Bifunctional small molecules targeting selective degradation of circulating proteins

Abstract

The present disclosure relates to bifunctional small molecules comprising a circulating protein binding moiety (CPBM) linked to a cell receptor binding moiety (CRBM) via a linker group, said (CRBM) being a membrane receptor of a degrading cell, such as a hepatocyte or other degrading cell. In certain embodiments, the (CRBM) is a moiety that binds to an asialoglycoprotein receptor of a hepatocyte (an asialoglycoprotein receptor binding moiety, or an ASGPRBM). In further embodiments, the (CRBM) is a moiety that binds to a receptor of another cell capable of degrading a protein such as LRP1, LDLR, Fc [gamma] RI, FcRN, transferrin or macrophage scavenger receptor.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. application No. 17 / 695,645, 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 No. GM067543 from the National Institutes of Health and Grant No. 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 14, 2023, is named "047162-7239WO2_sequence_listing.xml", and is 156.6 kilobytes in size. Background Art

[0007] Various diseases are associated with increased levels of certain proteins in the circulation, which play a role in disease progression. For example, an increase in the levels of a variety of circulating proinflammatory cytokines (i.e., signal transduction proteins that promote inflammatory effects) contributes to a variety of systemic inflammatory conditions and autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and atherosclerosis. Studies have also linked chronic inflammation to an increased risk of heart disease, stroke, cancer, and Alzheimer's disease. Specifically, an increase in the levels of cytokines such as TNFα or MIF is associated with rheumatoid arthritis (RA), atherosclerosis, and other diseases. In short, diseases and / or conditions associated with circulating proteins affect the lives of millions of people. New treatments are urgently needed to address these diseases.

[0008] Current strategies for targeting circulating proteins include the use of inhibitory antibodies, which have excellent specificity and affinity for the target protein. Despite these advantages, antibody-based therapies have several disadvantages, primarily related to their high molecular weight and / or peptide structure, the potential for eliciting immunogenicity, their high cost, short shelf life, and low oral bioavailability. Small molecule-based strategies according to the present disclosure have the potential to combine the beneficial attributes of antibody-based therapies while overcoming their most significant disadvantages.

[0009] The high incidence of inflammatory diseases in the population places a considerable economic burden on the health care system. The global sales of TNF-α antibodies, reaching $34.4 billion, reflect the high demand and high cost of current antibody-based treatments. In contrast, the bifunctional small molecules disclosed herein are easy to prepare through organic synthesis and have the potential to significantly reduce manufacturing, storage, and handling costs. Similarly, these bifunctional chemical constructs are more easily mass-produced to ultimately meet the high demand for treatment. Summary of the Invention

[0010] Conceptually, the present disclosure relates to bifunctional small molecules that can be used to remove circulating proteins that mediate disease states and / or conditions in a subject. The present disclosure aims to establish a general small molecule strategy for the selective degradation of targeted disease-associated circulating proteins. The bifunctional molecule construct comprises a protein targeting motif derived from a known small molecule ligand of the protein of interest. The inventors collectively refer to this portion as a circulating protein binding moiety (CPBM). The other end of the bifunctional molecule is a cell receptor binding moiety (CRBM), which binds to cell surface receptors and causes internalization of circulating proteins and bifunctional molecules. The two motifs are covalently linked via a linker such as a polyethylene glycol (PEG) linker of adjustable length, and optionally comprise one or more connector molecules that connect the linker to the CPBM and / or CRBM.

[0011] The currently claimed bifunctional compounds selectively bind to circulating proteins of interest and form protein complexes. This complex then binds to cellular receptors and is internalized and degraded. As a result of this mechanism, the protein of interest is cleared from the circulation by hepatocytes, macrophages, or other cell types, resulting in reduced levels of the protein of interest and the potential to alleviate symptoms of the corresponding disease. In some cases, the protein of interest can be eliminated, resulting in a significant reduction in symptoms or even cure or elimination of the disease state or condition.

[0012] Compared to the prior art classical antibody-based strategies for targeting disease-associated circulating proteins, the methods according to the present disclosure have inherent advantages. The small molecule-based methods of the present disclosure overcome the limitations of traditional antibody-based strategies, including lack of oral bioavailability, low temperature storage requirements, immunogenicity, and high cost.

[0013] Furthermore, compared to conventional inhibitory approaches, the present disclosure is expected to have a more sustained effect because disease-associated proteins are eliminated by degradation within hepatocytes rather than simply by reversibly blocking protein-receptor interactions. The bifunctional molecular constructs according to the present disclosure are also universal, meaning that different disease-associated proteins can be targeted simply by switching the protein targeting motif in the construct. Therefore, previously discovered non-inhibitory protein binders 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 [CPBM] is a circulating protein binding moiety that binds to a circulating protein as identified herein that is associated with and / or mediates a disease state and / or condition and is removed by the action of hepatocytes or other cells on the circulating protein (the compound preferably selectively binds to the CPBM in the plasma of a subject or patient);

[0017] [CRBM] is a cell receptor binding moiety, preferably an [ASGPRBM] group, which is a binding moiety that binds to hepatocytes or other cells through the asialoglycoprotein receptor or other receptors as identified herein on the surface of hepatocytes and other degradative cells, preferably in a patient or subject;

[0018] Each [CON] is an optional linker chemical moiety which, when present, directly links to a [CPBM] or [CRBM] or links a [Linker] to a [CPBM] or [CRBM], and

[0019] [Linker] 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] itself optionally comprises one or more [CON] or [MULTICON] groups;

[0020] k' is an integer from 1 to 15;

[0021] j' is an integer from 1 to 15;

[0022] h and h' are each independently an integer from 0 to 15;

[0023] i L is an integer from 0 to 15;

[0024] The premise is h, h' and i L At least one of is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0025] In various embodiments, the valence of [Linker] is 1 to 10. In various embodiments, the valence of [Linker] is 1 to 5. In various embodiments, the valence of [Linker] is 1, 2, or 3. The [MULTICON] group is capable of linking one or more of [CRBM] or [CPBM] to one or more of [Linker].

[0026] In one embodiment, [CPBM] is a [MIFBM] moiety according to the following chemical structure:

[0027]

[0028] where X M Yes - (CH2) IM 、-O-(CH2) IM 、S-(CH2) IM NR M -(CH2) IM 、C(O)-(CH2) IM -, a PEG (polyethylene glycol) group containing 1 to 8 ethylene glycol residues or -C(O)(CH2) IM NR M Group; R M is H or C1-C3 alkyl optionally substituted by one or two hydroxy groups; IM is an integer ranging from 0-6.

[0029] In various embodiments, [CPBM] is an [IgGMB] group according to the following chemical structure:

[0030] wherein DNP is 2,4-dinitrophenyl; or a group according to the following chemical structure:

[0031]

[0032] Where Y' is H or NO2; X is O, CH2, NR 1 , S(O), S(O)2, -S(O)2O, -OS(O)2 or OS(O)2O; and R 1 is H, C1-C3 alkyl or -C(O)(C1-C3) group; or a group according to the following chemical structure:

[0033]

[0034] where R1 Same as above; and K" is 1-5, or a group represented by the following chemical formula:

[0035]

[0036] Where X' is CH2, O, NR 1 'or S; R 1’ is H or C1-C3 alkyl; and Z is a bond, a monosaccharide, a disaccharide, an oligosaccharide, more preferably a sugar group selected from monosaccharides (including aldoses and ketoses) and disaccharides (including those described herein).

[0037] The monosaccharide aldoses include monosaccharides such as aldotrioses (D-glyceraldehyde, etc.), aldotrososes (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.), while the monosaccharide ketoses include monosaccharides such as dihydroxyacetone (dihydroxyacetone, etc.), ketotetroses (D-erythrulose, etc.), ketopentoses (D-ribulose and D-xylulose, etc.), ketohexoses (D-pseudofrucose (D-Psicone), D-fructose, D-sorbose, D-tagatose, etc.), amino sugars (including galactosamine, sialic acid, N-acetylglucosamine, etc.) and sulfo sugars (including sulfoquinolose, etc.).

[0038] 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), laminaribiose, (which may have one or two glucose residues that are optionally N-acetylated), gentiobiose (which may have one or two glucose residues that are optionally N-acetylated), turanose (which may have an optionally N-acetylated glucose residue), maltulose (which may have an optionally N-acetylated glucose residue), palatinose (which may have an optionally N-acetylated glucose residue), gentiobiluose (which may have an optionally N-acetylated glucose residue), mannobiose, melibiose (which may have an optionally N-acetylated glucose residue and / or galactose residue), melibiulose (which may have an optionally N-acetylated galactose residue), rutinose (which may have an optionally N-acetylated glucose residue), rutinulose, xylobiose, and the like; or

[0039] [CPBM] is the [IgGBM] group according to the following chemical structure:

[0040]

[0041] where X R Is O, S or NR 1 ; and X M It is O, NR 1 or S, and R 1 is H or C1-C3 alkyl; or

[0042] [CPBM] is the [IgGBM] group according to the following chemical structure:

[0043]

[0044] Where X" is O, CH2, NR 1, S; and R 1 is H, C1-C3 alkyl or a -C(O)(C1-C3) group; or

[0045]

[0046] where X b is a bond, O, CH2 or NR 1 or S; and R 1 is H, C1-C3 alkyl or -C(O)(C1-C3) group; or a group according to the following chemical structure:

[0047]

[0048] where R N02 is a dinitrophenyl group optionally attached via CH2, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; or a dinitrophenyl group according to the following chemical structure:

[0049]

[0050] Where X is O, CH2, NR 1 , S(O), S(O)2, -S(O)2O, -OS(O)2 or OS(O)2O; and R 1 is H, C1-C3 alkyl or -C(O)(C1-C3) group, or

[0051] [CPBM] is the [IgGBM] group, which is a 3-indoleacetic acid group according to the following chemical structure:

[0052]

[0053] where K'' is 1-4; or

[0054] group;

[0055] Or according to this article Figure 67 The group of the chemical structure shown is covalently linked to the [CON] group, the [linker] group or the [CRBM] group including the [ASGPRBM] group through an amine group, and the amine group is preferably a primary or secondary alkylamine group optionally substituted by a C1-C3 alkyl group on the amine group.

[0056] In various embodiments, [CPBM] is an [IgGBM] group, which is a peptide according to the following sequence (all cited references are incorporated herein by reference):

[0057] PAM(Fassina,et al.,J.Mol.Recognit.1996,9,564-569);

[0058] D-PAM(Verdoliva,et al.,J.Immunol.Methods,2002,271,77-88);

[0059] D-PAM-Φ(Dinon,et al.J.Mol.Recognit.2011,24,1087-1094);

[0060] TWKTSRISIF(Krook,et al.,J.Immunol.Methods 1998,221,151-157)SEQ ID NO:1;

[0061] FGRLVSSIRY(Krook,et al.,J.Immunol.Methods 1998,221,151-157)SEQ ID NO:2;

[0062] Fc-III(DeLano,et al.,Science 2000,287,1279-1283);

[0063] FcBP-1(Kang,et al.,J.Chromatogr.A 2016,1466,105-112);

[0064] FcBP-2(Dias,et al.,J.Am.Chem.Soc.2006,128,2726-2732);

[0065] Fc-III-4c(Gong,et al.,Bioconjug.Chem.2016,27,1569-1573);

[0066] EPIHRSTTLALL(Ehrlich,et al.,J.Biochem.Biophys.Method 2001,49,443-454)

[0067] SEQ ID NO:3:

[0068] APAR(Camperi,et al.,Biotechnol.Lett.2003,25,1545-1548)SEQ ID NO:4;

[0069] FcRM (Fc Receptor Mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242-1253);

[0070] HWRGWV (Yang, et al., J. Peptide Res. 2006, 66, 110-137) SEQ ID NO:5; <{

[0071] HYFKFD (Yang, et al., J. Chromatogr. A 2009, 1216, 910-918) SEQ ID NO:6;

[0072] HFRRHL (Menegatti, et al., J. Chromatogr. A 2016, 1445, 93-104) SEQ ID NO:7;

[0073] HWCitGWV (Menegatti, et al., J. Chromatogr. A 2016, 1445, 93-104) SEQ ID NO:8;

[0074] D2AAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr. A2012, 1225, 158-167);

[0075] DAAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr. A2012, 1225, 158-167);

[0076] Cyclo[(N-Ac)S(A)-RWHYFK-Lact-E] (Menegatti, et al., Anal. Chem. 2013, 85, 9229-9237)

[0077] (SEQ ID NO:9-Lact-E);

[0078] Cyclo[(N-Ac)-Dap(A)-RWHYFK-Lact-E] (Menegatti, et al., Anal Chem. 2013,85, 9229-9237) (SEQ ID NO:10-Lact-E);

[0079] Ring[Link-M-WFRHYK](Menegatti, et al., Biotechnol. Bioeng. 2013, 110, 857-870)

[0080] SEQ ID NO: 11;

[0081] NKFRGKYK (Sugita, et al., Biochem. Eng. J. 2013, 79, 33-40) SEQ ID NO: 12;

[0082] NARKFYKG (Sugita, et al., Biochem. Eng. J. 2013, 79, 33-40) SEQ ID NO: 13;

[0083] FYWHCLDE (Zhao, et al., Biochem. Eng. J. 2014, 88, 1-11) SEQ ID NO: 14;

[0084] FYCHWALE (Zhao, et al., J. Chromatogr. A2014, 1355, 107-114) SEQ ID NO: 15;

[0085] FYCHTIDE (Zhao, et al., J. Chromatogr. A 2014, 1359, 100-111) SEQ ID NO: 16;

[0086] Double 1 / 3 (Zhao, et al., J. Chromatogr. A 2014, 1369, 64-72);

[0087] RRGW (Tsai, et al., Anal. Chem. 2014, 86, 2931-2938) SEQ ID NO: 17; or

[0088] KHRFNKD (Yoo and Choi, BioChip J. 2015, 10, 88-94) SEQ ID NO: 18.

[0089] In some embodiments, [CPBM] is a CD40L targeting motif according to the following chemical structure:

[0090]

[0091] [CPBM] is a TNFα targeting motif based on the following chemical structure:

[0092]

[0093]

[0094] [CPBM] is a PCSK9 targeting motif based on the following chemical structure:

[0095]

[0096] [CPBM] is a VEGF targeting motif based on the following chemical structure:

[0097]

[0098] [CPBM] is a TGFβ targeting motif based on the following chemical structure:

[0099]

[0100] [CPBM] is a TSP-1 targeting motif according to the following chemical structure:

[0101]

[0102] [CPBM] is a soluble uPAR targeting motif based on the following chemical structure:

[0103]

[0104] [CPBM] is a soluble PSMA targeting motif based on the following chemical structure:

[0105]

[0106] [CPBM] is an IL-2 targeting motif based on the following chemical structure:

[0107]

[0108] [CPBM] is the GP120 targeting motif according to the following chemical structure:

[0109]

[0110] In certain embodiments, [CRBM] is [ASGPRBM], which is a group according to the following chemical structure:

[0111]

[0112] wherein X is 1-4 atoms in length and is independently selected at each occurrence from the group consisting of O, S, N (R N1 ) and C(R N1 )(R N1 ) such that:

[0113] If X is 1 atom in length, then X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[0114] If X is 2 atoms in length, no more than one atom in X is O, S, or N (R N1 ),

[0115] If X is 3 or 4 atoms in length, no more than 2 atoms in X are O, S, or N (R N1 );

[0116] where R N1 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups;

[0117] R1 and R3 are each independently H, -(CH2) K OH, -(CH2) K OC1-C4 alkyl, -C1-C4 alkyl, -(CH2) K Vinyl, -O-(CH2) K vinyl, -(CH2) K Alkynyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, --OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, wherein each alkyl, vinyl or alkynyl group is optionally substituted with 1-3 halogen groups. In various embodiments, each alkyl, vinyl or alkynyl group in R1 and R3 is optionally substituted with 1-3 fluorine (F). K is independently an integer from 0 to 4 at each occurrence.

[0118] In certain embodiments, R1 and R3 are each independently a group which is optionally substituted by 1-3 halogen groups, 1 to 3 C1-C4 alkyl groups or O-C1-C4 alkyl groups, wherein each of the alkyl groups is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently an integer from 0 to 4 at each occurrence; or

[0119] R1 and R3 are each independently a group according to the following chemical structure:

[0120]

[0121] where R 7 is O-C1-C4 alkyl, which is optionally substituted with 1 to 3 halo groups or 1 to 2 hydroxy groups, and K' is independently an integer from 0 to 4 at each occurrence; or

[0122] R 7 Yes-NR N3 R N4 Group or and K is independently an integer from 0 to 4 at each occurrence; or

[0123] R1 and R3 are each independently a group according to the following structure:

[0124] wherein K is independently 0-4 at each occurrence; or

[0125] Group,

[0126] wherein CYC is a ring selected from the group consisting of:

[0127]

[0128] and C3-C8 saturated carbon ring, wherein the linker X, R C and -(CH2) K Each of - is connected to the open valence in CYC, including NH;

[0129] R C is absent, is H, is C1-C4 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups; or a group according to the following structure:

[0130]

[0131] Wherein R4, R5 and R6 are each independently H, halogen, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, in any of which the alkyl group is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; or

[0132] R C yes

[0133]

[0134] where R N 、R N1 and R N2Each is independently H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups;

[0135] K is independently an integer from 0 to 4 at each occurrence;

[0136] K' is independently an integer from 0 to 4 at each occurrence;

[0137] R N3 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; and

[0138] R N4 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, or

[0139] R N4 yes Where K is 1;

[0140] is a linker group comprising at least one [CPBM] group and linking the [CPBM] group to the [CRBM] via one or more optional [CON] groups, or

[0141] is a linker group comprising at least one functional group that covalently bonds the linker group to at least one [CPBM] group or optional [CON] group;

[0142] R2 is where R N1 and K are the same as above;

[0143] R AM is H, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -(CH2) K -NR N3 R N4 , where R N3 is H or C1-C3 alkyl, wherein any of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; and

[0144] R N4 is H, C1-C3 alkyl optionally substituted by 1-3 halo or 1 or 2 hydroxy groups, or

[0145] R N4 yes and K is 1; or

[0146] R2 is

[0147] where R TA It is H, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, each of which is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, or

[0148] R TA It is C3-C 10 Aryl or 3- to 10-membered heteroaryl containing up to 5 heteroatoms, each of which is optionally substituted with 1-3 substituents selected from the group consisting of CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl and -(CH2) K C(O)-C1-C4 alkyl, each of which is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, or

[0149] R TA yes

[0150]

[0151] R TA yes group, which is optionally substituted by 1-3 C1-C3 alkyl groups, each of which is optionally substituted by 1-3 halogen groups, or

[0152] R TA yes

[0153] where R N 、R N1 and R N2 are each independently H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, and

[0154] Each of -(CH2) K The group is optionally substituted by 1-4 C1-C3 alkyl groups, each of which is optionally substituted by 1-3 fluorine or 1-2 hydroxy groups;

[0155] And K is independently 0-4 at each occurrence.

[0156] In various embodiments, any of the alkyl groups optionally substituted with 1-3 halo groups described herein is substituted with 1, 2, or 3 fluorine (F) atoms.

[0157] In various embodiments,

[0158]

[0159] where R C 、 and K are the same as above.

