WO2023178202A2 - Bifunctional small molecules to target the selective degradation of circulating proteins - Google Patents

Bifunctional small molecules to target the selective degradation of circulating proteins Download PDF

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WO2023178202A2
WO2023178202A2 PCT/US2023/064470 US2023064470W WO2023178202A2 WO 2023178202 A2 WO2023178202 A2 WO 2023178202A2 US 2023064470 W US2023064470 W US 2023064470W WO 2023178202 A2 WO2023178202 A2 WO 2023178202A2
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compound
disease
group
certain embodiments
formula
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French (fr)
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WO2023178202A3 (en
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David Spiegel
David CAIANIELLO
Mengwen ZHANG
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Yale University
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Yale University
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Priority claimed from US17/695,645 external-priority patent/US12485178B2/en
Priority to CN202380040388.5A priority Critical patent/CN119255822A/zh
Priority to KR1020247034017A priority patent/KR20240166514A/ko
Priority to AU2023236291A priority patent/AU2023236291A1/en
Priority to EP23771648.5A priority patent/EP4493222A2/en
Priority to IL315579A priority patent/IL315579A/en
Application filed by Yale University filed Critical Yale University
Priority to JP2024555107A priority patent/JP2025509730A/ja
Publication of WO2023178202A2 publication Critical patent/WO2023178202A2/en
Publication of WO2023178202A3 publication Critical patent/WO2023178202A3/en
Priority to MX2024011338A priority patent/MX2024011338A/es
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Definitions

