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give three TMS intermediates. The residual pyridine was removed by co-evaporation with toluene (3x). The intermediate was taken to dry MeOH (45 mL) and cooled to 0 ° before adding potassium carbonate (40 mg). The reaction was closely monitored within 1.5 hours and quenched with acetic acid (17 uL) once TLC showed that the starting material was completely exhausted. The product was then dry loaded onto silica and purified with a gradient of 0-50% EtOAc in hexane to give compound 5 (6.55 g, 18.0 mmol) with a yield of 79%.

[1206] 13 C NMR (101MHz, cdcl 3)δ103.36,75.29,73.71,72.37,71.41,70.94,70.38,64.04,62.49,62.15,61.05,60.36,57.15,55.1 7,34.60,31.52,25.21,22.59,20.93,14.11,14.05,0.85,0.57,0.55,0.52,0.22,0.14,0.01,-0.07.

[1207] HRMS:[M+Na] + 386.154, measured value 386.156

[1208]

[1209] 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 eq) was added and the mixture was stirred for 2 hours. The reaction was diluted into DCM and washed with water (2x) and brine (1x). The organic layer was dried over sodium sulfate and evaporated to give the intermediate aldehyde.

[1210] Compound 6 was dissolved in EtOH (100 mL) dried over molecular sieves. Paraformaldehyde (36.50 g, 384.9 mmol, 20 eq) and 21% sodium ethoxide solution (14.5 mL, 38.5 mmol, 2 eq) were added and the reaction was stirred for 8 hours. The solvent was evaporated and the product was adsorbed on 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.

[1211] HRMS:[M+Na] + Expected value 272.086 (+Na), measured value 272.083

[1212]

[1213] L6-7 (500 mg, 2.00 mmol) was dissolved in water (4.5 mL) and sulfuric acid (.5 mL). The reaction was sealed in a microwave vial and heated at 100 ° for 40 minutes. The reaction was cooled to 0 °, then diluted with MeOH (10 mL) and neutralized by adding concentrated ammonia solution. The salt was filtered out and washed several times with methanol. The filtrate was adsorbed on silica and purified by a gradient of 0-15% MeOH in DCM to give compound L6-8 (347 mg, 1.60 mmol) with a yield of 80%.

[1214] 13C NMR (101MHz, cd 3 od)δ102.70,85.32,71.03,69.59,69.49,66.07,61.85

[1215] Example 2-9. Bicyclic ASGPR ligand CF3 ( Fig.21 )

[1216]

[1217] The compound (400 mg, 1.84 mmol) was dissolved in methanol (30 mL) and the reaction flask was purged with nitrogen. Then Lindela catalyst (40.0 mg, 10 wt%) was added and the reaction mixture was stirred for 6 hours under 1 atm hydrogen atmosphere (balloon). The reaction was filtered through 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.

[1218] The 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 eq). The reaction was stirred for 6 hours, then diluted into 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) with a yield of 95%, which was used in other steps without purification.

[1219] 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 eq) was added. The reaction was stirred at room temperature for 1 hour, 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.

[1220] 1 H NMR (400 MHz, DMSO-d 6 )δ9.51(d,J=6.6Hz,1H),5.15(s,1H),4.98-4.90(m,1H),4.87(d,J=5.6Hz,1H ),4.75-4.70(m,1H),3.86-3.80(m,2H),3.80-3.70(m,2H),3.67-3.54(m,3H).

[1221] 13C NMR(101MHz,dmso)δ157.47,157.11,117.74,114.87,100.28,84.21,68.77,6 8.28,66.00,60.51,55.95,40.56,40.35,40.15,39.94,39.73,39.52,39.31.

[1222] HRMS:[M+H] + Expected value 288.069, measured value 288.064

[1223]

[1224] Compound 12 (110 mg, .383 mmol) was dissolved in DMF (8 mL) and dimethoxypropane (236 uL, 200 mg, 1.92 mmol, 5 eq) and camphorsulfonic acid (45 mg, .192 mmol, .5 eq) were added. The reaction was stirred overnight at 70° and the DMF was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, 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, .303 mmol) in 79% yield.