[0160] In certain embodiments, [CRBM] is an LRP1 (low-density lipoprotein receptor-related protein 1 or alpha-2-macroglobulin receptor) peptide binding group according to the following peptide sequence (note that in each case where a peptide is used, preferably the amino or carboxylic acid terminus of the peptide is linked, more preferably the carboxylic acid terminus of the peptide is a non-reactive carboxamide group and the amine terminus is covalently linked to a CON, linker, or CPBM group):

[0161] Ac-VKFNKPFVFLNleIEQNTK-NH2 SEQ ID NO: 19 (see Toldo, Stefano, et al. JACC: Basic to Translational Science 2.5 (2017): 561-574), wherein Nle is neorleucine,

[0162] VKFNKPFVFLMIEQNTK SEQ ID NO:20 (see Toldo, Stefano, et al. JACC: Basic to Translational Science 2.5 (2017): 561-574.),

[0163] TWPKHFDKHTFYSILKLGKH-OH SEQ ID NO:21 (see Sakamoto, Kotaro, et al. Biochemistry and biophysics reports 12 (2017): 135-139.),

[0164] Angiopep-2:TFFYGGSRGKRNNFKTEEY-OH SEQ ID NO:22 (see Sakamoto, Kotaro, et al. Biochemistry and biophysics reports 12 (2017): 135-139.),

[0165] LRKLRKRLLRDADDLLRKLRKRLLRDADDL SEQ ID NO: 23 (see Croy, Johnny E., Theodore Brandon, and Elizabeth A. Komives. Biochemistry 43.23 (2004): 7328-7335.)

[0166] TEELRVRLASHLRKLRKRLL SEQ ID NO: 24 (Croy, Johnny E., Theodore Brandon, and Elizabeth A. Komives. Biochemistry 43.23 (2004): 7328-7335.)

[0167] Rap12:EAKIEKHNHYQK(Ruan, Huitong, et al. "A novel peptide ligand RAP12of LRP1 for glioma targeted drug delivery." Journal of Controlled Release 279(2018):306-315.)

[0168] Rap22:EAKIEKHNHYQKQLEIAHEKLR SEQ ID NO:25(Ruan, Huitong, et al. "A novelpeptide ligand RAP12 of LRP1 for glioma targeted drug delivery." Journal of Controlled Release 279(2018):306-315.)

[0169] ANG:TFFYGGSRGKRNNFKTEEY SEQ ID NO:26 (Kim, Jong Ah, et al. Scientific reports 6 (2016):34297), or [CRBM] is an LDLR (low-density lipoprotein receptor) binding group according to the following peptide sequence:

[0170] VH4127: cM "Thz" RLRG "Pen" (cyclized c-Pen) SEQ ID NO: 27 (see Molino, Yves, et al.

[0171] The FASEB Journal 31.5(2017):1807-1827), wherein Pen is penicillamine and Thz is thiazolidine-4-carboxylic acid,

[0172] VH434: CMPRLRGC (cyclized CC) SEQ ID NO: 28 (Molino, Yves, et al. The FASEBJournal 31.5 (2017): 1807-1827),

[0173] VH101: HLDCMPRGCFRN (cyclized CC) SEQ ID NO: 29 David, Marion, et al. PloS one 13.2 (2018): e0191052,

[0174] VH202: CQVKSMPRC (cyclized CC) SEQ ID NO: 30 (David, Marion, et al. PloS one 13.2 (2018): e0191052),

[0175] VH203: CTTPMPRLC (cyclized CC) SEQ ID NO: 31 (David, Marion, et al. PloS one 13.2 (2018): e0191052),

[0176] VH204: CKAPQMPRC (cyclized CC) SEQ ID NO: 32 (David, Marion, et al. PloS one 13.2 (2018): e0191052),

[0177] VH205: CLNPSMPRC (cyclized CC) SEQ ID NO: 33 (David, Marion, et al. PloS one 13.2 (2018): e0191052),

[0178] VH306: CLVSSMPRC (cyclized CC) SEQ ID NO: 34 (David, Marion, et al. PloS one 13.2 (2018): e0191052),

[0179] VH307: CLQPMPRLC (Cyclized C-C) SEQ ID NO:35 (David, Marion, et al. PloS one 13.2(2018):e0191052),

[0180] VH308: CPVSSMPRC (Cyclized C-C) SEQ ID NO:36 (David, Marion, et al. PloS one 13.2(2018):e0191052),

[0181] VH309: CQSPMPRLC (Cyclized C-C) SEQ ID NO:37 (David, Marion, et al. PloS one 13.2(2018):e0191052),

[0182] VH310: CLTPMPRLC (Cyclized C-C) SEQ ID NO:38 (David, Marion, et al. PloS one 13.2(2018):e0191052),

[0183] VH411: DSGLCMPRLRGCDPR (Cyclized C-C) SEQ ID NO:39 (David, Marion, et al. PloSone 13.2(2018):e0191052),

[0184] VH549: TPSAHAMALQSLSVG SEQ ID NO:40 (David, Marion, et al. PloS one 13.2(2018):e0191052),

[0185] AcVH411: Ac-DSGLCMPRLRGCDPR-NH2 (Cyclized C-C) SEQ ID NO:41 (David, Marion,etal. PloS one 13.2(2018):e0191052),

[0186] Pr VH434: Pr-CMPRLRGC-NH2 (Cyclized C-C) SEQ ID NO:42 (David, Marion, et al. PloSone 13.2(2018):e0191052),

[0187] VH445: Pr-cMPRLRGC-NH2 (Cyclized C-C) SEQ ID NO:43 (David, Marion, et al. PloSone 13.2(2018):e0191052),

[0188] VH4127: Pr-cMThzRLRG"Pen"-NH2 (cyclized C-Pen) SEQ ID NO: 44 (David, Marion, et al. PloS one 13.2 (2018): e0191052), wherein Pen is penicillamine,

[0189] Ac VH434: Ac-CMPRLGC-NH2 (cyclization CC) SEQ ID NO: 45 (Jacquot, Guillaume, etal. Molecular pharmaceutical 13.12 (2016): 4094-4105),

[0190] Ac VH445: Ac-cMPRLRGC-NH2 (cyclization CC) SEQ ID NO: 46 (Jacquot, Guillaume, etal. Molecular pharmaceutical 13.12 (2016): 4094-4105),

[0191] VH4106:Ac- D - "Pen" M "Thz" RLRGC-NH2 (cyclized Pen-C) SEQ ID NO: 47 (Jacquot, Guillaume, et al. Molecular pharmaceutics 13.12 (2016): 4094-4105), wherein Pen is penicillamine and Thz is thiazolidine-4-carboxylic acid,

[0192] VH4127: Pr-cM"Thz"RLRG"Pen-NH2 (cyclized c-Pen) SEQ ID NO: 48 (Jacquot, Guillaume, et al. Molecular pharmaceutics 13.12(2016):4094-4105), wherein Pen is penicillamine and Thz is thiazolidine-4-carboxylic acid,

[0193] VH4128: Pr-cM"Thz"RLR"Sar""Pen"-NH2 (cyclized C-Pen) SEQ ID NO: 49 (Jacquot, Guillaume, et al. Molecular pharmaceutics 13.12(2016):4094-4105), wherein Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, and Sar is sarcosine,

[0194] VH4129: Pr-cM"Pip"RLR"Sar"C-NH2 (cyclized CC) SEQ ID NO: 50 (Jacquot, Guillaume, et al. Molecular pharmaceutics 13.12 (2016): 4094-4105), wherein Pip is a picoline group and Sar is a sarcosine group,

[0195] VH4130: Pr-cM"Pip"RLRG"Pen"-NH2 (cyclized c-Pen) SEQ ID NO: 51 (Jacquot, Guillaume, et al. Molecular pharmaceutics 13.12 (2016): 4094-4105), or

[0196] VH4131:Pr-[cM”Pip”RLR”Sar””Pen”-NH2 (cyclized c-Pen) SEQ ID NO: 52 (Jacquot, Guillaume, et al. Molecular pharmaceutical 13.12 (2016): 4094-4105),

[0197] Where Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, Pip is picoline and Sar is sarcosine,

[0198] wherein Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, Pip is picoline and Sar is sarcosine, or

[0199] [CRBM] is an FcγRI binding group based on the following peptide sequence:

[0200] Cp22:TDT C LMLPLLLG C DEE (cyclized CC) SEQ ID NO: 53, Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0201] Cp21:DPI C WYFPRLLG C TTL (cyclized CC) SEQ ID NO: 54, Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0202] Cp23: WYP C YIYPRLLG C DGD (Cyclized C-C) SEQ ID NO:55, Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0203] Cp24: GNI C MLIPGLLG C SYE (Cyclized C-C) SEQ ID NO:56 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0204] Cp33: VNS C LLLPNLLG C GDD (Cyclized C-C) SEQ ID NO:57 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0205] Cp25: TPV C ILLPSLLG C DTQ (Cyclized C-C) SEQ ID NO:58 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0206] Cp26: TVL C SLWPELLG C PPE (Cyclized C-C) SEQ ID NO:59 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0207] Cp27: TFS C LMWPWLLG C ESL (Cyclized C-C) SEQ ID NO:60 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0208] Cp32: FGT C YTWPWLLG C EGF (Cyclized C-C) SEQ ID NO:61 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0209] Cp34: SLF C RLLLTPVG C VSQ (Cyclized C-C) SEQ ID NO:62 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009):575-585,

[0210] P35:HLL V LPRGLLG C TTLA (cyclized CC) SEQ ID NO: 63 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0211] Cp28:TSL C SMFPDLLG C FNL (cyclized CC) SEQ ID NO: 64 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0212] Cp29:SHP C GRLPMLLG C AES (cyclized CC) SEQ ID NO: 65 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0213] P37: TST C SMVPGPLGAV STW (cyclized CC) SEQ ID NO: 66 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0214] Cp30: KDP C TRWAMLLG C DGE (cyclized CC) SEQ ID NO: 67 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585,

[0215] Cp31: IMT C SVYPFLLG C VDK (cyclized CC) SEQ ID NO: 68 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585, or

[0216] Cp36: IHS C AHVMRLLG C WSR (cyclized CC) SEQ ID NO: 69 Bonetto, Stephane, et al. The FASEB Journal 23.2 (2009): 575-585, or [CRBM] is an FcRN binding moiety according to the following peptide sequence:

[0217] SYN746: Ac-NH-QRFCTGHFGGLYPCNGP-CONH2 (cyclization CC) SEQ ID NO: 70 (Mezo, AdamR., et al. Proceedings of the National Academy of Sciences 105.7 (2008): 2337-2342.),

[0218] SYN1327: Ac-NH-RF-Pen-TGHFG-Sar-NMeLeu-YPC-CONH2 (cyclized CC) SEQ ID NO: 71 (Mezo, Adam R., et al. Proceedings of the National Academy of Sciences 105.7 (2008): 2337-2342), wherein Pen is penicillamine, Sar is sarcosine and NMeLeu is N-methylleucine, or

[0219] SYN1436: SYN1327 dimerized with succinic anhydride NN (each cyclized CC) (Mezo, Adam R., et al. Proceedings of the National Academy of Sciences 105.7 (2008): 2337-2342.), or

[0220] [CRBM] is a transferrin receptor binding moiety based on the following peptide sequence:

[0221] Tf1:CGGGPFWWWP SEQ ID NO:72(Santi,Melissa,et al."Rational design of atransferrin-binding peptide sequence tailored to targeted nanoparticleinternalization."Bioconjugate chemistry 28.2(2016):471-480),

[0222] Tf2:CGGGHKYLRW SEQ ID NO:73(Santi,Melissa,et al."Rational design of atransferrin-binding peptide sequence tailored to targetednanoparticleinternalization."Bioconjugate chemistry 28.2(2016):471-480),

[0223] Tf3:CGGGKRIFMV SEQ ID NO:74(Santi,Melissa,et al."Rational design of atransferrin-binding peptide sequence tailored to targeted nanoparticleinternalization."Bioconjugate chemistry 28.2(2016):471-480),

[0224] Tf2-scr:CGGGKWHYLR SEQ ID NO:75(Santi,Melissa,et al."Rational designof a transferrin-binding peptide sequence tailored to targetednanoparticleinternalization."Bioconjugate chemistry 28.2(2016):471-480),

[0225] TfR-T 12 :THRPPMWSPVWP SEQ ID NO:76(Mu,Li-Min,et al.Scientific reports7.1(2017):3487),

[0226] HAIYPRH SEQ ID NO:77(Lee,Jae H.,et al.European journal ofbiochemistry 268.7(2001):2004-2012),

[0227] THRPPMWSPVWP SEQ ID NO:78(Lee,Jae H.,et al.European journal of biochemistry 268.7(2001):2004-2012),

[0228] THRPPMWSPVWP SEQ ID NO:79( Carmen, et al. Molecular Imaging and Biology 13.2(2011):332-341), or

[0229] [CRBM] is a macrophage scavenger receptor binding moiety based on the following peptide sequence:

[0230] PP1:LSLERFLRCWSDAPA SEQ ID NO:80(Segers,Filip ME,etal.Arteriosclerosis,

[0231] thrombosis,and vascular biology 32.4(2012):971-978),

[0232] PP1-13: LERFLRCWSDAPA SEQ ID NO:81 (Segers, Filip ME, et al. Arteriosclerosis,

[0233] thrombosis,and vascular biology 32.4(2012):971-978),

[0234] PP1-11: RFLRCWSDAPA SEQ ID NO:82 (Segers, Filip ME, et al. Arteriosclerosis,

[0235] thrombosis,and vascular biology 32.4(2012):971-978),

[0236] PP1-9: LRCWSDAPA SEQ ID NO:83 (Segers, Filip ME, et al. Arteriosclerosis,

[0237] thrombosis,and vascular biology 32.4(2012):971-978.)

[0238] PP1-7: CWSDAPA SEQ ID NO: 84 (Segers, Filip ME, et al. Arteriosclerosis, thrombosis, and vascular biology 32.4 (2012): 971-978.)

[0239] 4F: DWFKAFYDKVAEKFKEAF SEQ ID NO: 85 (Neyen, Claudine, et al. Biochemistry 48.50 (2009): 11858-11871);

[0240] [CON] is a linker moiety (including [MULTICON], as described elsewhere herein); and

[0241] [Linker] is a linking moiety as described elsewhere herein, which links a [CPBM] to a [CRBM] 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 [CPBM] group or the [CRBM] group, or

[0242] Pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof.

[0243] In certain embodiments of the present disclosure, when the length of X of the [CRBM] / [ASGPRBM] group is 2 atoms, X is typically -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 ),

[0244] When the length of X is 3 atoms, X is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 )、C(R N1 )(R N1 )-O-C(R N1 )-、-O-C(R N1 )-O-、-O-C(R N1 )-S-、-O-C(R N1 )-N(R N1 )(R N1 )-、-S-C(R N1 )-C(R N1 )(R N1 )-、C(R N1 )(R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​)-C(R N1 )(R N1 )-C(R N1 )(R N1 ),and

[0245] 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(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(RN1 )(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 various embodiments, R N1 It’s H.

[0246] In certain embodiments of the present disclosure, X of the [CRBM] / [ASGPRBM] group is OCH2 or CH2O and R N1 H is preferred.

[0247] In various embodiments, the [CRBM] / [ASGPRBM] group is a group according to the following chemical structure:

[0248]

[0249] wherein R1, R2 and R3 are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0250] In certain embodiments, the [CRBM] / [ASGPRBM] group is a group according to the following chemical structure:

[0251]

[0252] where R A is a C1-C3 alkyl group optionally substituted by 1-5 halogen groups;

[0253] Z A Yes - (CH2) IM 、-O-(CH2) IM 、S-(CH2) IM NR M -(CH2) IM 、C(O)-(CH2) IM -, PEG groups containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) residues or -C(O)(CH2) IM NRM , where IM and R M Same as above; and

[0254] Z B Does not exist, is (CH2) IM 、C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M， Among them, IM and R M Same as above.

[0255] In various embodiments, R1 and R3 are each independently a group according to the following chemical structure:

[0256] where R C 、 and K as described herein.

[0257] In certain embodiments, preferred compounds include Figure 1 、 Figure 7 and Figure 13 as well as Figure 29-Figure 88 In certain embodiments, the additional compound is present in Figure 16-Figure 66 The present invention relates to and includes the final compounds described herein and the intermediates used to prepare the final compounds according to the present disclosure.

[0258] In certain embodiments, R1 and R3 of the [CRBM] / [ASGPRBM] group include Figure 68 In certain embodiments, R2 of the [CRBM] / [ASGPRBM] group comprises those presented herein Figure 69 Those parts in .

[0259] In certain embodiments, the [CPBM] / [IgGBM] group is a peptide moiety according to the following FcIII or FcIII-4c chemical structure:

[0260]

[0261] In further embodiments, 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.

[0262] In other embodiments, the present disclosure relates to methods of treating disease states or conditions in which circulating proteins are associated with the disease state and / or condition or with symptoms associated with the disease state or condition. 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), as well as various other diseases as described herein (including those described herein). Figure 89 The treatment methods according to the present disclosure comprise administering to a patient or subject in need of treatment an effective amount of at least one compound according to the present disclosure, optionally in combination with an additional biologically active agent, to reduce the likelihood of, inhibit and / or treat the disease state or condition by removing circulating proteins associated with the disease state and / or condition from the circulation of the patient or subject.

[0263] In further embodiments, 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.

[0264] In other embodiments, the present disclosure relates to methods for treating disease states or conditions in which circulating proteins are associated with symptomatology associated with the disease state or condition. These disease states and / or conditions include, for example, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer's disease, atherosclerosis, heart disease, stroke, and cancer (including leukemia), as well as a variety of other diseases as described herein. The methods comprise administering to a patient or subject in need of treatment an effective amount of at least one compound according to the present disclosure, optionally in combination with an additional bioactive agent, to reduce the likelihood of, inhibit, and / or treat the disease state or condition by removing circulating proteins associated with the disease state and / or condition. BRIEF DESCRIPTION OF THE DRAWINGS

[0265] Figure 1 Representative compounds according to the present disclosure are shown. It is 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 is noted that n in the PEG linker preferably ranges from 1-12, 1 to 10, 2 to 8, 2 to 6, 2 to 5, or 1, 2, 3, or 4.

[0266] Figure 2Fluorescence polarization data of MIF-FITC binding to human MIF are shown, indicating that our MIF-binding moieties bind 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.

[0267] Figure 3 It was shown that the bifunctional molecule was able to deplete human MIF from the supernatant of cultured HepG2 cells.

[0268] Figure 4 It was shown that MIF internalized by HepG2 cells was transported to lysosomes.

[0269] Figure 5 MIF-GN3 mediated depletion of injected human MIF from mice.

[0270] Figure 6 MIF-GN3 was shown to delay tumor growth in a mouse model of prostate cancer.

[0271] Figure 7 Shown are the molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind anti-DNP IgG and ASGPR.

[0272] Figure 8 It was shown that DNP-GN3 and DNP-AcF3-3 mediated the formation of a ternary complex between HepG2 cells and anti-DNP.

[0273] Figure 9 It was shown that DNP-GN3 and DNP-AcF3-3 mediated the uptake of Alexa 488-labeled anti-DNP by HepG2 cells.

[0274] Figure 10 We show that DNP-GN3 and DNP-AcF3-3 mediate the localization of Alexa 568-labeled anti-DNP to late endosomes and lysosomes.

[0275] Figure 11 It was shown that DNP-AcF3-3 mediated the degradation of alexa 488-labeled anti-DNP in HepG2 cells.

[0276] Figure 12 It was shown that DNP-GN3 mediated the depletion of anti-DNP from mouse serum.

[0277] Figure 13 The structures of the IgG-degrading molecules IBA-GN3, triazine-GN3, FcIII-GN3, and FcIII-4c-GN3 are shown.

[0278] Figure 14 FcIII-GN3 was shown to mediate human IgG uptake into HepG2 cells. The experiment was performed as described above.

[0279] Figure 15 It was shown that FcIII-GN3 mediates IgG localization to late endosomes in HepG2 cells. The experiments were performed as described above.

[0280] Figure 16-Figure 18 Shown are the syntheses of PEG linkers used in several molecules outlined in this disclosure.

[0281] Figures 19-21 Shown are the syntheses of ASGPR binding precursors and ligands used in several molecules of the present disclosure.

[0282] Figure 22-26 Shown are the syntheses of valency linkers used in several molecules of this disclosure.

[0283] Figure 27-28 The synthesis of MIF ligands used in several bifunctional molecules is shown.

[0284] Figure 29 The synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3 is described.

[0285] Figure 30 The synthesis of the bifunctional molecules MIF-GN3 and MIF-PEGn-GN3 is described.

[0286] Figure 31 The synthesis of a bifunctional molecule targeting MIF and ASGPR comprising a bicyclic ASGPR AcF3 ligand is described.

[0287] Figure 32 The synthesis of a bifunctional molecule targeting MIF and ASGPR comprising two bicyclic ASGPr AcF3 ligands is described.

[0288] Figure 33 The synthesis of a bifunctional molecule targeting MIF and ASGPR comprising three bicyclic ASGPR ligands is described.

[0289] Figure 34 The synthesis of DNP-GN3 is shown.

[0290] Figure 35 The synthesis of DNP-AcF3-3 is shown.

[0291] Figure 36 The synthetic scheme for obtaining IBA-GN3 is shown.

[0292] Figure 37 The synthesis of triazine-GN3 is shown.

[0293] Figure 38 The synthetic scheme used to obtain FcIII-GN3 is shown.

[0294] Figure 39 The synthetic scheme for obtaining FcIII-4c-GN3 is shown.

[0295] Figures 40-43 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 is described.

[0296] Figure 44 The synthesis of compound MIF-18-3 is shown.

[0297] Figure 45 The synthesis of compound MIF-31-3 is shown.

[0298] Figure 46 The synthesis of compound MIF-15-3 is shown.

[0299] Figure 47 The synthesis of compound MIF-19-3 is shown.

[0300] Figure 48 The synthesis of compound MIF-16-3 is shown.

[0301] Figure 49 The synthesis of compound MIF-20-3 is shown.

[0302] Figure 50 The synthesis of compound MIF-14-3 is shown.

[0303] Figure 51 The synthesis of compound MIF-21-3 is shown.

[0304] Figures 52-66 The synthesis of multiple MIF-binding compounds with various ASGPRBM moieties is shown.

[0305] Figure 67 Exemplary IgGBM groups are shown, each of which is covalently linked to a [CON] group, a [Linker] group, or a [ASGPRBM] group via an amine group, which is preferably a primary or secondary alkylamine group optionally substituted on the amine group with a C1-C3 alkyl group.

[0306] Figure 68 Exemplary R1 and R3 substituents on ASGPRBM groups as described elsewhere herein are shown.

[0307] Figure 69 Exemplary R2 substituents on ASGPRBM groups as described elsewhere herein are shown.

[0308] Figure 70 Shown is the synthesis of the CD40L-binding bifunctional molecule BIO8898-GN3.

[0309] Figure 71 The synthesis of the TNF-α binding bifunctional molecule c87-GN3 is shown.

[0310] Figure 72 Shown is the synthesis of the TNF-α binding bifunctional molecule 4e-GN3.

[0311] Figure 73 The synthesis of the TNF-α binding bifunctional molecule Cpd1-GN3 is shown.

[0312] Figure 74 The synthesis of the TNF-α binding bifunctional molecule SP307-GN3 is shown.

[0313] Figure 75 Shown is the synthesis of the TNF-α binding bifunctional molecule YCWSQYLCY-GN3.

[0314] Figure 76 Shown is the synthesis of the PCSK9 binding bifunctional molecule SBC110424-GN3.

[0315] Figure 77 Shown is the synthesis of the PCSK9 binding bifunctional molecule SBC110076-GN3.

[0316] Figure 78 Shown is the synthesis of the PSCK9-binding bifunctional molecule TVFTSWEEYLDWV-GN3.

[0317] Figure 79 Shown is the synthesis of the VEGF-binding bifunctional molecule VEPNCDIHVMWEWECFERL-GN3.

[0318] Figure 80 Shown is the synthesis of the VEGF-binding bifunctional molecule VEGFSM-GN3.

[0319] Figure 81 Shown is the synthesis of the TGF-β binding bifunctional molecule KRFK-GN3.

[0320] Figure 82 Shown is the synthesis of the TGF-β binding bifunctional molecule TGFBSM-GN3.

[0321] Figure 83Shown is the synthesis of the TSP-1 binding bifunctional molecule LSKL-GN3.

[0322] Figure 84 Shown is the synthesis of a soluble uPAR-binding bifunctional molecule, uPAR-GN3.

[0323] Figure 85 Shown is the synthesis of the soluble PSMA-binding bifunctional molecule PSMA-GN3.

[0324] Figure 86 Shown is the synthesis of the IL-2 binding bifunctional molecule IL2-GN3.

[0325] Figure 87 Shown is the synthesis of the GP120-binding bifunctional molecule BMS378806-GN3.

[0326] Figure 88 Shown is the synthesis of the GP120-binding bifunctional molecule CPD7-GN3.

[0327] Figure 89 Possible target proteins and their indications, examples of in vitro assays, and a list of known binding molecules are listed.

[0328] Figure 90 Includes derivatized sites for several ligands that bind target circulating proteins. DETAILED DESCRIPTION

[0329] In light of the present disclosure, conventional chemical synthesis and pharmaceutical formulation methods, as well as pharmacology, molecular biology, microbiology, and recombinant DNA techniques, which are within the skill of the art may be employed. These techniques are well known and otherwise fully described in the literature.

[0330] 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 containing multiple carbon atoms), every intervening value between the upper and lower limits of the range, up to one-tenth of the unit of the lower limit, and any other recited or intervening value within the recited range are encompassed within the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the present disclosure, subject to any specifically excluded limitations within the recited range. When a recited range includes one or both of the limits, ranges excluding either of the two included limits are also encompassed within the present disclosure.

[0331] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, preferred methods and materials are now described.

[0332] It must 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.

[0333] 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, it shall have the meaning generally used by persons of ordinary skill in the art in the context.

[0334] Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein and includes its tautomers, regioisomers, geometric isomers, stereoisomers, and, where appropriate, optical isomers (enantiomers), as well as pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When used in this 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 to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the present compounds, various substituents, linkers, and linker molecules and variables associated therewith 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 whether a single bond or a double bond is intended to depend on the context of the chemistry being described. It will be understood by those of ordinary skill in the art that the molecules described herein are stable compounds, as generally described below.

[0335] The term "patient" or "subject" is used throughout the specification to describe an animal, typically a mammal, and preferably a human, that is treated with a composition according to the present disclosure, including prophylactic treatment (prophylaxis, particularly including when the term is used to reduce the likelihood of metastasis of an existing cancer). For treatment of 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 male or female human patient, the term "patient" refers to that particular animal. The compounds according to the present disclosure are useful in 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.

[0336] Unless otherwise indicated, the term "effective" is used herein to describe an amount of a compound or composition used in the context of producing or achieving a desired result, whether that 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, among many other diseases, 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 in a subject. This term encompasses all other effective amount or effective concentration terms described elsewhere in this application, including the term "therapeutically effective."

[0337] As used herein, the terms "treat," "treating," and "treatment" refer to any of the following: providing a benefit to a patient at risk for 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 the 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 means 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.

[0338] As used in this application, the terms "about" and "approximately" are used as equivalents. Any number 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.

[0339] The term "circulating protein binding moiety," which includes "macrophage migration inhibitory factor binding moiety" or "MIFBM," "immunoglobulin G binding moiety," or "IgGBM," 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 protein (such as MIF, IgG, CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA, and IL-2) that is associated with or contributes to a disease state or condition described elsewhere herein. In the present disclosure, a CPBM is capable of binding to a circulating protein, forming a complex with the compound, and delivering the bound protein to hepatocytes or other cells, whereby the other end of the bifunctional molecule comprising a cell receptor binding moiety (CRBM) such as an asialoglycoprotein receptor binding moiety (ASGPRBM) or as described elsewhere herein is capable of binding to the surface of a hepatocyte or other cell, respectively. Once attached to a cell, the bifunctional molecule bound to the circulating protein is internalized by the cell via a phagocytosis / endocytosis mechanism, whereby the cell destroys the protein via 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 molecules according to the present disclosure for ultimate destruction in hepatocytes. In certain instances of describing the present disclosure, the terms MIFBM and IgGBM are used synonymously with other cell-binding moieties.

[0340] Exemplary MIFBMs included in bifunctional compounds according to the present disclosure include those present in the presence of Figure 1 The MIFBM according to the present disclosure includes a moiety according to the following chemical structure:

[0341]

[0342] where X M Yes - (CH2) IM 、-O-(CH2) IM 、S-(CH2) IM NR M -(CH2) IM、 C(O)-(CH2) IM -, a PEG (polyethylene glycol) group containing 1 to 8 ethylene glycol residues or -C(O)(CH2) IM NR M Group; R M is H or a C1-C3 alkyl group optionally substituted with one or two hydroxy groups; IM is an integer from 0 to 6. In various embodiments, IM is 1.

[0343] Other CPBM groups such as IgGBM and various previously described moieties that bind to CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA, and 11-2 have been described above. These groups bind to the respective circulating proteins, thereby forming a complex with the bifunctional compounds according to the present disclosure, and the bifunctional compounds complexed with the bound circulating proteins can bind to cell receptors on cells, which can take up the complexed compound using the cell's phagocytosis / endocytosis mechanism and remove the protein through degradation processes. It is important to note that CPBMs are peptides that bind to IgGBM, CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA, and 11-2, which are covalently linked to other moieties of the bifunctional molecules according to the present disclosure via the terminal amine or carboxylic acid group of the peptide. In preferred embodiments, the carboxylic acid is typically a free amine group (substituted with two H) or a C1-C ... 10 The amine group alkylated with an alkyl group, more typically at least one C1-C3 alkyl group, is amidated to form a non-reactive amide group so that the free amine at the other end of the peptide can be used for covalent attachment to other parts of the bifunctional molecule. In other embodiments, the amine group alkylated with a C2-C 10 Acyl groups, preferably C2-C4 acyl groups, cap the amine groups rendering the amine termini unreactive, allowing the carboxylic acid groups to react, typically with an amine to form an amide.

[0344] The term "cell receptor binding moiety" refers to a portion of a bifunctional compound according to the present disclosure that is capable of binding to a receptor on a cell that is capable of degrading a circulating protein according to the present disclosure herein. These moieties are moieties that bind to asialoglycoprotein receptors, LRPR, LDLR, RcγRI, FcRN, transferrin receptor, or macrophage scavenger receptors (e.g., membrane receptors that degrade cells) as described elsewhere herein. Many of these binding moieties are peptides that are covalently linked to other moieties of a bifunctional compound according to the present disclosure via a terminal amine or carboxylic acid group. For the above-mentioned CPBM groups, in preferred embodiments, the carboxylic acid is typically a free amine group (substituted with two Hs) or a C1-C 10 The amine group alkylated with an alkyl group, more typically at least one C1-C3 alkyl group, is amidated to form a non-reactive amide group so that the free amine at the other end of the peptide can be used for covalent attachment to other parts of the bifunctional molecule. In other embodiments, the amine group alkylated with a C2-C 10 Acyl groups, preferably C2-C4 acyl groups, cap the amine groups rendering the amine termini unreactive, allowing the carboxylic acid groups to react, typically with an amine to form an amide.

[0345] The term "asialoglycoprotein receptor binding moiety" ("ASGPRBM") refers to a binding moiety that binds to the hepatocyte asialoglycoprotein receptor. This binding moiety is also a component of the currently claimed bifunctional compound—the CRBM group, which is covalently bound to the CPBM group via a CON group, a linker, or directly. 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 it is degraded by lysosomal degradation.

[0346] Exemplary ASGPRBM groups for compounds according to the present disclosure, as well as other ASGPRBM groups, include moieties according to the following chemical structures:

[0347]

[0348] wherein X is 1-4 atoms in length and is independently selected at each occurrence from O, S, N (R N1 ) and C(R N1 )(R N1 ) such that:

[0349] If X is 1 atom in length, then X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[0350] If X is 2 atoms in length, no more than one atom in X is O, S, or N (R N1 ),

[0351] If X is 3 or 4 atoms in length, no more than 2 atoms in X are O, S, or N (R N1 );

[0352] where R N1 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups;

[0353] R1 and R3 are each independently H, -(CH2) K OH, -(CH2) K OC1-C4 alkyl, -C1-C4 alkyl, -(CH2) K Vinyl, -O-(CH2) K vinyl, -(CH2) K Alkynyl, -(CH2) K COOH, -(CH2) KC(O)O-C1-C4 alkyl, --OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, wherein each alkyl, vinyl or alkynyl group is optionally substituted with 1-3 halogen groups. In various embodiments, each alkyl, vinyl or alkynyl group in R1 and R3 is optionally substituted with 1-3 fluorine (F). K is independently an integer from 0 to 4 at each occurrence.

[0354] In certain embodiments, R1 and R3 are each independently a group which is optionally substituted by 1-3 halogen groups, 1 to 3 C1-C4 alkyl groups or O-C1-C4 alkyl groups, wherein each of the alkyl groups is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently an integer from 0 to 4 at each occurrence; or

[0355] R1 and R3 are each independently a group according to the following chemical structure:

[0356]

[0357] where R 7 is O-C1-C4 alkyl, which is optionally substituted with 1 to 3 halo or 1 to 2 hydroxy groups, and K' is independently an integer from 0 to 4 at each occurrence; or

[0358] R 7 Yes-NR N3 R N4 Group or and K is independently an integer from 0 to 4 at each occurrence; or

[0359] R1 and R3 are each independently a group according to the following structure:

[0360] R1 and R3 are each independently a group according to the following structure:

[0361] wherein K is independently 0-4 at each occurrence; or

[0362] Group,

[0363] wherein CYC is a ring selected from the group consisting of:

[0364]

[0365] and C3-C8 saturated carbon ring, wherein the linker X, R C and (CH2) K Each of - is connected to the open valence in CYC, including NH;

[0366] R Cis absent, is H, is C1-C4 alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxy groups; or is a group according to the following structure:

[0367]

[0368] Wherein R4, R5 and R6 are each independently H, halogen, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, in any of which the alkyl group is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; or

[0369] R C yes

[0370]

[0371] where R N 、R N1 and R N2 Each is independently H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups;

[0372] K is independently an integer from 0 to 4 at each occurrence;

[0373] K' is independently an integer from 0 to 4 at each occurrence;

[0374] R N3 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; and

[0375] R N4 is H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, or

[0376] R N4 yes Where K is 1;

[0377] is a linker group comprising at least one [CPBM] group and linking the [CPBM] group to the [CRBM] via one or more optional [CON] groups, or

[0378] is a linker group comprising at least one functional group that covalently bonds the linker group to at least one [CPBM] group or optional [CON] group;

[0379] R2 is where R N1 and K are the same as above;

[0380] R AM is H, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -(CH2) K -NR N3 R N4 , where R N3 is H or C1-C3 alkyl, wherein any of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; and

[0381] R N4 is H, C1-C3 alkyl optionally substituted by 1-3 halo or 1 or 2 hydroxy groups, or

[0382] R N4 yes and K is 1; or

[0383] R2 is

[0384] where R TA It is H, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, each of which is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, or

[0385] R TA It is C3-C 10 aryl or 3- to 10-membered heteroaryl containing up to 5 heteroatoms, each of said aryl or heteroaryl being selected from CN, NR N1 R N2 、-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2)K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl and -(CH2) K 1-3 substituents of C(O)-C1-C4 alkyl are optionally substituted, wherein each alkyl group is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, or

[0386] R TA yes

[0387]

[0388] R TA yes group, which is optionally substituted by 1-3 C1-C3 alkyl groups, each of which is optionally substituted by 1-3 halogen groups, or

[0389] R TA yes

[0390] where R N 、R N1 and R N2 are each independently H or C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, and

[0391] Each of -(CH2) K The group is optionally substituted by 1-4 C1-C3 alkyl groups, each of which is optionally substituted by 1-3 fluorine or 1-2 hydroxy groups;

[0392] and K is independently at each occurrence 0-4. In various embodiments, K is 0. In various embodiments, K is 1. In various embodiments, K is 2. In various embodiments, K is 3. In various embodiments, K is 4.

[0393] [CON] is a linker moiety as otherwise described herein (including [MULTICON]); and [Linker] is a linking moiety as otherwise described herein, which links a [CPBM] to a [CRBM] 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 [CPBM] group or the [CRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0394] In various embodiments, when X is 2 atoms in length, X is -OC(R N1 )(R N1 )、C(R N1)(R N1 )-O-,-S-C(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 )或C(R N1 )(R N1 )-C(R N1 )(R N1 ),

[0395] When the length of X is 3 atoms, X is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 )、C(R N1 )(R N1 U )-O-C(R N1 )(R N1 )-、-O-C(R N1 )(R N1 )-O-、-O-C(R N1 )(R N1 )-S-、-O-C(R N1 )(R N1 )-N(R N1 )-、-S-C(R N1 )(R N1 )-C(R N1 )(R N1 )、C(R<o000388>)(R N1 )-S-C(R N1 )(R N1 )-、C(R N1 )(R N1 )-C(R N1 )(R N1 )-S、-S-C(R N1 )(R N1 )-S-、-S-C(R N1 )(R N1 )-O-、-S-C(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

[0396] 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(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.

[0397] In various embodiments, X is OCH2 or CH2O and R N1 It’s H.

[0398] In various embodiments, the [CRBM] / [ASGPRBM] group is a group according to the following chemical structure:

[0399]

[0400] wherein R1, R2 and R3 are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0401] In various embodiments, the [CRBM] / [ASGPRBM] group is a group according to the following chemical structure:

[0402]

[0403] where RA is -C1-C3 alkyl optionally substituted by 1-5 halogen groups;

[0404] Z A Yes - (CH2) IM 、-O-(CH2) IM 、S-(CH2) IM NR M -(CH2) IM 、C(O)-(CH2) IM -, PEG groups containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) units or -C(O)(CH2) IM NR M , where IM and R M Same as above; and

[0405] Z B Does not exist, is (CH2) IM 、C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M , where IM and R M Same as above.

[0406] In various embodiments, Z A is a PEG group comprising 1-4 ethylene glycol units. In various embodiments, Z A is a PEG group comprising 2-4 ethylene glycol units. In various embodiments, R A is a C1-C3 alkyl group optionally substituted with 1-5 fluorine atoms. A is -CH3 optionally substituted by 1-3 fluorine atoms. In various embodiments, R A is -CH2CH3 optionally substituted by 1-3 fluorine atoms;

[0407] Note that the [CRBM][ASGPRBM] group described above can also be represented by:

[0408]

[0409] Throughout the specification, the term "neoplasmosis" 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 tissue that grows by cell proliferation, usually faster than normal, and continues to grow after the stimulus that triggers new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissues, and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and cause the patient's death 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. Tumors include, but are not limited to, morphological irregularities of cells in a subject or host tissue and pathological proliferation of cells in a subject's tissue compared to normal proliferation in the same type of tissue. In addition, tumors include benign and malignant tumors (e.g., colon tumors) that are invasive or non-invasive. Malignant tumors (cancer) are distinguished from benign tumors in that the former exhibit a greater degree of degeneration, or loss of cell differentiation and orientation, and have invasive and metastatic properties. Examples of tumors or neoplasias derived from target cells of the present disclosure include, but are not limited to, carcinomas (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), 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., glioma, sarcoma, and sarcoma); tumours of the germ line (e.g., intestinal, breast, prostate, cervix, uterus, lung, ovary, testis, thyroid, astrocytoma, esophageal, pancreatic, stomach, liver, 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 are treatable using the compounds according to the present disclosure.