[1225] HNMR: 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.87 (d, J = 9.0 Hz, 1H), 5.35 (d, J = 2.1 Hz, 1H), 4.18-4.11 (m, 2H), 4.11-4.03 (m, 2H), 3.84 (t, J = 8.2 Hz, 2H), 3.74 (d, J = 7.9 Hz, 1H), 2.66 (d, J = 6.6 Hz, 1H), 1.52 (s, 3H), 1.32 (s, 3H).

[1226] CNMR: 13 C NMR (101MHz, cdcl 3 )δ157.87,157.50,157.12,156.75,119.93,117.07,114.21,112.04,11 1.35,100.22,81.55,75.57,75.00,68.44,60.96,55.16,27.67,26.16.

[1227] HRMS:[M+H] + Expected value 328.101, measured value 328.095

[1228]

[1229] Compound 13 (99.1 mg, .303 mmol) was dissolved in DMF (5 mL) and treated with sodium hydride (8.7 mg, .364 mmol, 1.2 eq) and then stirred under nitrogen for 15 minutes. Compound 18 (108 mg, .364 mmol, 1.2 eq) was then added and the reaction was stirred for 1 hour. The reaction was neutralized by adding acetic acid dropwise. The solvent was removed under reduced pressure, and the residue was taken into ethyl acetate and washed with brine (4x), and the organic layer was dried over sodium sulfate and evaporated onto silica. The crude mixture was purified on silica (50-100% EtOAc in hexane) to give compound 14 (131 mg, .248 mmol) in 82% yield.

[1230] HNMR: 1 H NMR (400 MHz, DMSO-d 6 )δ9.75(d,J=8.3Hz,1H),5.29(s,1H),4.40(t,J=6.7Hz,1H),4.30(d,J=5.9Hz,1H),3. 88-3.66(m,5H),3.64-3.48(m,14H),3.39(t,J=5.0Hz,2H),1.41(s,3H),1.28(s,3H).

[1231]

[1232] Compound 14 (131 mg, 240 mmol) was dissolved in methanol (10 mL) and stirred under nitrogen atmosphere. Lindela catalyst (13.1 mg, 10 wt%) was then added and stirred at 4 °C for 2 h. 2 The reaction was stirred under atmosphere (1 atm) for 6 hours. The reaction was then filtered through Celite and the solvent was evaporated to give compound 15 (120 mg, .240 mmol) in quantitative yield which was used without further purification.

[1233] HRMS:[M+H] + Expected value 503.222, measured value 503.223

[1234] Example 2-10. MIF binding bivalent ( Fig.23 )

[1235]

[1236] 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 eq) was then added and the reaction was stirred for 4 hours. 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) with a yield of 95%, which was used in other steps without purification.

[1237]

[1238] 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 eq) was then added dropwise over 2.5 hours, and the reaction was stirred under nitrogen for 24 hours. 2M HCl (16 mL) was added to neutralize the reaction 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 hexane) to give compound 20 (4.96 g, 16.7 mmol) in 80% yield.

[1239] HNMR: 1 H NMR (400MHz, chloroform-d) δ4.91 (d, J = 8.9 Hz, 1H), 3.94-3.81 (m, 1H), 3.68 (t, J = 6.1 Hz, 4H), 3.65-3.48 (m, 4H), 2.60 (t, J = 6.1 Hz, 4H), 1.42 (s, 9H).

[1240] CNMR: 13 C NMR (101MHz, cdcl 3 )δ171.11,155.31,117.88,79.70,69.12,65.53,49.24,28.30,18.83,14.16.

[1241]

[1242] 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 for 24 hours under a nitrogen atmosphere 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 eq) and the reaction was stirred at room temperature for 6 hours. The turbid mixture was partitioned between water and ethyl acetate, and the organic fraction was washed with water (1x), .5 M HCl (2x), saturated sodium bicarbonate (1x) and brine (1x), dried over sodium sulfate, and evaporated. Compound 20 was purified on silica with a gradient of 0-10% MeOH in DCM with a yield of 74% (4.50 g, 12.4 mmol).