[0410] Representative common cancers to be treated with the compounds of the present disclosure include, for example, prostate cancer, metastatic prostate cancer, stomach 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 lymphoblastic 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 of 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 to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0411] In some specific aspects of the present disclosure, the cancer treated is metastatic cancer, recurrent cancer or drug-resistant cancer, especially including multi-drug resistant cancer. Respectively, metastatic cancer may be found in almost all tissues of cancer patients in the late stage of the disease, generally in the lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue and almost any tissue, including 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.

[0412] The term "tumor" is used to describe a growth or enlargement, whether malignant or benign.

[0413] The term "autoimmune disease" refers to a disease or condition that occurs when body tissue is attacked by its own immune system. The immune system is a complex tissue in the body, usually designed to "seek and destroy" the invaders of the body, including infectious agents. In diseases described as autoimmune diseases, MIF levels usually increase. The present 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 morbid states and conditions by reducing MIF levels. The example of the autoimmune disease that usually shows high MIF expression levels includes multiple other diseases such as systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis and pulmonary fibrosis.

[0414] A more complete list of autoimmune diseases treatable by the compounds and pharmaceutical compositions according to the present disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune bowel disease, 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, leukemia, leukemia, leukemia, urticaria, urticaria, leukemia ... 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 syndromesyndrome), 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 encephalitis erstaff's encephalitis), 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 syndrome), Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Moore's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic eye disease, Thornhill-Henriched 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, leukocytolytic 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 esophagitis), gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency and pyoderma gangrenosum, etc.

[0415] The term "inflammatory disease" is used to describe diseases or conditions that have acute, but more commonly 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, Inflammation), chronic inflammatory diseases (including, for example, 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). MIF is elevated in some diseases (elevated in some cases in the presence of inflammatory bowel 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 with the 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.

[0416] The term "linker" refers to a chemical entity comprising a composite linker that covalently links a circulating protein binding moiety (CPBM) to a cellular receptor binding moiety (CRBM), including an asialoglycoprotein receptor binding moiety (ASGPRBM), in a compound according to the present disclosure, optionally via at least one (preferably one or two) linker moieties [CON]. The length of the linker between the two active moieties of the molecule (i.e., the CPBM group and the CRBM / ASGPRBM group) ranges from about to about or longer, 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 about to about Etc. Linkers based on ethylene glycol units and having lengths between 2 and 15 ethylene glycol units, between 1 and 8 ethylene glycol units, and lengths of 1, 2, 3, 4, 5, and 6 ethylene glycol units may be preferred, although some linkers may be much longer. By having a linker of a certain length as disclosed elsewhere herein, the CPBM group and the CRBM / ASGPRBM group can be positioned to advantageously utilize the biological activity of the compounds according to the present disclosure, which bind to receptors on hepatocytes and other cells (including asialoglycoprotein receptors), resulting in selective and targeted degradation of circulating proteins within the lysosomal degradation machinery of hepatocytes or other degradation machinery. The choice of linker component is based on its documented biocompatibility, solubility in aqueous and organic media, and low immunogenicity / antigenicity, among other properties. 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 linkers according to the present disclosure (including polyethylene glycol linkers or other linkers), one or more additional groups (e.g., methylene, amide, keto, amine, etc.) can be covalently attached at either end of the linker group to connect to a CRBM / ASGPRBM group, a [CON] group, other linker groups, or a CPBM group.

[0417] 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, preferably 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 (preferably 1 or 2 linking groups at one or both ends of the polyamino acid linker).

[0418] Preferred linkers include linkers according to the following chemical structure:

[0419]

[0420] or polypropylene glycol or a polypropylene-co-polyethylene glycol linker having 1 to 100 alkylene glycol units (preferably 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);

[0421] where R a is H, C1-C3 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 (preferably naturally occurring L-amino acids), preferably 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 (ethylmethylsulfide), phenylalanine (benzyl), proline hydroxyproline (R 3 With R a and adjacent nitrogen groups to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylenephenol) or valine (isopropyl), wherein R 3Groups are indicated in brackets;

[0422] m (in the context of this use) is an integer from 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 12, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.

[0423] In other embodiments, linkers according to the present disclosure include polyethylene glycol linkers comprising 1 to 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 ethylene glycol units, to which a lysine group or other amino acid moiety is attached at one or both ends of the linker (which may consist of 1 to 10 amino acids that can bind to a CPBM and / or CRBM / ASGPRBM group). Still other linkers include lysine groups or other amino acid moieties attached to a CPBM and / or CRBM / ASGPRBM moiety. Amino acid residues (D or L), as described elsewhere herein. In other embodiments, as described elsewhere 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:

[0424]

[0425] Among them Ra m is H or C1-C3 alkyl optionally substituted by one or two hydroxy groups;

[0426] na is 1-15, 1-12, 1-10, 1-8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

[0427] m is an integer from 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 12, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5.

[0428] In various embodiments, the linker is according to the following formula:

[0429]

[0430] wherein Z and Z' are each independently a bond, -(CH2)iO, -(CH2)iS, -(CH2)iNR,

[0431] wherein the -(CH2)i group, if present in Z or Z', is bound to a linker (CON), CPBM or CRBM / ASGPRBM;

[0432] Each R is H or a C1-C3 alkyl or alkanol group;

[0433] Every R 2 are independently H or C1-C3 alkyl;

[0434] each Y is independently a bond, O, S or NR;

[0435] each i is independently 0 to 100, 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;

[0436] D is

[0437]

[0438] -(CH2) m′ -;

[0439]

[0440] a bond, provided that Z, Z' and D are not each a bond at the same time;

[0441] j is 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;

[0442] m' is 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;

[0443] n is 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 (n is preferably 2);

[0444] X 1 is O, S, or NR; and

[0445] R is H or a C1-C3 alkyl or alkanol group, or a pharmaceutical salt thereof.

[0446] In certain embodiments, other linkers included herein include linkers according to the following chemical structures:

[0447]

[0448] wherein each n and n' is independently 1 to 25, 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 1, 2, 3, 4, 5, 6, 7 or 8; and

[0449] Each n" is independently 0 to 8, typically 1 to 7 or 1, 2, 3, 4, 5 or 6 (preferably 2, 3, 4 or 5).

[0450] 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 connecting a first and a second (PEG) linker group include the following structures:

[0451]

[0452] wherein each n and n' is independently 1 to 25, 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 1, 2, 3, 4, 5, 6, 7 or 8; and

[0453] Each n" is independently 0 to 8, typically 1 to 7 or 1, 2, 3, 4, 5 or 6 (preferably 3).

[0454] 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 attachment of the linker group.

[0455] Other linkers including the linker group [CON] include groups represented by the following formula:

[0456] PEG-[CON]-PEG,

[0457] 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. In various embodiments, [CON] is:

[0458]

[0459] 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 moiety (which is sometimes also activated to allow the linker to be covalently bound to the moiety) or an ASGPRBM group and an activated linker. The linker group is typically the resulting moiety formed from 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 a bifunctional or multifunctional compound according to the present disclosure. It is to be noted that the linker can be distinguishable from the linker in that the linker is the result of a specific chemistry used to provide the 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 therewith.

[0460] 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 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 positions denoted by the following symbols for attachment to other groups:

[0461]

[0462] When two or more such groups (symbols) are present in a linker or connector, any one of the CRBM / ASGPRBM, linker or CPBM groups may be combined with such groups. Where the symbol is not used, the linker may be located at one or more positions on a moiety in the presence of an open valence.

[0463] In various embodiments, suitable [CON] linker groups for use in the present disclosure include the following chemical groups:

[0464]

[0465]

[0466] where RCON1 and R CON2 Each is independently H, methyl or a bond (for connection to another moiety); or a diamide group according to the following structure:

[0467]

[0468] where X 2 It is CH2, O, S, NR 4 , C(O), S(O), S(O)2, -S(O)2O, -OS(O)2 or OS(O)2O;

[0469] X 3 O, S, NR 4 ;

[0470] R 4 is H, a C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group;

[0471] R 1 is H or C1-C3 alkyl (preferably H); and

[0472] n" is independently 0 to 8, typically 1 to 7 or 1, 2, 3, 4, 5 or 6 (preferably 3);

[0473] Or a linker group [CON] is a group according to the following chemical structure:

[0474]

[0475] where R 1CON 、R 2CON and R 3CON are each independently H, -(CH2) MC1 、-(CH2) MC1a C(O) XA (NR 4 ) XA -(CH2) MC1a 、-(CH2) MC1a (NR 4 ) XA C(O) XA -(CH2) MC1a or -(CH2) MC1a O-(CH2) MC1 -C(O)NR 4 -, provided that R 1CON 、R 2CON and R 3CON Not at the same time H;

[0476] Each MC1 is independently an integer from 1 to 4;

[0477] Each MC1a is independently an integer from 0 to 4; and

[0478] R 4 is H, a C1-C3 alkyl or alkanol group or a -C(O)(C1-C3) group.

[0479] In various embodiments, MC1 is 1 or 2. In various embodiments, MC1a is 0, 1, or 2.

[0480] The triazole group shown above may be a preferred linker group. Other preferred linker groups are:

[0481]

[0482] It is linked to at least one CPBM and / or at least one CRBM / ASPRGBM (preferably 3 CRBM / ASPRGBM moieties).This linker group can be used to form GN3 as described elsewhere herein.

[0483] It is noted that each linker may be extended with one or more methylene groups to facilitate attachment to linker groups, other CON groups, CPBM groups or CRBM / ASGPRBM. It is noted that under certain circumstances in the context, diamide groups may also independently function as linker groups.

[0484] Additional galactosyl and talosyl ASGPR binding moieties

[0485] 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:

[0486]

[0487] As used herein, the term "extracellular protein targeting ligand" is used interchangeably with the term CPBM (cellular protein binding moiety). As used herein, the term "ASGPR ligand" is used interchangeably with the asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0488] In the compounds of formula II, each [CON] is an optional linker chemical moiety which, when present, either directly links to [CPBM] or [CRBM] or links [Linker-2] to [CPBM] or [CRBM].

[0489] In the compound of formula II:

[0490] [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;

[0491] k' is an integer from 1 to 15;

[0492] j' is an integer from 1 to 15;

[0493] h and h' are each independently an integer from 0 to 15;

[0494] i L is an integer from 0 to 15;

[0495] The premise is h, h' and i L At least one of the is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0496] The [MULTICON] group can link 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 compound of Formula II, [Linker-2] comprises a linker as defined herein. A , connector B , connector C , connector D and / or one or more of their combinations.

[0497] 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.

[0498] In the compound 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.

[0499] In the compound 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.

[0500] In the compound of formula II, X1 are independently selected from O, S, N(R 6 ) and C(R 4 )(R 4 ) of 1 to 5 consecutive atoms, wherein if X 1 is 1 atom, then X 1 It is 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 );

[0501] 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, and heteroaryl, heterocycle, -OR 8 and -NR 8 R 9 ;

[0502] 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 ,

[0503] 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)2R 3 ;

[0504] R 8 and R 9 and alkyl, wherein each occurrence is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0505] A. Galactosyl ASGPR Binding Cell Receptor Binding Portion of Formula II

[0506] In certain embodiments, the compound of Formula II is selected from:

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525] In certain embodiments, the compound of Formula II has one of the following structures:

[0526]

[0527]

[0528] In various embodiments, the ASGPR ligand is linked to C 1 or C 5 (R 1 or R5 ) position to form a degradation compound. In various embodiments, the ASGPR ligand is attached to C 6 For example, when the ASGPR ligand is

[0529] hour,

[0530] Non-limiting examples of ASGPR binding compounds of Formula II include:

[0531]

[0532] or disubstituted or trisubstituted versions thereof, or pharmaceutically acceptable salts thereof, wherein disubstituted or trisubstituted refers to the number of additional galactose derivatives attached to the linker moiety.

[0533] In any embodiment herein where an ASGPR ligand is drawn for use in a degrader, the ASGPR ligand is generally present in C 5 bit (eg, it may refer to an adjacent C 6 When the linker is connected to the extracellular protein targeting ligand via C 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.

[0534] In various embodiments, the ASGPR ligand is not attached to the C 3 or C 4 In certain embodiments, the ASGPR ligand for incorporation into the compound of formula II is selected from:

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547] In certain embodiments, the compound of Formula II is selected from:

[0548]

[0549]

[0550]

[0551]

[0552]

[0553] B. Talosyl ASGPR Binding Cellular Receptor Binding Portion of Formula II In certain embodiments, the compound of Formula II is selected from the group consisting of:

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591] In certain embodiments, the compound of formula II is an extracellular protein degradation compound wherein the ASGPR ligand is a ligand as described herein.

[0592]

[0593] In certain embodiments, in the compound of Formula II, the ASGPR ligand is attached at 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

[0594] hour,

[0595] Non-limiting examples of ASGPR binding compounds of Formula II include:

[0596]

[0597]

[0598] or a disubstituted or trisubstituted form thereof or a pharmaceutically acceptable salt thereof, wherein 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:

[0599]

[0600] 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.

[0601] In certain embodiments, the compound of Formula II is selected from:

[0602]

[0603]

[0604] 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.

[0605] In certain embodiments, the compound of Formula II is selected from:

[0606]

[0607]

[0608] 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.

[0609] In certain embodiments, the compound of Formula II is selected from:

[0610]

[0611]

[0612] 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.

[0613] In certain embodiments, the compound of Formula II is selected from:

[0614]

[0615]

[0616] 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.

[0617] In certain embodiments, the compound of Formula II is selected from:

[0618]

[0619]

[0620] 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.

[0621] In certain embodiments, the compound of Formula II is selected from:

[0622]

[0623]

[0624] 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.

[0625] In certain embodiments, the compound of Formula II is selected from:

[0626]

[0627]

[0628] 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.

[0629] In certain embodiments, the compound of Formula II is selected from:

[0630]

[0631]

[0632] 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.

[0633] In certain embodiments, the compound of Formula II is selected from:

[0634]

[0635]

[0636]

[0637] 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.

[0638] In certain embodiments, the compound of Formula II is selected from:

[0639]

[0640]

[0641] In certain embodiments, R2 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.

[0642] In certain embodiments, the compound of Formula II is selected from:

[0643]

[0644]

[0645] 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.

[0646] In certain embodiments, the compound of Formula II is selected from:

[0647]

[0648]

[0649] 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.

[0650] In certain embodiments, the compound of Formula II is selected from:

[0651]

[0652]

[0653] 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.

[0654] In certain embodiments, the compound of Formula II is selected from:

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666] In certain embodiments, the ASGPR ligand for incorporation into the compound of Formula II is selected from:

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679] C. ASGPR Ligand / Binding Moiety in the Compounds of Formula II

[0680] In certain embodiments, in the compound of Formula II, R 1 It's hydrogen.

[0681] In certain embodiments, in the compound of Formula II, R 1 yes

[0682] In certain embodiments, in the compound of Formula II, R 1 yes

[0683] In certain embodiments, in the compound of Formula II, R 1 yes

[0684] In certain embodiments, in the compound of Formula II, R 1 yes

[0685] In certain embodiments, in the compound of Formula II, R 1 yes

[0686] In certain embodiments, in the compound of Formula II, R 1 yes

[0687] In certain embodiments, in the compound of Formula II, R 1 is a C0-C6 alkyl-cyano group optionally substituted by 1, 2, 3 or 4 substituents.

[0688] In certain embodiments, in the compound of Formula II, R 1 is alkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0689] In certain embodiments, in the compound of Formula II, R 1is an alkenyl group optionally substituted with 1, 2, 3 or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is alkynyl optionally substituted with 1, 2, 3 or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is a haloalkyl group optionally substituted with 1, 2, 3 or 4 substituents. 1 It's F.

[0690] In certain embodiments, in the compound of Formula II, R 1 It's Cl.

[0691] In certain embodiments, in the compound of Formula II, R 1 It's Br.

[0692] In certain embodiments, in the compound of Formula II, R 1 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0693] In certain embodiments, in the compound of Formula II, R 1 is aralkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0694] In certain embodiments, in the compound of Formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0695] In certain embodiments, in the compound of Formula II, R 1 is heteroaralkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0696] In certain embodiments, in the compound of Formula II, R 1 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents.

[0697] In certain embodiments, in the compound of Formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0698] In certain embodiments, in the compound of Formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3 or 4 substituents.

[0699] In certain embodiments, in the compound of Formula II, R 1 Is -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6R 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 or C0-C6 alkyl-OS(O)2R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents.

[0700] In certain embodiments, in the compound of Formula II, R 2 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0701] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents.

[0702] 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.

[0703] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0704]

[0705] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3 or 4 substituents.

[0706] In certain embodiments, in the compound of Formula II, R 2is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)-R 3 .

[0707] 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 .

[0708] 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)(NR 6 )-R 3 .

[0709] In certain embodiments, in the compound of Formula II, R 2 is -N=S(O)(R 3 )2.

[0710] 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)2R 3 .

[0711] 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 .

[0712] 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 .

[0713] In certain embodiments, in the compound of Formula II, R 2 It's hydrogen.

[0714] In certain embodiments, in the compound of Formula II, R 2 It is R 10 .

[0715] In certain embodiments, in the compound of Formula II, R 2 is alkyl-C(O)-R 3 .

[0716] In certain embodiments, in the compound of Formula II, R 2 Yes-C(O)-R 3 .

[0717] In certain embodiments, in the compound of Formula II, R 2 It is an alkyl group.

[0718] In certain embodiments, in the compound of Formula II, R 2 It is a haloalkyl group.

[0719] In certain embodiments, in the compound of Formula II, R 2 Yes-OC(O)R 3 .

[0720] In certain embodiments, in the compound of Formula II, R 2 Yes-NR 8 -C(O)R 10 .

[0721] In certain embodiments, in the compound of Formula II, R 2 is alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0722] In certain embodiments, in the compound of Formula II, R 2 is allyl optionally substituted with 1, 2, 3 or 4 substituents.

[0723] In certain embodiments, in the compound of Formula II, R 2 is alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0724] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkenyl.

[0725] In certain embodiments, in the compound of Formula II, R 2 is -O-alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0726] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkynyl.

[0727] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -heteroaryl.

[0728] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -aryl.

[0729] In certain embodiments, in the compound of Formula II, R 2 is -O-heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0730] In certain embodiments, in the compound of Formula II, R 2 is -O-aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0731] In certain embodiments, in the compound of Formula II, R 2 is -O-alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0732] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0733] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0734]

[0735] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0736]

[0737] wherein R is an optional substituent as defined herein.

[0738] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0739]

[0740] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0741]

[0742] wherein R is an optional substituent as defined herein.

[0743] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0744]

[0745] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0746]

[0747] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0748]

[0749] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0750]

[0751] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0752] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0753]

[0754] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0755]

[0756] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0757]

[0758] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0759]

[0760] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0761]

[0762] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0763]

[0764] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0765]

[0766] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0767]

[0768] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0769]

[0770] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0771]

[0772] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0773]

[0774] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0775]

[0776] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0777]

[0778] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0779]

[0780] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0781]

[0782] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0783]

[0784] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0785]

[0786] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0787]

[0788] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0789]

[0790] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0791]

[0792] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0793]

[0794] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0795]

[0796] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0797]

[0798] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0799]

[0800] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0801]

[0802] In certain embodiments, in the compound of Formula II, R 2 or R 2A Selected from

[0803]

[0804] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0805]

[0806] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0807]

[0808] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0809]

[0810] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0811]

[0812] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0813] In certain embodiments, in the compound of Formula II, R 2 is a spirocyclic heterocycle, for example, and without limitation,

[0814] In certain embodiments, in the compound of Formula II, R 2 is a silicon-containing heterocycle, for example, and without limitation,

[0815] In certain embodiments, in the compound of Formula II, R 2 replaced by SF5, for example, and without limitation,

[0816]

[0817] In certain embodiments, in the compound of Formula II, R 2 is substituted with a sulfoxime, for example, and without limitation,

[0818]

[0819] In certain embodiments, in the compound of Formula II, R 10 is selected from bicyclic heterocycles.

[0820] In certain embodiments, in the compound of Formula II, R 10 is selected from spirocyclic heterocycles.

[0821] In certain embodiments, in the compound of Formula II, R 10 Selected from-NR 6 -heterocycle.

[0822] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0823]

[0824] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0825]

[0826] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0827]

[0828] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0829]

[0830] In certain embodiments, in the compound of formula II, the ring is selected from

[0831]

[0832] In certain embodiments, in the compound of Formula II, R 30 Selected from:

[0833]

[0834] In certain embodiments, in the compound of Formula II, R 200 yes

[0835] In certain embodiments, in the compound of Formula II, R 200 yes

[0836] In certain embodiments, in the compound of Formula II, R 200 yes

[0837] In certain embodiments, in the compound of Formula II, R 200 yes

[0838]

[0839] In certain embodiments, in the compound of Formula II, R 200 yes

[0840] In certain embodiments, in the compound of Formula II, R 200 yes

[0841] In certain embodiments, in the compound of Formula II, R 200 yes

[0842] In certain embodiments, in the compound of Formula II, R 200 yes

[0843] In certain embodiments, in the compound of Formula II, R 200 yes

[0844] In certain embodiments, in the compound of Formula II, R 200 yes

[0845] In certain embodiments, in the compound of Formula II, R 200 yes

[0846] In certain embodiments, in the compound of Formula II, R 200 yes

[0847] connector

[0848] In a non-limiting embodiment, in the compound of formula II, the linker A and connectors B Independently selected from:

[0849]

[0850] in:

[0851] R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -、-NR 6C(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, as well as heterocyclic, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR 6 -、-CH2CH2-[O-(CH2)2] n -、-[-(CH2)2-O-] n -、-[O-(CH2)2] n -,-[O-CH(CH3)C(O)] n -, -[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -, -[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated monocarboxylic acid or a dicarboxylic acid; each of which is independently selected from R 21 The substituents are optionally substituted;

[0852] n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0853] 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 SO2R 3 、-NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl and heterocyclic;

[0854] The remaining variables are as defined in this article.

[0855] In certain embodiments, in the compound of formula II, the linker A Is the key and the connector B yes

[0856]

[0857] In certain embodiments, in the compound of formula II, the linker BIs the key and the connector A yes

[0858]

[0859] In certain embodiments, in the compound of formula II, the divalent amino acid residue is selected from

[0860]

[0861]

[0862] wherein the amino acids may be oriented in either direction and wherein the amino acids may be in the L- or D- form or a mixture thereof.

[0863] In certain embodiments, in the compound of Formula II, the divalent residue of the dicarboxylic acid is generated by a nucleophilic addition reaction:

[0864]

[0865] Non-limiting embodiments of the divalent residue of a dicarboxylic acid generated by the nucleophilic addition reaction include:

[0866]

[0867] In certain embodiments, in the compound of Formula II, the divalent residue of the dicarboxylic acid is formed by the condensation reaction:

[0868]

[0869] Non-limiting embodiments of the divalent residue of a dicarboxylic acid produced by the condensation include:

[0870]

[0871] Non-limiting embodiments of divalent residues of saturated dicarboxylic acids include:

[0872]

[0873] Non-limiting embodiments of divalent residues of saturated dicarboxylic acids include:

[0874]

[0875] Non-limiting embodiments of the divalent residue of a saturated monocarboxylic acid are selected from butanoic acid (-OC(O)(CH2)2CH2-), hexanoic acid (-OC(O)(CH2)4CH2-), octanoic acid (-OC(O)(CH2)5CH2-), decanoic acid (-OC(O)(CH2)8CH2-), lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2)12 CH2-), Pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-) and lignoceric acid (-OC(O)(CH2) 22 CH2-);

[0876] Non-limiting embodiments of divalent fatty acid residues 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:

[0877]

[0878] Non-limiting embodiments of the divalent fatty acid residue are selected from linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y -linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3,(CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), eicosenoic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13CHCH(CH2)3CH2-), mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0879] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0880]

[0881] in:

[0882] R 22 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, heterocycle and heteroaryl, each of which is replaced by 1, 2, 3 or 4 independently selected R 21 The substituents are optionally substituted;

[0883] The remaining variables are as defined in this article.

[0884] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0885]

[0886] in:

[0887] R 32 is independently selected at each occurrence from alkyl, N + X-, -C-, alkenyl, haloalkyl, aryl, heterocycle and heteroaryl, each of which is replaced by 1, 2, 3 or 4 independently selected R 21 The substituents are optionally substituted;

[0888] X- is an anionic group, such as Br- or Cl-; and

[0889] All other variables are as defined herein.

[0890] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0891]

[0892] Each heteroaryl, heterocycle, cycloalkyl and aryl group may be optionally substituted with 1, 2, 3 or 4 of the following: halogen, alkyl, haloalkyl and any combination of heteroaryl, heterocycle or cycloalkyl, as valence permits.

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

[0894]

[0895] 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 valence permits.

[0896] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0897]

[0898] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0899]

[0900] In certain embodiments, in the compound of formula II, the linker B , connector C or connector D Selected from:

[0901]

[0902] wherein tt is independently selected from 1, 2 or 3 and ss is 3 minus tt (3-tt).

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

[0904]

[0905] wherein tt and ss are as defined herein.

[0906] In certain embodiments, in the compound of formula II, the linker B , connector C or connector D Selected from:

[0907]

[0908]

[0909]

[0910]

[0911]

[0912] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl is 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.

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

[0914]

[0915]

[0916] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl is 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.

[0917] In certain embodiments, in the compound of formula II, the linker B , connector C or connector D Selected from:

[0918]

[0919] wherein each heteroaryl and aryl is optionally substituted with 1, 2, 3 or 4 of any combination of halo, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl, as valence permits: and tt and ss are as defined herein.

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

[0921]

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

[0923]

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

[0925]

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

[0927]

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

[0929]

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

[0931]

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

[0933]

[0934]

[0935] In certain embodiments, in the compound of formula II, the linker B Selected from:

[0936]

[0937]

[0938] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0939]

[0940] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0941]

[0942] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0943]

[0944]

[0945] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0946]

[0947] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0948]

[0949] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0950]

[0951] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0952]

[0953] In certain embodiments, in the compound of formula II, the linker C Selected from:

[0954]

[0955] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0956]

[0957] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0958]

[0959]

[0960] In certain embodiments, in the compound of formula II, the linker D is selected from:

[0961]

[0962]

[0963] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0964]

[0965]

[0966] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0967]

[0968] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0969]

[0970]

[0971] In certain embodiments, in the compound of formula II, the linker D Selected from:

[0972]

[0973]

[0974] In certain embodiments, in the compound of formula II, the linker A Selected from

[0975]

[0976] In certain embodiments, in the compound of formula II, the linker A Selected from

[0977]

[0978] In certain embodiments, in the compound of formula II, the linker A Selected from

[0979]

[0980] In certain embodiments, the linker A Selected from

[0981]

[0982]

[0983] Each of which is selected from 1, 2, 3 or 4 21 The substituents are optionally substituted.

[0984] In certain embodiments, in the compound of formula II, the linker A Selected from:

[0985]

[0986] In certain embodiments, in the compound of formula II, the linker A Selected from

[0987]

[0988] In certain embodiments, in the compound of formula II, the linker A Selected from

[0989]

[0990] In certain embodiments, in the compound of formula II, the linker A Selected from

[0991]

[0992] In certain embodiments, in the compound of formula II, the linker A Selected from

[0993]

[0994] In certain embodiments, in the compound of formula II, the linker A Selected from

[0995]

[0996] In certain embodiments, in the compound of formula II, the linker A Selected from

[0997] In certain embodiments, in the compound of formula II, the linker A Selected from

[0998]

[0999]

[1000] In certain embodiments, in the compound of formula II, the linker A Selected from

[1001]

[1002]

[1003] In certain embodiments, in the compound of formula II, the linker A Selected from

[1004]

[1005]

[1006] In certain embodiments, in the compound of formula II, the linkerA Selected from

[1007] In certain embodiments, in the compound of formula II, the linker A Selected from

[1008]

[1009] In certain embodiments, in the compound of formula II, the linker A Selected from

[1010]

[1011]

[1012] In certain embodiments, in the compound of formula II, the linker A Selected from

[1013]

[1014] In certain embodiments, in the compound of formula II, the linker A Selected from

[1015]

[1016] In certain embodiments, in the compound of formula II, the linker B Selected from

[1017]

[1018] In certain embodiments, in the compound of formula II, the linker B Selected from

[1019]

[1020] In certain embodiments, in the compound of formula II, the linker B Selected from

[1021]

[1022] 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.

[1023] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1024]

[1025] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1026]

[1027] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1028]

[1029] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1030]

[1031] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1032]

[1033] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1034]

[1035] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1036]

[1037] In certain embodiments, in the compound of formula II, the linker B Selected from:

[1038]

[1039] In certain embodiments, in the compound of formula II, the linker B -Connectors A Selected from:

[1040]

[1041] In certain embodiments, in the compound of formula II, the linker B -Connectors A Selected from:

[1042]

[1043] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1044]

[1045] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1046]

[1047] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1048]

[1049] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1050]

[1051] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1052]

[1053] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1054]

[1055] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1056]

[1057]

[1058] 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.

[1059] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1060]

[1061] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1062]

[1063] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1064]

[1065] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1066]

[1067] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1068]

[1069] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1070]

[1071] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1072]

[1073] In certain embodiments, in the compound of formula II, the linker C Selected from:

[1074]

[1075] In certain embodiments, in the compound of formula II, the linker C -(Connector A )2Selected from:

[1076]

[1077] In certain embodiments, in the compound of formula II, the linker C -(Connector A )2Selected from:

[1078]

[1079] In certain embodiments, in the compound of formula II, the linker C -(Connector A )2Selected from:

[1080]

[1081] In certain embodiments, in the compound of formula II, the linker C-(Connector A )2Selected from:

[1082]

[1083] In certain embodiments, in the compound of formula II, the linker D Selected from:

[1084]

[1085] In certain embodiments, in the compound of formula II, the linker D Selected from:

[1086]

[1087] Each of which is selected from 1, 2, 3 or 4 21 The substituents are optionally substituted.

[1088] In certain embodiments, in the compound of formula II, the linker B -(Connector A )

[1089]

[1090] In certain embodiments, in the compound of formula II, the linker C -(Connector A )

[1091]

[1092] In certain embodiments, in the compound of formula II, the linker D -(Connector A )

[1093]

[1094] 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)2R 3 .

[1095] In various embodiments, in the compound of Formula II, R 5 are 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.

[1096] 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)2R 3 .

[1097] In various embodiments, in the compound of Formula II, R 8 and R 9 and alkyl, wherein each occurrence is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[1098] In various embodiments, the compound of Formula II has the structure of Formula II-A.

[1099] The compound of formula II-A has the following structure:

[1100]

[1101] in:

[1102] [CPBM] is a circulating protein binding moiety that binds to a circulating protein in a subject, wherein the circulating protein mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject;

[1103] [ASGPBM] is an asialoglycoprotein receptor binding moiety having a structure selected from the group consisting of:

[1104]

[1105]

[1106] Each [CON] is an optional linker chemical moiety which, when present, connects [LIN] to [CPBM] or to [ASGPBM];

[1107] [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;

[1108] Z B Does not exist, is (CH2) IM 、C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M ;

[1109] R M is H or C1-C3 alkyl optionally substituted by one or two hydroxy groups;

[1110] R2 is

[1111] where R AM is H, C1-C4 alkyl optionally substituted with up to 3 halo and one or two hydroxy groups, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 halogen groups KC(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halogen groups, -C(O)-(C1-C4 alkyl) optionally substituted by 1-3 halogen groups, or -(CH2) K -NR N3 R N4 ,or

[1112] R2 is

[1113] in

[1114] R TA It is H, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 halogen groups K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 halogen groups, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 halogen groups K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halogen groups, or -C(O)-(C1-C4 alkyl) optionally substituted by 1-3 halogen groups, or

[1115] R TA It is C3-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 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 halogen groups K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, -O-(C1-C3-alkyl) optionally substituted by 1-3 halogen groups, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 halogen groups K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halogen groups, or -(CH2) optionally substituted by 1-3 halogen groups K C(O)-(C1-C4 alkyl), or

[1116] R TA yes which is optionally substituted with up to three C1-C3 alkyl groups, which are optionally substituted with up to three halo groups; or

[1117] R TA yes

[1118] R N 、R N1 、R N2 、R N3 、R N4 are each independently H or C1-C3 alkyl optionally substituted with one to three halo or one or two hydroxyl groups, and each -(CH2) K The group is optionally substituted by 1-4 C1-C3 alkyl groups, and the C1-C3 alkyl group is optionally substituted by 1-3 fluoro groups or 1-2 hydroxy groups;

[1119] IM is independently an integer from 0 to 6 at each occurrence;

[1120] K is independently an integer from 0 to 4 at each occurrence;

[1121] k' is an integer ranging from 1 to 15;

[1122] j' is an integer ranging from 1 to 15;

[1123] h and h' are each independently an integer ranging from 0 to 15;

[1124] i L It is 0 to 15;

[1125] The premise is h, h' and i L At least one of is at least 1,

[1126] or a salt, stereoisomer or solvate thereof.

[1127] In various embodiments, in the compound of Formula II-A, R2 is -NC(=O)CH3.

[1128] D. Other ASGPR binding sites

[1129] In some embodiments, the ASGPR binding moiety can be any of the moieties described in the following references: 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.

[1130] 1.GalNAc-tyrosine moiety

[1131] 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 Formula II can have one, two, or three ASGPR binding moieties having a structure of M1, M2, M3, or M4.

[1132]

[1133] 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 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.

[1134] 2. Trivalent triazole moiety

[1135] In some embodiments, the ASGPR binding moiety can be a moiety having the structure of M5:

[1136]

[1137] In the structure of M5, each R is independently R1 or R2 at each occurrence,

[1138]

[1139] 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 R1. In various embodiments, each R in M5 is R2.

[1140] In various embodiments, the ASGPR binding moiety M5 can be conjugated / bound to any suitable [CON], [Linker], or [Linker-2] as described herein and in Reshitko, GS, et al., “Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor,” Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00202.

[1141] 3. Galactose-derivatized behenate moiety and agarose-derivatized behenate moiety

[1142] In various embodiments, the ASGPR binding moiety can be a galactosylbehenate-derived moiety M7:

[1143]

[1144] In the structure of M7, Y is OH or NHAc.

[1145] In various embodiments, the ASGPR binding moiety can be an agarose behenate-derived moiety M8:

[1146]

[1147] In various embodiments, the ASGPR binding moieties M7 and M8 can be conjugated to any suitable [CON], [Linker], or [Linker-2] as described herein and in Dhawan, V., et al., “Polysaccharide 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.

[1148] 4. Other small molecule ASGPR binding moieties

[1149] In various embodiments, the ASGPR binding moiety can be any one of the following compounds 2-18:

[1150]

[1151]

[1152] In various embodiments, in compounds 15 and 16, R is CH2OAc, COOH, or CH2OH. 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 on glycoconjugated 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 cycloadditions, amidations, oxidations, alkylations, rearrangement reactions (e.g., Claisen, Cope, etc.), and the like.

[1153] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include: oxygen-containing groups such as alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylates; sulfur-containing groups such as alkyl and arylthioether groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, SO2N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R、(CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N (R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R and substituted or unsubstituted (C1-C 100 ) hydrocarbyl, where R can be hydrogen (in examples including other carbon atoms) or a carbyl moiety, and where the carbyl moiety can be substituted or unsubstituted.

[1154] As defined herein, the term "substituted" as used with a molecule or organic group refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. Substitution may be direct, whereby a hydrogen atom is replaced by a functional group or substituent, or indirect, whereby an intervening linker group replaces a hydrogen atom and the substituent or functional group is bonded to the intervening linker group. A non-limiting example of direct substitution is: RR-H → RR-Cl, where RR is an organic moiety / fragment / molecule. A non-limiting example of indirect substitution is: RR-H → RR-(LL) zz-Cl, wherein RR is an organic moiety / fragment / molecule, LL is an intermediate linker group, and 'zz' is an integer from 0 to 100 (inclusive). When zz is 0, LL is absent and direct substitution occurs. The intermediate linker group L1 is independently selected from -H, -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C≡, -CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, -C(=NR)-, and combinations thereof at each occurrence. (LL) zz It can be linear, branched, cyclic, acyclic, or a combination thereof.

[1155] As used herein, the term "functional group" or "substituent" refers to a group that can be or is substituted onto a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylates; sulfur atoms in groups such as thiol, alkyl and aryl sulfide, sulfoxide, sulfone, sulfonyl, and sulfonamide; nitrogen atoms in groups such as amine, hydroxylamine, nitrile, nitro, N-oxide, hydrazide, azide, and enamine; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be attached to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O(oxo), S(thiocarbonyl), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, S02N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R、(CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SON(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R and C(=NOR)R, wherein R can be hydrogen or a carbonyl moiety; for example, R can be hydrogen, (C1-C 100) hydrocarbon, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl; or wherein two R groups bound to a nitrogen atom or adjacent nitrogen atoms may form a heterocyclyl together with one or more nitrogen atoms.

[1156] As used herein, the term "alkyl" refers to straight and branched chain alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or in various embodiments, 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl groups. Representative substituted alkyl groups may be substituted one or more times by any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy, and halogen groups.

[1157] As used herein, the term "alkenyl" refers to straight and branched chains and cyclic alkyl groups as defined herein, except that there is at least one double bond between two carbon atoms. Thus, an alkenyl group has 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or 2 to 8 carbon atoms in various embodiments. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, etc.

[1158] As used herein, the term "alkynyl" refers to straight and branched chain alkyl groups, except that there is at least one triple bond between two carbon atoms. Thus, an alkynyl group has 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in various embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc.

[1159] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bound via the carbonyl carbon atom. The carbonyl carbon atom is bound to a hydrogen forming a "formyl" group or to another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, or similar group. An acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bound to the carbonyl group. An acyl group may include double or triple bonds within the meaning herein. Acryloyl is an example of an acyl group. Acyl groups may also include heteroatoms within the meaning herein. Nicotinoyl (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, among others. When the group containing the carbon atom bound to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is trifluoroacetyl.

[1160] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl further includes polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings such as, but not limited to, decahydronaphthyl. Cycloalkyl groups also include rings substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl or mono-, di-, or tri-substituted norbornyl or cycloheptyl, which may be substituted, for example, with amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy, and halogen groups. The term "cycloalkenyl," used alone or in combination, refers to a cyclic alkenyl group.

[1161] The term "heterocycloalkyl" as used herein refers to a cycloalkyl group as defined herein wherein one or more carbon atoms in the ring are replaced with a heteroatom such as O, N, S, P, etc., each of which may be substituted as described herein if open valences are present, and each heteroatom may be in any suitable stable oxidation state.

[1162] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group containing no heteroatoms in the ring. Thus, aryl includes, but is not limited to, phenyl, azulenyl, heptenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthyl, In some embodiments, the aryl group contains about 6 to about 14 carbon atoms in the ring portion of the group. As defined herein, the aryl group can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or substituted more than once, such as, but not limited to, phenyl substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring or naphthyl substituted at any one or more of the 2-8-positions thereof.