[1243] HNMR: 1 H NMR (400MHz, chloroform-d) δ4.90 (d, J = 8.6Hz, 1H), 3.82 (br s, 1H), 3.70-3.59 (m, 10H), 3.51-3.34 (m, 4H), 2.51 (t, J = 6.3Hz, 4H), 1.38 (s, 9H).

[1244] CNMR: 13 C NMR (101MHz, cdcl 3 )δ171.86,155.34,79.20,69.19,66.41,51.58,49.29,34.75,28.28.

[1245]

[1246] Compound 25 (1.00 g, 2.75 mmol) was dissolved in dry MeOH (10 mL) and TFA (1 mL) and stirred for 15 min. The volatiles were evaporated under reduced pressure to give compound 26 (1.04 g) as a TFA salt in quantitative yield.

[1247]

[1248] Compound 34 (50.0 mg, .123 mmol) was dissolved in DMF (5 mL) and DIPEA (214 uL, 159 mg, 1.23 mmol, 10 eq) and stirred under nitrogen. HBTU (102.4 mg, .270 mmol, 2.2 eq) was then added and the reaction was stirred for 15 minutes. Compound 26 (102 mg, .270 mmol, 2.2 eq) dissolved in DMF (1 mL) was then added dropwise and the reaction was stirred for 1 hour. The mixture was diluted into ethyl acetate and washed with 1 M HCl (2x) and brine (5x). The organic layer was evaporated to give a sticky residue which was purified by reverse phase HPLC (35-45% MeCN, .1% TFA in water) to give compound 40 (62.6 mg, .0959 mmol) in 78% yield.

[1249] HRMS: expected value 654.258, measured value 654.259

[1250] Compound 40 (62.6 mg, .0959 mmol) was dissolved in dioxane (1.8 mL) and 1 M NaOH (.2 mL) was added. The solution was stirred at room temperature for 2 hours, then acidified (pH 3) and evaporated. The residue was resuspended in EtOAc, washed with 1 M HCl, and dried over sodium sulfate. Evaporation of the organic layer gave compound 41 (57.6 mg, .0921 mmol) as an oil in 96% yield, which was used without further purification.

[1251] Example 2-11. MIF binding trivalent ( Fig.23 )

[1252]

[1253] Compound 34 (50.0 mg, .123 mmol) was dissolved in DMF (5 mL) and DIPEA (214 uL, 159 mg, 1.23 mmol, 10 eq) and stirred under nitrogen. HBTU (154 mg, .405 mmol, 3.3 eq) was then added and the reaction was stirred for 15 minutes. Compound 29 (200 mg, .405 mmol, 3.3 eq) dissolved in DMF (1 mL) was then added dropwise and the reaction was stirred for 1 hour. The mixture was diluted into ethyl acetate and washed with 1 M HCl (2x) and brine (5x). The organic layer was evaporated to give a sticky residue which was purified by reverse phase HPLC (35-50% MeCN, .1% TFA in water) to give compound 44 (79.3 mg, .103 mmol) in 84% yield.

[1254] HRMS:[M+H] +Expected value 770.305, measured value 770.308

[1255] Compound 44 (79.3 mg, .103 mmol) was dissolved in dioxane (1.8 mL) and 1 M NaOH (.2 mL) was added. The solution was stirred at room temperature for 2 hours, then acidified (pH 3) and evaporated. The residue was resuspended in EtOAc, washed with 1 M HCl, and dried over sodium sulfate. Evaporation of the organic layer gave compound 41 (68.9 mg, .0948 mmol) as an oil in 92% yield, which was used without further purification.

[1256] Example 2-12. MIF-AcF3-2 ( Fig.24 )

[1257]

[1258] Compound 41 (57.6 mg, .0921 mmol) was dissolved in DMF (1.8 mL) and DIPEA (.2 mL). HBTU (84.0 mg, .222 mmol, 2.4 eq) was then added and the reaction was stirred for 15 minutes before compound 15 (111 mg, .222 mmol, 2.4 eq) was added. The reaction was stirred for 1 hour and then evaporated to give a red residue which was used in the next reaction without purification.