[1163] As used herein, the term "aralkyl" refers to an alkyl group as defined herein in which a hydrogen bond or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenethyl, as well as fused (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen bond or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[1164] As used herein, the term "heterocyclyl" refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, a heterocyclyl group can be a cycloheteroalkyl group or a heteroaryl group, or, if polycyclic, any combination thereof. In some embodiments, a heterocyclyl group includes 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings in which the CH2 group in the ring is replaced by one or more C=O groups, such as those found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing C=O groups include, but are not limited to, β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam, as well as the corresponding lactones. A heterocyclyl group designated as a C2-heterocyclyl group can be a 5-ring having two carbon atoms and three heteroatoms, a 6-ring having two carbon atoms and four heteroatoms, and the like. Similarly, a C4-heterocyclyl group can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so on. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. The heterocyclyl ring may also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, dioxolane and benzodioxolane ring systems (methylenedioxyphenyl ring systems) are heterocyclyl groups within the meaning of this article. The phrase also includes polycyclic systems containing heteroatoms, such as, but not limited to, quinoline. The heterocyclyl group may be unsubstituted or substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso oxazolyl, thiazolyl, pyridyl, phenylthio, benzophenylthio, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolinyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzo oxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, iso Representative substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with those groups listed herein.

[1165] As used herein, the term "heteroaryl" refers to an aromatic cyclic compound containing 5 or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, and S; for example, a heteroaryl ring can have 5 to about 8-12 ring members. A heteroaryl is a type of heterocyclic group that has an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring containing two carbon atoms and three heteroatoms, a 6-ring containing two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so on. The sum of the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heteroaryl group designated as a C x-y The heterocyclyl ring may be any ring containing "x" members up to "y" members (including all intermediate integers between "x" and "y") and containing one or more heteroatoms as defined herein. x-y In the ring, all non-heteroatom members are carbon. x-y The heterocyclyl ring may also be a polycyclic system, such as a bicyclic or tricyclic system. Heteroaryl includes, but is not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso oxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzo oxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, iso The heteroaryl groups may be unsubstituted or substituted with groups as discussed herein. Representative substituted heteroaryl groups may be substituted one or more times with the groups listed herein.

[1166] Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, Oxazolyl, iso oxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), Azolyl (2- Azolyl, 4- Azolyl, 5- oxazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridinyl (2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl), quinolinyl, 8-isoquinolinyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), [b]furyl), 7-(2,3-dihydro-benzo[b]furyl), benzo[b]thienyl (2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), 2,3-dihydro-benzo[b]thienyl, (2-(2,3-dihydro-benzo[b]thienyl), 3-(2,3-dihydro-benzo[b]thienyl), 4-(2,3-dihydro-benzo[b]thienyl), 5-(2,3-dihydro-benzo[b]thienyl) thienyl), 6-(2,3-dihydro-benzo[b]thienyl), 7-(2,3-dihydro-benzo[b]thienyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzo Azolyl (1-benzo Azolyl, 2-benzo oxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H- dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), and the like.

[1167] The term "heterocyclylalkyl" as used herein refers to an alkyl group as defined herein, wherein a hydrogen bond or a carbon bond of the alkyl group as defined herein is replaced by a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[1168] The term "aralkyl" as used herein refers to an alkyl group, as defined herein, wherein a hydrogen bond or a carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[1169] The term "heteroaralkyl" as used herein refers to an alkyl group, as defined herein, wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group, as defined herein.

[1170] As used herein, term "alkoxy" refers to an oxygen atom connected to an alkyl group (including cycloalkyl) as defined herein. The example of a straight chain alkoxy group includes but is not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. The example of a branched chain alkoxy group includes but is not limited to isopropyloxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. The example of a cycloalkoxy group includes but is not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy can include approximately 1 to approximately 12, approximately 1 to approximately 20, or approximately 1 to approximately 40 carbon atoms that are combined with an oxygen atom, and can further include a double bond or triple bond, and can also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups within the meaning of this article, as are the methylenedioxy groups in the case where two adjacent atoms of a structure are substituted with them.

[1171] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group) 3, wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, wherein each R is independently selected, such as dialkylamines, diarylamines, arylalkylamines, heterocyclylamines, and the like; and R3N, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

[1172] As used herein, the term "amino" refers to -NH2, -NHR, -NR2, -NR3 + Substituents of the form wherein each R is independently selected, and the protonated form of each, except -NR3 which cannot be protonated + Therefore, any compound substituted with an amino group can be considered an amine. In the meaning of this article, "amino" can be a primary amino group, a secondary amino group, a tertiary amino group or a quaternary amino group. "Alkylamino" includes monoalkylamino, dialkylamino and trialkylamino groups.

[1173]

[0046] The terms "halo," "halogen," or "halide" as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[1174] As used herein, the term "haloalkyl" group includes monohaloalkyl, polyhaloalkyl, which may have all the halogen atoms the same or different, and perhaloalkyl, in which all hydrogen atoms are replaced by halogen atoms such as fluorine. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[1175] As used herein, the term "epoxy-functional" or "epoxy-substituted" refers to a functional group in which an oxygen atom, ie, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5-epoxypentyl, 2,3-epoxypropoxy, glycidoxypropyl, 2-epoxypropoxyethyl, 3-epoxypropoxypropyl, 4-epoxypropoxybutyl, 2-(epoxycarbonyl)propyl, 3-(3,4-epoxycyclohexyl)propyl, 2-(3,4-epoxycyclohexyl)ethyl, 2-(2,3-epoxycyclopentyl)ethyl, 2-(4-methyl-3,4-epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcyclohexyl)-2-methylethyl, and 5,6-epoxyhexyl.

[1176] As used herein, the term "monovalent" refers to a substituent that is attached to the substituted molecule via a single bond. When a substituent is monovalent, such as, for example, F or Cl, it is attached to the atom it replaces via a single bond.

[1177] As used herein, the term "hydrocarbon" or "hydrocarbyl" refers to a molecule or functional group that includes carbon atoms and hydrogen atoms. The term can also refer to a molecule or functional group that typically includes both carbon atoms and hydrogen atoms but in which all hydrogen atoms are replaced by other functional groups.

[1178] As used herein, the term "hydrocarbyl" refers to a functional group derived from a linear, branched, or cyclic hydrocarbon and may be an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. a -C b )alkyl, wherein a and b are integers and mean having any one of a to b carbon atoms. For example, (C1-C4)alkyl means that the alkyl group can be methyl (C1), ethyl (C2), propyl (C3) or butyl (C4), and (C0-C b ) hydrocarbyl means in certain embodiments that there is no hydrocarbyl group.

[1179] As used herein, the term "C 6-10 5-6 membered heterobiaryl refers to a C group covalently bound to a 5- or 6-membered heteroaryl moiety via a single bond. 6-10 Aryl moiety. C 6-10 The aryl moiety and the 5-6 membered heteroaryl moiety can be any suitable aryl and heteroaryl groups described herein. 6-10 Non-limiting examples of 5-6 membered heterobiaryl groups include:

[1180]

[1181] When C 6-10 When a 5-6 membered heterobiaryl group is listed as a substituent (e.g., as an "R" group), C 6-10 5-6 membered heterobiaryl groups through C 6-10 part binds to the rest of the molecule.

[1182] As used herein, the term "5-6 C 6-10 Heterobiaryl" and C 6-10 5-6 membered heterodiaryl is the same except that when the 5-6 membered C 6-10 When a heterobiaryl group is listed as a substituent (e.g., as an "R" group), a 5-6 membered C 6-10 The heterobiaryl group is bound to the rest of the molecule via the 5-6 membered heteroaryl moiety.

[1183] As used herein, the term "C 6-10 -C 6-10"Diaryl" means a group bonded to another C 6-10 The aromatic moiety is covalently bound to the C 6-10 Aryl moiety. C 6-10 The aryl moiety may be any suitable aryl group described herein. 6-10 -C 6-10 Non-limiting examples of diaryl groups include biphenyl and binaphthyl.

[1184] 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 fluid of the patient's gastrointestinal tract to promote 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 well known in the pharmaceutical art. Sodium salts and potassium salts are used as neutralized salts of the 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.

[1185] The term "co-administered" 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 is present in the patient's body at a given point in time. Although the 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. The 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 the symptoms of cancer, particularly prostate cancer, including metastatic prostate cancer.

[1186] The term "anticancer agent" or "additional anticancer agent" refers to a compound other than a chimeric compound according to the present disclosure that 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, nolatrexed, AZD2171, batabulin, ofatumumab,Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-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, acetate of [D-Ser(Bu t)6,Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate) [C, 59 H84 N 18 Oi4-(C2H4O2) X, wherein x = 1 to 2.4], goserelin acetate, leuprolide acetate, 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 acetate, 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, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil 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 Tamoxifen (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, metoclopramide 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.

[1187] In addition to anticancer agents, a variety of other agents can 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 have shown some efficacy in inhibiting cancer tissue or its growth, or are otherwise useful in treating cancer. For example, one or more of 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.

[1188] Without being limited by theory, the compounds according to the present disclosure comprising a CPBM binding portion (CPBM) and a CRBM / ASGPR binding portion selectively bind to circulating proteins and, through this binding, promote the introduction of the cellular protein into hepatocytes or other cells (degradative cells) that selectively bind to the CRBM / ASGPRBM, wherein the circulating protein is degraded within the hepatocytes or other degradative cells 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 that is particularly effective for treating disease states and conditions.

[1189] Pharmaceutical compositions comprising an effective amount of at least one compound disclosed herein, typically a bifunctional chimeric compound according to the present 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, all in an effective amount in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent further aspects of the present disclosure. These compounds may be used in combination with at least one additional, optional anticancer agent, as disclosed herein.

[1190] The compositions of the present disclosure can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, or can be administered in the form of a controlled release formulation. 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.

[1191] The compositions of the present disclosure are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally (including via cannula through the mouth or nose into the stomach), intraperitoneally, or intravenously.

[1192] The sterile injectable forms of the compositions of the present disclosure can be aqueous or oily suspensions. These suspensions can be formulated 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 a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil (especially its polyoxyethylated forms). These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[1193] The pharmaceutical compositions of the present disclosure can be orally administered in any orally 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 also 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 desired, certain sweeteners, flavorings, or coloring agents may also be added.

[1194] 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.

[1195] The 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 areas 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.

[1196] 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.

[1197] 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.

[1198] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably 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 the form of an ointment such as petrolatum.

[1199] 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 enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[1200] The amount of compound that can be combined with the carrier materials 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, and preferably, the composition should be 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 the 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.

[1201] Methods of treating a patient or subject in need thereof for a specific disease state or condition as described elsewhere herein (particularly cancer) comprise 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 according to the present disclosure. The amount of active ingredient(s) used in the treatment methods of the present disclosure that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated, the particular mode of administration, and the specific mode of administration. For example, the compositions can be formulated so that 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, a therapeutically effective dose of greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg / kg patient / day of the novel compound can be administered to a patient receiving these compositions.

[1202] 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.

[1203] 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, preferably agents that can assist in the treatment of autoimmune diseases and / or inflammatory diseases or cancer (including metastatic cancer or recurrent cancer) or improve secondary effects and / or symptoms associated with these disease states and / or conditions. This treatment can also be administered in combination with other conventional therapies such as radiation therapy or cancer surgery.

[1204] The present compounds, alone or in combination with other agents described herein, can be administered by any suitable route (e.g., oral, parenteral, intravenous, intradermal, subcutaneous, or topical), in liquid, cream, gel, or solid form, or by aerosol.

[1205] The amount of active compound included in the pharmaceutically acceptable carrier or diluent is sufficient to deliver a therapeutically effective amount to the patient for the desired indication without causing serious toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein range from about 10 ng / kg to 300 mg / kg per day, preferably 0.1 to 100 mg / kg per day, more usually 0.5 to about 25 mg / kg per day of the recipient / patient's body weight. Typical topical dosages will range from about 0.01-3% wt / wt in a suitable carrier.

[1206] 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, preferably 5 to 500 mg of active ingredient per unit dosage form. Oral dosages of about 25-500 mg are generally convenient.

[1207] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, preferably 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.

[1208] 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 particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising 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.

[1209] Oral compositions will typically include an inert diluent or edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with an excipient and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and / or auxiliary materials can be included as part of the composition.

[1210] 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, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. When the 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. Furthermore, 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.

[1211] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. In addition to the active compound, a syrup may contain sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavors.

[1212] 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, antifungals, or antiviral compounds. In certain preferred aspects of the present disclosure, one or more chimeric / bifunctional CPBM binding compounds according to the present disclosure are co-administered with another anticancer agent and / or another biologically active agent, as described elsewhere herein.

[1213] 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 in ampoules, disposable syringes or multiple-dose vials made of glass or plastic.

[1214] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[1215] 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.

[1216] 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 and then evaporating, thereby leaving a thin film of dried lipids on the surface of the container. The aqueous solution of the active compound is then 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.

[1217] Chemical synthesis

[1218] Attached to this article Figure 1 、 Figure 7 and Figure 13 Specific compounds according to the present disclosure have been identified that exhibit activity in binding to 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 to which an ASPGR group, such as a GN3 or AcF3-3 group, is covalently linked 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, optionally linked via a [CON] group, such as a 1,2,3-triazole or other [CON] group as described herein.

[1219] Figure 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 precursors) to provide carboxylic acid-terminated intermediates that can be used to provide bifunctional molecules.

[1220] Figure 17 A general method for converting PEG molecules into hydroxy azides is described. The PEG compound is tosylated (TsCl, DCM, in the presence of a base) at reduced temperature and further reacted with sodium azide in a non-nucleophilic solvent at elevated temperature. The final azido alcohol is used in the following figure.

[1221] Figure 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.

[1222] Figure 19 Shown is the synthesis of a GalNAc ASGPR ligand linked to a terminal amine via PEG. Pentaacetyl galactosamine reacts with TMSOTf in DCE at elevated temperatures to form a bicyclic intermediate, which then reacts with azido alcohol to yield the azido intermediate (TMSOTf, DCE). This molecule then undergoes a Staudinger reduction to yield the amine, which is used in the following figure.

[1223] Figure 20 The synthesis of a high-affinity bicyclic ASGPR ligand is demonstrated. Galactose pentaacetate was treated with HBr / AcOH to yield a bromide intermediate, which was then treated with Zn and CuSO₄ (water / AcOH) to yield the galactaldehyde. Treatment with ceric ammonium nitrate and sodium azide at reduced temperature (MeCN) yielded a disubstituted intermediate compound. This was then treated with a strong base (NaOH / MeOH) to yield a triol azide intermediate. This compound was 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 afforded a tetraol intermediate, which was then cyclized in a strong acid (H₂SO₄ / water) to yield the bicyclic azide ligand.

[1224] Figure 21 Shown is the synthesis of trifluoroacetate derivatives of bicyclic ASGPR ligands. Triol azides are reduced (Pd / C, MeOH) to intermediate amines, which are then peracylated with trifluoroacetic anhydride. These esters are hydrolyzed with a strong base (NaOMe / HOMe) to intermediate amides, which are protected with dimethoxypropane in the presence of camphorsulfonic acid in DMF at elevated temperatures. These amides are then reacted with mesylated azido alcohols in the presence of a strong base (NaH / DMF) to yield intermediate azides, which are then reduced (Lindella's catalyst, MeOH) to yield the final amines.

[1225] Figure 22 The synthesis of the MIF targeting linker as a monovalent linker is shown, which was synthesized by a method similar to that described in the previous figure. The boc-protected methyl ester was deprotected with TFA in DCM and then coupled with a MIF targeting carboxylic acid (HBTU, DIPEA, DMF). Subsequent hydrolysis with a strong base (NaOH / dioxane / HO) gave the MIF targeting carboxylic acid.

[1226] Figure 23 Shown is the synthesis of the dicarboxylic acid MIF targeting motif, which was synthesized as described in the previous figure.

[1227] Figure 24 Shown is the synthesis of a tris-base-derived trivalent linker. Treatment of the tris base with di-tert-butyl dicarbonate in the presence of a base affords a BOC-protected triol, which then reacts with acrylonitrile in the presence of a base (dioxane / HO) to afford the 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 affords the tricarboxylic acid used in the following figure.

[1228] Figure 25 The synthesis of an ASGPR targeting moiety 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).

[1229] Figure 26 Shown is the synthesis of the tricarboxylic acid MIF targeting motif, which was synthesized as described in the previous figure.

[1230] Figure 27 Shown is the synthesis of a MIF NVS alkyne precursor, which can be reacted with a carboxylic acid-containing azide reactant (as illustrated in the following figure) to provide a MIF-NVS-carboxylic acid-terminated reactant, thereby producing a bifunctional compound according to the present disclosure.

[1231] Figure 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 yield 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 yield the ethyl ester intermediate, which was then hydrolyzed with a strong base (NaOH / dioxane) to yield the carboxylic acid, used in the following figures.

[1232] Figure 29 The synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3 by HBTU-mediated coupling of an ASPGR-targeting amine with a MIF-targeting carboxylic acid in DMF is described. It is prepared by first condensing the reactant azidoPEG-carboxylic acid onto a MIF moiety containing an alkyne-terminated PEG group to form the MIF-targeting carboxylic acid.

[1233] Figure 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.

[1234] Figure 31 The synthesis of a bifunctional molecule targeting MIF and ASGPR containing a bicyclic ASGPR AcF3 ligand is described. The MIF-binding monocarboxylic acid is treated with HBTU, DIPEA, an amine-terminated ligand, and DMF to form an amide, which is then deprotected with 1 M HCl to afford the final compound.

[1235] Figure 32 The synthesis of a bifunctional molecule targeting MIF and ASGPR containing two bicyclic ASGPr ligands is described. It was synthesized as described above.

[1236] Figure 33 The synthesis of a bifunctional molecule targeting MIF and ASGPR containing three bicyclic ASGPr ligands is described. It was synthesized as described above.

[1237] Figure 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 dinitro analine carboxylic acid intermediate. Further steps are performed as described for the previous molecule.

[1238] Figure 35 The synthesis of DNP-AcF3-3 is shown and was performed using a method similar to that of the previous compound.

[1239] Figure 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 temperature to give the azido alcohol. This compound is then oxidized using Jones' reagent and 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 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.

[1240] Figure 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]heptan-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.

[1241] Figure 38 The synthetic scheme for obtaining FcIII-GN3 is shown. This hexyl peptide was prepared using standard solid-phase peptide synthesis techniques. The peptide was removed from 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 was reacted with GN3-azide to obtain the product triazole FcIII-GN3.

[1242] Figure 39 Shown is a synthetic scheme to obtain FcIII-4c-GN3, which was accomplished using the methods described above.

[1243] Figures 40-43 The synthesis of bifunctional molecules targeting MIF and ASGPr is described, 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 and are illustrated in the accompanying figures.

[1244] Figure 44 The synthesis of compound MIF-18-3 is shown. The triacylgalactaldehyde is deprotected with ammonia in methanol, and the tribenzyl group is then protected with benzyl bromide in the presence of a base. The olefin is hydrolyzed with HCl in THF / H2O overnight and then oxidized with PCC to give the aldehyde. Sodium azide is then added to the carbonyl group with KHMDS and TIBSN3 at 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 in the presence of BF3-Et2O at reduced temperature. 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 elevated temperature. The remainder of the synthesis is carried out as described for the previous molecule.

[1245] Figure 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 provide the allylic intermediate. Treatment with pivaloyl chloride in pyridine provides the di-Piv-protected intermediate, which is then treated with trifluoromethanesulfonic anhydride and hydrolyzed in water at elevated temperatures. Treatment with NaOMe in MeOH removes the pivaloyl group to provide the allyl triol intermediate. Subsequent steps are performed as described for the previous molecule.

[1246] Figure 46 Shown is the synthesis of compound MIF-15-3, which was synthesized using a similar method to the above compounds.

[1247] Figure 47 The synthesis of compound MIF-19-3 is shown. This molecule was synthesized by a late-stage 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.

[1248] Figure 48 Shown is the synthesis of compound MIF-16-3, which was synthesized using a similar procedure to the above compounds.

[1249] Figure 49 Shown is the synthesis of compound MIF-20-3, which was synthesized using a similar procedure to the above compounds.

[1250] Figure 50 Shown is the synthesis of compound MIF-14-3, which was synthesized using a similar procedure to the above compounds.

[1251] Figure 51 Shown is the synthesis of compound MIF-21-3, which was synthesized using a similar procedure to the above compounds.

[1252] Figure 52The synthesis of the compound MIF-NVS-PEGN-GN3 is shown. The PEG compound is treated with p-toluenesulfonyl chloride in the presence of a base, followed by sodium azide at elevated temperature to produce the azido alcohol. These intermediates are oxidized using Jones reagent to produce the carboxylic acid azide. Diethylene glycol is treated with a base and propargyl bromide, respectively, to produce the alkynyl alcohol, which is then tosylated in the presence of a base and subsequently treated with sodium iodide to produce the iodinated intermediate. This iodinated compound is then treated with 4-N-boc-aminophenol in the presence of a base to produce the ether intermediate, which is then treated with hydrochloric acid in dioxane to produce the aminoalkyne. This amine is reacted with 2-hydroxy-4-(tert-butyldimethylsilyloxy)benzaldehyde in the presence of sodium borohydride to produce the cyclic intermediate, which is then treated with TBAF in THF to produce the resulting alcohol. A CuI-mediated cyclization is then performed between this alkyne and the azide in acetonitrile. The resulting carboxylic acid is reacted with NH2-GN3 as described in the previous scheme.

[1253] Figures 53-66 The synthesis of multiple MIF binding compounds with various ASGPRBM moieties is shown. These compounds were synthesized by methods similar to those described above.

[1254] Figures 70-88 The synthesis of various other bifunctional compounds according to the present disclosure is shown.

[1255] Example

[1256] 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 terminated with sialic acid. As proteins age, terminal sialic acid residues are removed by circulating endogenous glycosidases. This natural protein aging process exposes galactose and N-acetylgalactose (GalNAc) residues, which bind to asialoglycoprotein receptors (ASGPRs) on the surface of hepatocytes.

[1257] 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. 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), allowing ASGPR to recycle back to the hepatocyte surface. The endocytosed proteins are then trafficked to late endosomes, which fuse with lysosomes. Lysosomal proteases then degrade the endocytosed proteins, permanently removing them from the circulation.

[1258] It is known that non-glycosylated proteins are not natural targets of ASGPR. One such protein is macrophage inhibitory factor (MIF), a 12.5 kDa protein that may have catalytic activity. Genetic depletion or antibody neutralization of MIF has been shown to have positive results in models of sepsis, multiple sclerosis, rheumatoid arthritis, and burn recovery. A bifunctional molecule for the degradation of circulating MIF has been proposed that utilizes ASGPR as a gateway for proteins 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 to ASGPR.

[1259] Biological data

[1260] Various compounds according to the present disclosure were tested to determine their biological activity. The active compounds are shown in Figure 1 、 Figure 7 and Figure 13 The results of the biological experiments are described below.

[1261] Figure 1 Representative compounds according to the present disclosure are shown. Note that compounds 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 preferably ranges from 1-12, 1 to 10, 2 to 8, 2 to 6, 2 to 5, or 1, 2, 3, or 4.

[1262] The results are shown in Figure 2 In the experiment, A. Fluorescence polarization data of MIF-FITC binding to human MIF demonstrates that the MIF-binding moieties of the present disclosure bind to MIF. B. The bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3, and NVS-PEG3-GN3 competitively bind to MIF-FITC, demonstrating that the bifunctional molecules maintain the ability to bind to human MIF.

[1263] The results are shown in Figure 3 In an 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 weeks 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 0.3 cm 2) were used for the experiment. HepG2 cells were grown to 90% confluence in RPMI culture medium, then washed with PBS (2x) and treated with serum-free culture medium (optimem+.1% BSA,+Pen / Strep) and compound (where applicable) containing 100nM huMIF (Cayman Chemical). Compounds were diluted with the 1mM stock solution in DMSO. After 24 hours, supernatant samples (2uL) were collected, diluted 1:100, and analyzed for MIF content (and incubated for 24 hours in the presence or absence of compound) by sandwich ELISA. The remaining MIF levels were determined by sandwich ELISA (biolegend monoclonal anti-MIF antibody and biotinylated anti-MIF antibody). The data represent the mean values ​​of at least 3 biological replicates, and the error bars represent standard deviations. After 24 hours, up to 95.3% of MIF was exhausted from cell culture medium (in the case of MIF-AcF3-3).

[1264] Figure 4 The results of the experiment for determining whether MIF internalized by HepG2 cells is transported to lysosomes are shown. In this experiment, cells were incubated with 100nM rhuMIF (Cayman) and 200nM MIF-GN3 at a concentration of 100nM. After 12 hours, cells were fixed with formaldehyde, permeabilized, and probed with anti-Lamp2 antibody (mouse monoclonal, Abcam), polyclonal rabbit anti-MIF antibody (Thermo) and Alexa-488-labeled anti-mouse antibody and Alexa 568-labeled anti-rabbit antibody to demonstrate internalization in lysosomes.

[1265] 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 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 ). MIF-GN3 was then injected at the indicated concentrations and 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. In mice treated with MIF-GN3, moderate increases in huMIF levels were seen, up to 20 ng / ml, while in mice injected with PBS negative control, serum levels as high as 150 ng / ml were observed, demonstrating a significant decrease in huMIF levels after administration of MIF-GN3.

[1266] Figure 6 MIF-GN3 has been shown to slow tumor growth in a mouse model of prostate cancer. In this experiment, nude mice were implanted with PC3 human prostate cancer cells. Treatment with a non-bifunctional MIF inhibitor (3 weeks), an anti-MIF antibody, or MIF-GN3 was immediately initiated. Over the course of the experiment, MIF-GN3 was shown to slow tumor growth, comparable to that of a MIF-neutralizing antibody. The lack of tumor growth inhibition after 3 weeks confirms the importance of MIF degradation for therapeutic efficacy.

[1267] 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.

[1268] Figure 8 DNP-GN3 and DNP-AcF3-3 were shown to mediate ternary complex formation between HepG2 cells and anti-DNP, validating the bifunctional nature of these molecules. In this experiment, HepG2 cells expressing ASGPR were incubated with the bifunctional molecules and Alexa-488-labeled anti-DNP (Thermo). The readout was the mean fluorescence intensity of the cell population. Fluorescence was measured using flow cytometry.

[1269] In another experiment, the results are shown in Figure 9 In Figure 3, it is shown that DNP-GN3 and DNP-AcF3-3 mediate the uptake of Alexa 488-labeled anti-DNP in 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.

[1270] Figure 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 colocalization studies.

[1271] These experimental results are shown in Figure 11 In, show that DNP-AcF3-3 mediates the degradation of the anti-DNP of alexa 488 mark in HepG2 cells.In this experiment, cells are incubated with the anti-DNP (Thermo) of 1uM alexa 488 mark and 200nM DNP-AcF3-3. At given time, cell lysis (RIPA in PBS, containing protease inhibitors) and measured by SDS-PAGE gel. Reading is the fluorescence of protein fragments.

[1272] These results are shown in Figure 12In 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 was used as a non-bifunctional control molecule.

[1273] Figure 13 The structures of the IgG-degrading molecules IBA-GN3, triazine-GN3, FcIII-GN3, and FcIII-4c-GN3 are shown.

[1274] Figure 14 This study demonstrated that FcIII-GN3 mediates the uptake of human IgG into HepG2 cells.

[1275] Figure 15 FcIII-GN3 was shown to mediate the localization of IgG to late endosomes in HepG2 cells. The experiment was performed as described above. Additional biological data for compounds containing different CRBM groups

[1276] A cell line expressing a high level of the cellular receptor is selected. These cells are known in the art and most are commercially available. The cells are treated with the bifunctional molecule and the target protein. The target protein is measured in the cell supernatant and / or cell lysate by ELISA. The molecule shows that the uptake of the target protein is time-dependent and concentration-dependent as measured by ELISA.

[1277] Alternatively, the target protein is labeled with an NHS fluorophore and taken up by cells. This uptake is time-dependent and concentration-dependent. Uptake is measured by flow cytometry, which counts cells based on their fluorescence. Uptake of the fluorophore-protein conjugate is correlated with an increase in cellular brightness.

[1278] In addition, also measure the ability that compound causes target protein to be localized to lysosome.With target protein and compound treatment cell, incubate several hours (usually about 6-24 hours), and fix with standard method (paraformaldehyde, acetone).Use orthogonal first antibody (anti-Lamp2 and anti-target protein) to locate lysosome and target protein, then add fluorescently labeled second antibody.The total localization of fluorescence is corresponding with target protein localization to lysosome, shows that they are endocytosed and transported to degradation organelle.

[1279] Compounds are also tested in mice, where the target protein is injected and then treated with the compound consistent with its activity in in vitro or cell-based assays. Weeks of compound treatment result in a reduction in circulating target protein levels.

[1280] 1. MIF binding molecules ( Figure 13 )

[1281] MIF-1

[1282]

[1283] 2-Chloroquinoline-6-ol (1.00 g, 5.57 mmol) and K2CO3 (1.53 g, 11.1 mmol, 2.0 eq) were 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 to ethyl acetate and washed with water (2x) and salt solution (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. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.40-7.32 (m, 2H), 7.07 (d, J = 2.7 Hz, 1H), 4.20-4.09 (m, 5H), 2.56 (t, J = 7.2 Hz, 2H), 2.19 (t, J = 6.7 Hz, 2H), 1.26 (t, J = 7.1 Hz, 4H). 13 C NMR (101MHz, CDCl3) δ173.24,157.46,148.18,143.87,137.83,130.05,128.06,1 23.40,122.67,106.20,77.48,77.16,76.84,67.30,60.69,30.87,24.63,14.39. HRMS:[M+H] + Expected value 294.090, measured value 294.11.

[1284] MIF-2

[1285]

[1286] Compound 30 (1.52 g, 5.17 mmol) was dissolved in THF (20 mL) and triethylamine (2.88 mL, 20.7 mmol, 4 eq). Copper (I) iodide (49.0 mg, 0.258 mmol, 0.05 eq), Pd(PPh3)2Cl2 (181 mg, 0.258 mmol, 0.05 eq), and TMS-acetylene (1.07 mL, 762 mg, 7.75 mmol, 1.5 eq) were then 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. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.00 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.43-7.33 (m, 1H), 7.04 (d, J = 2.2 Hz, 1H), 4.15 (dt, J = 12.7, 6.5 Hz, 4H), 2.56 (t, J = 7.2 Hz, 2H), 2.24-2.13 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.30 (s, 9H). 13 CNMR(151MHz, CDCl3)δ173.07,124.73,105.65,67.11,60.51,30.67,24.42,14.21,-0.27. HRMS:[M+H] + Expected value 356.168, measured value 356.505.

[1287] MIF-3

[1288]

[1289] program

[1290] 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. 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). 13C NMR (151MHz, CDCl3) δ173.06,137.60,129.91,128.64,124.50,123.18,122.48,105.99,10 5.58,77.20,76.99,76.77,67.12,60.51,59.14,30.67,24.42,24.22,19.80,14.21,13.69. HRMS:[M+H] + Expected value 284.129, measured value 284.327.

[1291] MIF-4

[1292]

[1293] 2-Fluoro-4-iodophenol (126 mg, 0.529 mmol) and sodium azide (38 mg, 0.528 mmol, 1.0 eq) were dissolved in DMSO (2.5 mL) and stirred at 70 ° for 2 hours. Compound 32 (150 mg, 0.529 mmol, 1 eq), trans-N, N'-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol, 0.15 eq), sodium ascorbate (10 mg, 0.053 mmol, 0.1 eq), copper (I) iodide (15 mg, 0.079 mmol, 0.15 eq) and H2O (2.5 mL) were then added and the mixture was stirred overnight at 70 °. The reaction was diluted with ethyl acetate and washed with H2O (1x) and brine (1x). The organic layer was dried over sodium sulfate, evaporated, and purified on silica (DCM / EtOAc) to give compound 33. 1 H NMR (600MHz, DMSO-d6) δ10.46(s,1H),9.32(s,1H),8.39(d,J=8.6Hz,1H),8.23(d,J=8. 5Hz,1H),7.95(dd,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). 13C NMR(151MHz,DMSO-d6)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. HRMS: expected value 437.163, measured value 437.164.

[1294] MIF-5

[1295]

[1296] 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 point it was diluted with water and the pH adjusted to 3-4 with 1M HCl. The mixture was cooled to 4°C and filtered to afford compound 34, which was used without further purification.

[1297] 2.GaINAc spacer ( Figure 14 )

[1298]

[1299] 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. 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). 13CNMR(101MHz, CDCl3)δ144.98,133.09,129.95,128.09,72.58,70.91,70.44,69.28,68.84,61.88,21.76.

[1300]

[1301] Compound 64 (2.00 g, 6.57 mmol) and sodium azide (0.470 g, 7.23 mmol, 1.1 eq) were dissolved in DMF (40 mL) and stirred at 60 ° overnight. 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.

[1302] 3.GaINAc ASGPR ligand ( Figure 15 )

[1303]

[1304] Galactosamine pentaacetate (100 mg, 0.257 mmol) was dissolved in dichloroethane (1 mL) and stirred at room temperature before the addition of TMSOTf (70 uL, 86.0 mg, 0.387 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 afford compound 66 (0.236 mmol, 77.7 mmol, 92%) as a dark gum, which was used without further purification. 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). 13C NMR (101MHz, CDCl3) δ170.46,170.13,169.78,166.35,121.82,118.64,101.41,71 .76,69.44,65.25,63.53,61.56,46.82,20.77,20.68,20.54,14.41,8.64,-0.06.

[1305]

[1306] Compound 66 (200 mg, .607 mmol) and compound 65 (160 mg, .913 mmol, 1.5 eq) were dissolved in 1,2-dichloroethane (5 mL). Molecular sieves were added and the reaction was stirred for 30 minutes. TMSOTf (55 mL, 67.5 mg, 0.304 mmol, 0.5 eq) 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 (245 mg, 0.486 mmol) in 80.1% yield. 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). 13 C NMR (101MHz, CDCl3) δ170.24,170.09,169.99,101.84,72.06,71.27,70.50,70.29,70.27,70.20,7 0.00,69.98,69.67,69.37,68.18,66.30,61.38,61.17,50.32,50.26,50.11,22.80,20.37,20.31. HRMS:[M+Na] + 527.207 Measured value 527.203

[1307]

[1308] 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 mL, 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.

[1309] 4. Trivalent glycine ( Figure 16 )

[1310]

[1311] 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 the other steps without purification.

[1312]

[1313] 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 under nitrogen for 24 hours. 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. 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).

[1314]

[1315] 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. 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. 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). 13 C NMR (101MHz, CDCl3) δ172.03,72.52,66.77,56.10,51.62,34.80.

[1316]

[1317] 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. The MeCN was then evaporated, and the residue was adsorbed onto silica and purified using a gradient of 0-75% EtOAc in hexane. Compound 71 (866 mg, 1.52 mmol) was recovered in 80% yield. 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). 13 C NMR (151MHz, cdcl3) 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. HRMS Expected:[M+H] + 571.250, measured value 571.243.

[1318]

[1319] Compound 71 (100 mg, 0.175 mmol) was dissolved in dioxane (2 mL) and 2 M NaOH (2 mL). The reaction was stirred for 3 hours, then acidified and extracted twice into ethyl acetate. The organic fraction was washed with 1 M HCl, then dried over sodium sulfate and evaporated to give compound 72, which was used in the other steps without purification.

[1320] 5.GaINAc trivalent ( Figure 17 )

[1321]

[1322] Compound 72 (372 mg, 0.704 mmol, 1 eq) was dissolved in DMF (40 mL) and DIPEA (981 mL, 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, then 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 afford compound 73 (831 mg, 0.436 mmol) in a 62% yield. 1 H NMR(500MHz,DMSO-d6)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 ),3.23-3.16(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). 13C 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.

[1323]

[1324] Compound 73 (710 mg, 0.372 mmol) was dissolved in dry methanol (90 mL) and cooled to 0°C under nitrogen. Pd / C (71.0 mg, 10% w / w) was then added, and the reaction was stirred at 0°C under hydrogen (1 atm) for 16 hours. After completion of the reaction, the product was filtered through Celite and the methanol evaporated to afford compound 74 (657 mg, 0.370 mmol) in a 99.5% yield, which was used without further purification.

[1325] Compound 74 (441 mg, 0.248 mmol) was dissolved in methanol (15 mL) and cooled to 0°. Sodium methoxide solution (400 mL, 5.4 M in MeOH) was then added, and the reaction was stirred for 30 minutes. Dowex 50WX8 was then added until the solution became slightly acidic. The resin was filtered and washed thoroughly with methanol. The combined methanol fractions were evaporated under reduced pressure to give compound 75 (274 mg, 0.196 mmol) in a 79% yield. Compound 75 was used in the remaining steps without purification.

[1326] 6.MIF-GN3( Figure 18 )

[1327]

[1328] Compound 34 (23.5 mg, 0.0575 mmol, 1.1 eq) and HATU (20.0 mg, 0.0522 mmol, 1 eq) were dissolved in dry DMF (5 mL) and DIPEA (23.3 uL, 16.9 mg, 0.131 mmol, 2.5 eq) and stirred at room temperature for 10 minutes. Compound 75 (73.0 mg, 0.0522 mmol) was then added and the reaction stirred for 30 minutes. The mixture was directly loaded onto an HPLC and purified (20-30% MeCN, 3% TFA in water) to give compound 76 (12 mg, 0.0067 mmol) in a yield of 12.8%. Expected value [M+H] + 1787.801, measured value 1787.823.

[1329] 7. Bicyclic ASGPR spacer ( Figure 19 )

[1330]

[1331] 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 the 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 the other steps without purification.

[1332]

[1333] 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 at reflux for 16 hours, 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 compound 17 (4.82 g, 22.1 mmol) as a yellow oil in 87% yield. 1 HNMR (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). 13C NMR (101MHz, CDCl3) δ72.47,70.65,70.63,70.59,70.52,70.28,69.99,61.60,50.59.

[1334]

[1335] 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 stirred under nitrogen for 6 hours. The mixture was then diluted into ethyl acetate and washed with water (3x), .5 M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), dried over sodium sulfate, and evaporated to afford compound 18 (5.71 g, 19.2 mmol) in 84% yield. 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). 13 C NMR (101 MHz, CDCl3) δ 70.79, 70.75, 70.71, 70.15, 69.39, 69.11, 50.77, 37.78. HRMS: expected 298.107, found 298.105.

[1336] 8. Bicyclic ASGPR precursor ( Figure 20 )

[1337]

[1338] 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 Compound 1 as a light yellow oil in quantitative yield. The compound was used without further purification.