[1259] Compound 42 (crude material, 0.0921 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 hours. 2 The reaction was directly purified by HPLC (20-40% MeCN in 4% O, +3% TFA) to afford compound 43 (44.66 mg, 0.0295 mmol) in 32% yield.

[1260] Expected value (H) 1514.570, measured value 1514.561

[1261] Example 2-13. MIF-AcF3-3( Fig.25 )

[1262]

[1263] Compound 45 (68.9 mg, .0948 mmol) was dissolved in DMF (1.8 mL) and DIPEA (.2 mL). HBTU (126 mg, .333 mmol, 3.6 eq) was then added and the reaction was stirred for 15 minutes before compound 15 (167 mg, .333 mmol, 3.6 eq) was added. The reaction was stirred for 1 hour before evaporation to give a light red residue which was used in the next reaction without purification.

[1264] Compound 38 (crude material, 0.0948 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 hours. 2 The reaction was directly purified from 4% MeCN in 0.5% MgSO (20-40% MeCN, +3% TFA) to afford compound 39 (78.1 mg, 0.0379 mmol) in 40% yield.

[1265] Expected value (2H, / 2) 1030.891 Measured value 1030.903

[1266] Example 2-14. Synthesis of MIF-AcF2-3, MIF-Ac-3, and MIF-Et-3

[1267] Figure 26-Figure 29 Shown in FIG. 5 is the chemical synthesis of MIF-AcF2-3, MIF-Ac-3, MIF-Et-3, and MIF-EtF3-3, which were produced using methods similar to and slightly modified from those presented above.

[1268] The foregoing summarizes the features of several embodiments so that those skilled in the art can better understand the various aspects of the present disclosure. Those skilled in the art will appreciate that they can easily use the present disclosure as a basis for designing or modifying other processes and structures to achieve the same purpose and / or obtain the same advantages of the various embodiments introduced herein. Those skilled in the art will also recognize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they can make various changes, substitutions and modifications herein without departing from the spirit and scope of the present disclosure.

Claims

1. A bifunctional compound according to the following chemical structure, or a salt, stereoisomer or solvate thereof: in: [MIFBM / IgGBM] is a MIF or IgG binding moiety that binds to circulating MIF or IgG, respectively, each of which is associated with a disease state and / or condition and is to be removed by the action of hepatocytes on the circulating protein; [ASGPRBM] is a binding moiety that binds to a hepatocyte via an asialoglycoprotein receptor on the surface of a hepatocyte, preferably in a patient or subject; Each [CON] is an optional linker chemical moiety which, when present, directly links to [MIFBM / IgGBM] or [ASGPRBM] or links the [Linker] to [MIFBM / IgGBM] or [ASGPRBM], and [Linker] is a chemical moiety with a valence of 1 to 15, typically 1 to 10, more typically 1 to 5 or 1, 2 or 3, which is covalently linked to one or more [ASGPRM] and / or [MIFBM / IgGBM] groups, optionally via a [CON] including a [MULTICON] group, wherein the [Linker] itself optionally comprises one or more [CON] or [MULTICON] groups; k' is 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1, 2, or 3; j' is 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1, 2, or 3; h and h' are each independently 0 to 15; i L is 0 to 15, typically 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, provided that h, h' and i L At least one of is preferably at least 1, Wherein the compound is selected from: in: The extracellular protein targeting ligand is a MIF or IgG binding moiety that binds to circulating MIF or IgG, respectively, in a subject, each of which is associated with a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject; X 1 are independently selected from O, S, N(R 6 ) and C(R 4 )(R 4 ) of 1 to 5 groups, wherein if X 1 is 1 group, then X 1 O, S, N (R 6 ) or C(R 4 )(R 4 ), if X 1 is 2 groups, then X 1 No more than one of the groups is O, S or N (R 6 ), if X 1 is 3, 4 or 5 groups, then X 1 No more than 2 groups are O, S or N (R 6 ); R 2 Selected from (i) aryl, heterocycle and heteroaryl, the heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1, 2, 3 or 4 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, (iii)-NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 and-NR 8 -C(NR 6 )-R 3 each of which is optionally substituted with 1, 2, 3 or 4 substituents; 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 ; R 10 Selected from aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl containing 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, alkynyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -Alkynyl, -NR 6 -heteroaryl, -NR 6 -aryl, -O-heteroaryl, -O-aryl and -O-alkynyl, R 10 Each of which is optionally substituted with 1, 2, 3 or 4 substituents; R 1 and R 5 independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, 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 alkyl N3 and C0-C6 alkyl-OS(O)2R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 and-NR 8 R 9 ; R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 ; R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, 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 ; R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; Ring is a 3-8 membered fused ring group, which is optionally substituted by 1, 2, 3 or 4 substituents; Each connector A The ASGPR ligand is covalently linked to the linker B a key or part of; Connectors B The connector A a bond or moiety that is covalently attached to an extracellular protein targeting ligand; Connectors C Each joint A a chemical group attached to the extracellular protein targeting ligand; Connectors D Each joint A a chemical group attached to said extracellular protein targeting ligand; and Among them, when R 2 YesNR 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 -aryl, the extracellular protein targeting ligand does not include an oligonucleotide; and As long as valence permits, so that a stable compound is produced, the optional substituents are selected from alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 、F、Cl、Br、I、-NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , 2. The bifunctional compound according to claim 1, which is selected from:

3. The bifunctional compound according to claim 1, which is selected from:

4. The bifunctional compound according to any one of claims 1 to 3, wherein R 1 It's H.

5. The bifunctional compound according to any one of claims 1 to 4, wherein R 2 YesR 10 .

6. The bifunctional compound according to any one of claims 1 to 5, wherein R 10 Yes - NR 6 -heteroaryl.

7. The bifunctional compound according to any one of claims 1 to 6, wherein R 6 It's H.

8. A bifunctional compound according to any one of claims 1 to 7, wherein -NR 6 - Heteroaryl is selected from:

9. The bifunctional compound of any one of claims 1 to 8, wherein the extracellular protein targeting ligand is a MIF binding moiety.

10. The bifunctional compound according to any one of claims 1 to 9, wherein the extracellular protein targeting ligand is an IgG binding moiety.

11. The bifunctional compound according to any one of claims 1 to 10, wherein the linker A Selected from 12. A pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 11 in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally further comprising an additional bioactive agent, which is effective in treating, ameliorating and / or preventing cancer, autoimmune disease or inflammatory disease in a patient or subject or associated with upregulation of MIF or IgG in the patient or subject.

13. The composition of claim 12, wherein the additional anticancer agent is selected from the group consisting of everolimus, trabectedin, abdomin, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, inzatole, 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, ogavuzumab, Lep-etu, nolatrexate, azd2171, batabulin, ofatumumab (Arzerra), zalimumab, etanercept, tetrandrine, rubicin, tesmilifene, oblimersen, tocilizumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanthone, LY 317615, Newlodi, Vitspon, Rta 744, Sdx 102, Talanpanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Cericili; PD0325901, AZD-6244, Capecitabine, L-Glutamic acid, N-[4-[2-(2-amino -4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, 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-(Methylsulfonylpiperidinylmethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6,Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) X , wherein 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, Sola Fenni, KRN951, aminoglutethimide, ansacol, anagrelide, L-asparaginase, BCG vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, orthoclase Sariplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil nitrogen mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, mastastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, white Interleukin-12, IM862, angiostatin, vitacin, droloxifene, iodoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab, cetuximab, paclitaxel without polyoxyethylene castor oil, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD184352, 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, zoledronic acid, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, peginterferon alfa-2a, interferon alfa-2a, peginterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab , all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunomycin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, a Repitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, PD-L1 checkpoint inhibitors, PD-1 checkpoint inhibitors, or CTLA-4 checkpoint inhibitors.

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

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

16. The method of claim 15, wherein the disease state or condition is cancer, an autoimmune disease, or an inflammatory disease.

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

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