[1339] Compound 1 (26.34 g, 64.06 mmol) was dissolved in acetic acid (510 mL) and zinc (67.01 g, 1024 mmol) was added. The mixture was stirred vigorously. A solution of CuSO4 (2.96 g, 18.6 mmol) in aqueous NaH2PO4 (128 mL, 0.1 M, 1.53 g) was then added, and the reaction was stirred for 1 hour. The reaction mixture was filtered through a celite filter 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. 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). 13 C 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. HRMS: [M+Na] + Expected value 295.079, measured value 295.078

[1340]

[1341] Compound 2 (12.0 g, 44 mmol) is dissolved in acetonitrile (250 mL) and cooled to -10 °. In a separate -10 ° flask flushed with nitrogen, NaN3 (4.3 g, 66 mmol) and ceric ammonium nitrate (87.0 g, 158 mmol) are mixed and stirred vigorously. A solution of compound 2 in acetonitrile is added dropwise via a cannula, and the mixture is slowly brought to room temperature. The reaction mixture is stirred for a total of 12 hours, then diluted with ethyl acetate (500 mL) and washed with water (3x) and brine (1x). The organic layer is dried over sodium sulfate, evaporated, and purified on silica (20-50% EtOAc in hexane) to obtain compound 3 (13.1 g, 34.9 mmol) in 79% yield. 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). 13 C NMR (101MHz, CDCl3) δ170.15-169.06,97.91,97.79,96.91,71.68,71.45,69.35,68 .42,66.98,66.53,65.85,64.75,61.07,60.84,57.38,55.82,55.08,20.31-20.20. HRMS:[M+Na] + Expected value 399.076, measured value 399.073

[1342]

[1343] A 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 using a gradient of 0-20% MeOH in DCM to give compound 4 (6.64 g, 30.3 mmol) in 95% yield. 13C NMR(101MHz,cd3od)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. HRMS:[M+Na] + Expected value 242.075, measured value 242.072.

[1344]

[1345] 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. 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 over 1.5 hours and quenched with acetic acid (17 mL) once TLC showed that the starting material was completely consumed. 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%. 13 C NMR(101MHz,cdcl3)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 .15,55.17,34.60,31.52,25.21,22.59,20.93,14.11,14.05,0.85,0.57,0.55,0.52,0.22,0.14,0.01,-0.07. HRMS:[M+Na] + 386.154, measured value 386.156.

[1346]

[1347] 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.

[1348] 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. HRMS: [M+Na] + Expected value 272.086 (+Na), measured value 272.083.

[1349]

[1350] L6-7 (500 mg, 2.00 mmol) was dissolved in water (4.5 mL) and sulfuric acid (0.5 mL). The reaction was sealed in a microwave vial and heated at 100 ° 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%. 13 C NMR (101MHz, CD3OD) δ102.70,85.32,71.03,69.59,69.49,66.07,61.85.

[1351] 9. Bicyclic ASGPR ligand CF3 ( Figure 21 )

[1352]

[1353] The compound (400 mg, 1.84 mmol) was dissolved in methanol (30 mL) and the reaction flask was purged with nitrogen. Lindela's catalyst (40.0 mg, 10 wt%) was then added, and the reaction mixture was stirred under a 1 atm hydrogen atmosphere (balloon) for 6 hours. The reaction mixture was filtered through Celite and evaporated to afford compound 10 (351 mg, 1.84 mmol) in quantitative yield, which was used in the subsequent reaction without further purification.

[1354] 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) in 95% yield, which was used in the other steps without purification.

[1355] 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. 1 H NMR(400MHz,DMSO-d6)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). 13 C 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. HRMS:[M+H] + Expected value 288.069, measured value 288.064.

[1356]

[1357] Compound 12 (110 mg, 0.383 mmol) was dissolved in DMF (8 mL) and dimethoxypropane (236 mL, 200 mg, 1.92 mmol, 5 eq) and camphorsulfonic acid (45 mg, 0.192 mmol, 0.5 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, 0.303 mmol) in 79% yield. 1H 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). 13 C NMR (101MHz, CDCl3) δ157.87,157.50,157.12,156.75,119.93,117.07,114.21,1 12.04,111.35,100.22,81.55,75.57,75.00,68.44,60.96,55.16,27.67,26.16. HRMS:[M+H] + Expected value 328.101, measured value 328.095.

[1358]

[1359] Compound 13 (99.1 mg, 0.303 mmol) was dissolved in DMF (5 mL) and treated with sodium hydride (8.7 mg, 0.364 mmol, 1.2 eq) and then stirred under nitrogen for 15 minutes. Compound 18 (108 mg, 0.364 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, 0.248 mmol) in 82% yield. 1 H NMR (400MHz, DMSO-d6) δ9.75(d,J=8.3Hz,1H),5.29(s,1H),4.40(t,J=6.7Hz,1H),4.30(d,J=5.9 Hz, 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).

[1360]

[1361] Compound 14 (131 mg, 0.240 mmol) was dissolved in methanol (10 mL) and stirred under a nitrogen atmosphere. Lindela's catalyst (13.1 mg, 10 wt%) was then added, and the reaction was stirred under a H2 atmosphere (1 atm) for 6 hours. The reaction was then filtered through Celite and the solvent evaporated to afford compound 15 (120 mg, 0.240 mmol) in quantitative yield, which was used without further purification. HRMS: [M+H] + Expected value 503.222, measured value 503.223.

[1362] 10. MIF binding bivalent ( Figure 23 )

[1363]

[1364] 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) in 95% yield, which was used in other steps without purification.

[1365]

[1366] 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. 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). 13C NMR (101MHz, CDCl3) δ171.11,155.31,117.88,79.70,69.12,65.53,49.24,28.30,18.83,14.16.

[1367]

[1368] 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 refluxed 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 distributed between water and ethyl acetate, and the organic fraction was washed with water (1x), 0.5 M HCl (2x), saturated sodium bicarbonate (1x) and brine (1x), dried over sodium sulfate, and evaporated. Compound 20 was purified on silica with a gradient of 0-10% MeOH in DCM and recovered in a yield of 74% (4.50 g, 12.4 mmol). 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). 13 C NMR (101MHz, CDCl3) δ171.86,155.34,79.20,69.19,66.41,51.58,49.29,34.75,28.28.

[1369]

[1370] Compound 25 (1.00 g, 2.75 mmol) was dissolved in dry MeOH (10 mL) and TFA (1 mL) and stirred for 15 minutes.

[1371] The volatiles were evaporated under reduced pressure to give compound 26 (1.04 g) as a TFA salt in quantitative yield.

[1372]

[1373] Compound 34 (50.0 mg, 0.123 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, 0.270 mmol, 2.2 eq) was then added, and the reaction was stirred for 15 minutes. Compound 26 (102 mg, 0.270 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 a sticky residue, which was purified by reverse phase HPLC (35-45% MeCN, 0.1% TFA in water) to afford compound 40 (62.6 mg, 0.0959 mmol) in 78% yield. HRMS: expected value 654.258, found value 654.259.

[1374] Compound 40 (62.6 mg, 0.0959 mmol) was dissolved in dioxane (1.8 mL) and 1 M NaOH (0.2 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. The organic layer was evaporated to give compound 41 (57.6 mg, 0.0921 mmol) as an oil in 96% yield, which was used without further purification.

[1375] 11.MIF binding trivalent ( Figure 23 )

[1376]

[1377] Compound 34 (50.0 mg, 0.123 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, 0.405 mmol, 3.3 eq) was then added, and the reaction was stirred for 15 minutes. Compound 29 (200 mg, 0.405 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 a sticky residue, which was purified by reverse phase HPLC (35-50% MeCN, 0.1% TFA in water) to afford compound 44 (79.3 mg, 0.103 mmol) in 84% yield. HRMS: [M+H] + Expected value 770.305, measured value 770.308.

[1378] Compound 44 (79.3 mg, 0.103 mmol) was dissolved in dioxane (1.8 mL) and 1 M NaOH (0.2 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, 0.0948 mmol) as an oil in 92% yield, which was used without further purification.

[1379] 12.MIF-AcF3-2( Figure 24 )

[1380]

[1381] Compound 41 (57.6 mg, 0.0921 mmol) was dissolved in DMF (1.8 mL) and DIPEA (0.2 mL). HBTU (84.0 mg, 0.222 mmol, 2.4 eq) was then added, and the reaction was stirred for 15 minutes before compound 15 (111 mg, 0.222 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.

[1382] Compound 42 (crude, 0.0921 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 hours. The reaction was directly purified by HPLC (20-40% MeCN in H₂O + 3% TFA) to afford compound 43 (44.66 mg, 0.0295 mmol) in a 32% yield. HRMS expected (H) 1514.570, found 1514.561.

[1383] 13.MIF-AcF3-3( Figure 25 )

[1384]

[1385] Compound 45 (68.9 mg, 0.0948 mmol) was dissolved in DMF (1.8 mL) and DIPEA (0.2 mL). HBTU (126 mg, 0.333 mmol, 3.6 eq) was then added and the reaction stirred for 15 minutes before compound 15 (167 mg, 0.333 mmol, 3.6 eq) was added. The reaction was stirred for 1 hour and then evaporated to a light red residue that was used in the next reaction without purification.

[1386] Compound 38 (crude, 0.0948 mmol scale) was dissolved in 1 M HCl (1 mL) and stirred for 2 hours. The reaction was directly purified by HPLC (20-40% MeCN in H₂O + 3% TFA) to afford compound 39 (78.1 mg, 0.0379 mmol) in a 40% yield. HRMS expected (2H, / 2) 1030.891, found 1030.903.

[1387] Synthesis of MIF-AcF2-3, MIF-Ac-3, and MIF-Et-3

[1388] Figure 26-Figure 29 Shown in FIG are the chemical syntheses 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.

[1389] Figure 30-Figure 66 and Figures 70-88 Shown in the Figures are chemical synthesis schemes that provide additional compounds according to the present disclosure. The schemes in these figures illustrate exemplary synthetic chemistries that can be used to synthesize compounds according to the present disclosure.

[1390] Peptide synthesis

[1391] N-linked non-cyclized peptide, C-terminal amide, no amine-containing (side chain) amino acids.

[1392] Peptides were synthesized using Rink amide resin on a 200 mmol scale. All couplings used standard Fmoc amino acids, whose side chains were protected with acid-labile protecting groups. Between each deprotection, coupling, and capping reaction, the resin was washed 5 times with DMF, 5 times with DCM, and 5 times with DMF. The resin was Fmoc-deprotected (20% piperidine in DMF, incubated on a rotator twice for 3 minutes each) and coupled with the first amino acid (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) overnight. The resin was then washed and treated with 10% acetic anhydride in pyridine to cap any unreacted amines (10 minutes on a rotator). The resulting resin-amino acid conjugate was Fmoc-deprotected as described above and coupled with the next amino acid (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) for 40 minutes. The resin was then capped as described above. Subsequent iterative deprotection, coupling, and capping steps provide the final peptide. After the last amino acid, {2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid is coupled to the peptide and Fmoc deprotected to give the N-terminal amine. The peptide is cleaved from the resin using 90% TFA, 5% TIPS, 5% water (2 hour treatment), ether precipitated, and purified to 95% purity using RPHPLC before reacting with a carboxylic acid to provide a bifunctional compound. Alternatively, these peptides are treated with succinic anhydride to give a terminal carboxylic acid for coupling with an amine; treated with azidoacetic acid to give a terminal alkyne; or treated with 5-hexynoic acid to give a terminal alkyne. Copper-mediated cross-coupling is used in the case of terminal azides or alkynes to produce triazole-linked bifunctional molecules.

[1393] N-linked disulfide cyclized peptide with an amide at the C-terminus and no amine-containing (side chain) amino acids.

[1394] As above, but after cleavage from the resin, the peptide is then resuspended in PBS pH 8, MeOH / ammonium bicarbonate or another acceptable buffer to provide the disulfide-containing oxidized peptide. Alternatively, the peptide is cyclized oxidatively with iodine.

[1395] N-linked non-cyclized peptide, C-terminal amide, with amine-containing (side chain) amino acids.

[1396] As above, but the amine-containing amino acid is protected on its side chain with Cbz, which is removed under reducing conditions (H2, Pd / C) in a subsequent step of the synthesis.

[1397] N-linked disulfide cyclized peptide with an amide at the C-terminus and amine-containing (side chain) amino acids.

[1398] As above, but the amine-containing amino acid is protected on its side chain with Cbz, which is removed under reducing conditions (H2, Pd / C) in a subsequent step of the synthesis. After cleavage from the resin, the peptide is resuspended in PBS pH 8, MeOH / ammonium bicarbonate, or another acceptable buffer to provide an oxidized peptide containing a disulfide. Alternatively, the peptide is cyclized oxidatively with iodine.

[1399] C-linked non-cyclized peptide, without carboxylic acid (side chain) containing amino acids.

[1400] Peptides were synthesized on a 200 mmol scale using 2-chlorotrityl resin. All couplings used standard Fmoc amino acids, whose side chains were protected with acid-labile protecting groups. Between each deprotection, coupling, and capping reaction, the resin was washed 5 times with DMF, 5 times with DCM, and 5 times with DMF. The resin was treated overnight with 4 eq of 2,4,6-collidine in DCM for the first amino acid of the sequence (4 eq). The resin was then capped by treating with methanol in DIPEA / DCM for 1 hour at room temperature. The amino acid was then deprotected (20% piperidine in DMF, incubated on a rotator twice for 3 minutes each) and coupled with the first amino acid (4 eq of oxyma, 4 eq of Fmoc-protected amino acid, 4 eq of DIC in DMF) overnight. The resin was then washed and capped with 10% acetic anhydride in pyridine to remove any unreacted amines (on a rotator for 10 minutes). The resulting resin-amino acid conjugate was Fmoc-deprotected as described above and coupled with the next amino acid (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) for 40 minutes. The resin was then capped as described above. Subsequent repeated deprotection, coupling, and capping steps provided the final peptide. After the last amino acid, the peptide was optionally capped with acetic anhydride, propionic anhydride, or another suitable activated acid. The peptide was cleaved from the resin with hexafluoroisopropanol (20%) in DCM for 1.5 hours at room temperature and ether precipitated. The peptide was then purified to 95% purity using RPHPLC and then reacted with a carboxylic acid to provide a bifunctional compound. Alternatively, these peptides were treated with N-boc-ethylenediamine and subsequently treated with HCl / DCM to provide a terminal amine for coupling with a carboxylic acid. Alternatively, these peptides were treated with 3-azidopropane-1-amine under standard coupling conditions (HBTU, DIPEA, DMF) to generate terminal azides. Alternatively, these peptides were treated with 4-pentyn-1-amine under standard amide coupling conditions (HBTU, DIPEA, DMF) to afford the C-terminal alkyne. Copper-mediated cross-coupling was used in the case of terminal azides or alkynes to generate triazole-linked bifunctional molecules.

[1401] C-linked disulfide cyclized peptide, no carboxylic acid (side chain) containing amino acids.

[1402] As above, but after cleavage from the resin, the peptide is then resuspended in PBS pH 8, MeOH / ammonium bicarbonate or another acceptable buffer to provide the disulfide-containing oxidized peptide. Alternatively, the peptide is cyclized oxidatively with iodine.

[1403] C-linked non-cyclic peptides with carboxylic acid-containing amino acids (side chains).

[1404] As above, but the carboxylic acid-containing amino acid is protected on its side chain with Bz, which is removed under reducing conditions (H2, Pd / C) in a subsequent step of the synthesis.

[1405] C-linked disulfide cyclized peptides with carboxylic acid (side chain) containing amino acids.

[1406] As above, but the carboxylic acid-containing amino acids are protected on their side chains with Bz, which is removed under reducing conditions (H2, Pd / C) in a subsequent step of the synthesis. After cleavage from the resin, the peptide is resuspended in PBS pH 8, MeOH / ammonium bicarbonate, or another acceptable buffer to provide an oxidized peptide containing a disulfide. Alternatively, the peptide is cyclized oxidatively with iodine.

[1407] The foregoing has outlined the features of several embodiments so that those skilled in the art may better understand various aspects of the present disclosure. Those skilled in the art will appreciate that they may readily use this disclosure as a basis for designing or modifying other processes and structures to achieve the same objectives and / or obtain the same advantages of the various embodiments introduced herein. Those skilled in the art will also appreciate that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and modifications herein without departing from the spirit and scope of the present disclosure.

Claims

1. Bifunctional compounds of the following chemical structures, or their salts, stereoisomers or solvates: in: [CPBM] is a circulating protein binding moiety that binds to a circulating protein in a subject, wherein the circulating protein mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject, [CRBM] is a cell receptor binding moiety that binds to the asialoglycoprotein receptor or other cell receptor of the hepatocytes in the subject, Each [CON] is an optional linker chemical moiety which, when present, connects the [Linker] to a [CPBM] or to a [CRBM], [Linker] is a chemical moiety with a valence of 1 to 15, which is covalently linked to one or more [CRBM] or [CPBM] groups, optionally via [CON], wherein the [Linker] itself optionally comprises one or more [CON] groups, k' is an integer ranging from 1 to 15, j' is an integer ranging from 1 to 15, h and h' are each independently an integer ranging from 0 to 15, i L is 0 to 15, The premise is h, h' and i L At least one of is at least 1; Wherein the bifunctional compound is selected from: in: The extracellular protein targeting ligand is a circulating protein binding moiety that binds to a circulating protein in a subject, wherein the circulating protein mediates 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 1-8, wherein the extracellular protein targeting ligand is a MIF binding moiety.

10. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is an IgG binding moiety.

11. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a CD40L binding moiety.

12. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a TNFα binding moiety.

13. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a PCSK9 binding moiety.

14. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a VEGF binding moiety.

15. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a TGFβ binding moiety.

16. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a TSP-1 binding moiety.

17. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a uPAR binding moiety.

18. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a PSMA binding moiety.

19. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is an IL-2 binding moiety.

20. The bifunctional compound according to any one of claims 1 to 19, wherein the linker A Selected from 21. A pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier, additive or excipient, Optionally further included is an additional bioactive agent effective to treat, ameliorate and / or prevent cancer, autoimmune disease or inflammatory disease in the patient or associated with upregulation of circulating protein in the patient.

22. The composition of claim 21, wherein at least one of the following applies: (a) the circulating protein is MIF, IgG, CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA or IL-2; (b) The composition comprises an additional anticancer agent 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, EGFRTK 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, dekatanib, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexate, azd2171, batabulin, ofatumumab (Arzerra), zalimumab, etakaline, tetrandrine, rubicin, tesmilifen, oblimersen, tosicilumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanthone, LY 317615, Newlodi, Vitexpon, Rta744, 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, cericisili; 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 , darbepoietin, 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, azacitidine ramucirumab, 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, palo Nosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, immunotherapeutic agents PDL1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors.

23. A method for treating, ameliorating and / or preventing a disease state or condition associated with upregulation of a circulating protein in a patient or subject, the method comprising: A therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 20 is administered to the patient or subject, wherein the circulating protein is MIF, IgG, CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA or IL-2.

24. The method of claim 23, wherein the disease state or condition is cancer, an autoimmune disease, or an inflammatory disease.

25. The method according to claim 24, wherein the disease state or condition is systemic lupus erythematosus, Sjögren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, auto Immune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell dysplasia, thrombocytopenia, obesity dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, arthritis associated with focal inflammation, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parro 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 encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, primary inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis type II, Oshtoran syndrome, streptococcal association Pediatric autoimmune neuropsychiatric disorders (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Syndenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Coggan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Moore's ulcer, neuromyelitis optica, opsoclonus-myoclonus 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 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, or, Wherein the disease state or condition is Alzheimer's disease, Parkinson's disease, Huntington's disease, other ataxias, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren's syndrome, hyperglycemia, diabetes (I and II), pancreatic beta cell death and related hyperglycemia, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes, dyslipidemia, metabolic syndrome, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke, age-related dementia, sporadic Alzheimer's disease, depression, stroke, spinal cord injury, and arteriosclerosis.

26. A method of removing excess circulating protein in a patient or subject, the method comprising: A therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 20 is administered to the patient or subject, wherein the circulating protein is MIF, IgG, CD40L, TNFα, PCSK9, VEGf, TGFβ, TSP-1, uPAR, PSMA or IL-2.

Images