  • cytokines such as TNF ⁇ or MIF are associated with Rheumatoid arthritis (RA), atherosclerosis and other diseases.
  • RA Rheumatoid arthritis
  • MIF MIF-binding protein
  • Current strategies to target circulating proteins include the use of inhibiting antibodies, which possess excellent specificity and affinity for target proteins.
  • antibody-based therapies have several drawbacks that relate primarily to their high molecular weights and/or peptidic structures the likelihood of invoking immunogenicity, their high cost, short shelf life and low oral bioavailability.
  • the small molecule based strategy pursuant to the present disclosure has the potential to combine the beneficial attributes of antibody-based therapies while overcoming their most significant disadvantages.
  • the high prevalence of inflammatory diseases in the population presents a considerable economic burden to the healthcare system.
  • the high demand and high cost of current antibody-based treatments is reflected in the 34.4 billion USD global sales of TNF- ⁇ antibodies.
  • the bifunctional small molecule according to the present disclosure is readily prepared by organic synthesis, and has the potential to substantially lower the cost of manufacturing, storage and treatment.
  • these bifunctional chemical constructs are easier to produce in large quantity to ultimately meet high demand of treatments.
  • the present disclosure is directed to bifunctional small molecules which can be used to remove circulating proteins, which mediate disease states and/or conditions in subjects.
  • the present disclosure aims to establish a general small molecule strategy to target the selective degradation of disease-related circulating proteins.
  • the bifunctional molecule construct contains a protein targeting motif derived from known small molecule ligands of the proteins of interest. The inventors refer to this moiety generically as a circulating protein binding moiety (CPBM).
  • the other end of the bifunctional molecule is a cellular receptor binding moiety (CRBM) that binds to a cell surface receptor and leads to internalization of the circulating protein and bifunctional molecule.
  • the two motifs are covalently linked via a linker such as a polyethylene glycol (PEG) linker with adjustable length and optionally contains one or more connector molecule which connects the linker to the CPBM and/or the CRBM.
  • PEG polyethylene glycol
  • the presently claimed bifunctional compounds selectively bind to the protein of interest in circulation and form a protein complex that then binds a cellular receptor and is endocytosed and degraded.
  • the protein of interest is eliminated from circulation by hepatocytes, macrophages, or another cell type, thus resulting in lowered level of the protein of interest with the potential of attenuating the corresponding disease symptoms.
  • the protein of interest may be eliminated, resulting in substantially reduced symptoms or even a cure or elimination of the disease state or condition.
  • the approach pursuant to the present disclosure is inherently advantageous compared to the classical antibody-based strategy to target disease-related circulating proteins of the prior art.
  • the small molecule based approach of the current disclosure overcomes limitations of traditional antibody-based strategies, including lack of oral bioavailability, low- temperature storage requirements, immunogenicity, and high-cost. Furthermore, the present disclosure is expected to have a more lasting effect compared to the conventional inhibitory approach because the disease relevant proteins are eliminated by degradation inside hepatocytes rather than simply inhibited by reversibly blocking the protein-receptor interaction.
  • the bifunctional molecule construct pursuant to the present disclosure is also versatile in the sense that different disease related proteins can be targeted by simply switching the protein targeting motif in the construct. Thus, previously discovered non-inhibitory protein binders can be potentially therapeutically useful in these small molecules.
  • the present disclosure is directed to compounds which are useful for removing circulating proteins which are associated with a disease state or condition in a patient or subject according to the general chemical structure: wherein [CPBM] is a Circulating Protein Binding Moiety which binds respectively to circulating proteins as identified herein, which are related to and/or mediate a disease state and/or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the CPBM in plasma of the subject or patient); [CRBM] is a Cellular Receptor binding moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [
  • [LINKER] has a valency of 1 to 10. In various embodiments, [LINKER] has a valency of 1 to 5. In various embodiments, [LINKER] has a valency of 1, 2 or 3.
  • a [MULTICON] group can connect one or more of a [CRBM] or [CPBM] to one or more of a [LINKER].
  • [CPBM] is a [MIFBM] moiety according to the chemical structure: wherein XM is -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG (polyethylene glycol) group containing from 1 to 8 ethylene glycol residues or a - C(O)(CH 2 ) IM NR M group; R M is H or a C 1 -C 3 alkyl group which is optionally substituted with one or two hydroxyl groups; IM is an integer ranging from 0-6.
  • [CPBM] is a [IgGMB] group according to the chemical structure: dinitrophenyl group; or a group according to the chemical structure: , 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, a C1-C3 alkyl group, or a -C(O)(C1-C3) group; or a group according to the chemical structure: , where R 1 is the same as above; and K'' is 1-5, or a group represented by the chemical formula: , where X’ is CH 2 , O, N-R 1 ’, or S; R 1’ is H or C 1 -C 3 alkyl; and Z is a bond, a monosaccharide, disaccharide, oligosaccharide, more preferably a sugar group selected from the monosacchari
  • Monosaccharide aldoses include monosaccharides such as aldotriose (D- glyceraldehdye, among others), aldotetroses (D-erythrose and D-Threose, among others), aldopentoses, (D-ribose, D-arabinose, D-xylose, D-lyxose, among others), aldohexoses (D- allose, D-altrose, D-Glucose, D-Mannose, D-gulose, D-idose, D-galactose and D-Talose, among others), and the monosaccharide ketoses include monosaccharides such as ketotriose (dihydroxyacetone, among others), ketotetrose (D-erythrulose, among others), ketopentose (D-ribulose and D-xylulose, among others), ketohexoses (D-Psicone, D-Fructose, D-Sorb
  • Exemplary disaccharides which find use in the present disclosure include sucrose (which may have the glucose optionally N-acetylated), lactose (which may have the galactose and/or the glucose optionally N-acetylated), maltose (which may have one or both of the glucose residues optionally N-acetylated), trehalose (which may have one or both of the glucose residues optionally N-acetylated), cellobiose (which may have one or both of the glucose residues optionally N-acetylated), kojibiose (which may have one or both of the glucose residues optionally N-acetylated), nigerose (which may have one or both of the glucose residues optionally N-acetylated), isomaltose (which may have one or both of the glucose residues optionally N-acetylated), ⁇ , ⁇ -trehalose (which may have one or both of the glucose residues optionally N-acetylated), sopho
  • [CPBM] is a [IgGBM] group which is a peptide according to the sequence (all references cited are incorporated by reference herein): PAM (Fassina, et al., J. Mol. Recognit.1996, 9, 564–569); D-PAM (Verdoliva, et al., J. Immunol. Methods, 2002, 271, 77–88); D-PAM- ⁇ (Dinon, et al. J. Mol. Recognit.2011, 24, 1087–1094); TWKTSRISIF (Krook, et al., J. Immunol.
  • EPIHRSTLTALL (Ehrlich, et al., J. Biochem. Biophys. Method 2001, 49, 443–454) SEQ ID NO:3; APAR (Camperi, et al., Biotechnol. Lett.2003, 25, 1545–1548) SEQ ID NO:4; FcRM (Fc Receptor Mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242–1253); HWRGWV (Yang, et al., J. Peptide Res.2006, 66, 110–137) SEQ ID NO:5; HYFKFD (Yang, et al., J. Chromatogr.
  • Bioeng.2013, 110, 857–870 SEQ ID NO:11; NKFRGKYK (Sugita, et al., Biochem. Eng. J.2013, 79, 33–40) SEQ ID NO:12; NARKFYKG (Sugita, et al., Biochem. Eng. J.2013, 79, 33–40) SEQ ID NO:13; FYWHCLDE (Zhao, et al., Biochem. Eng. J.2014, 88, 1–11) SEQ ID NO:14; FYCHWALE (Zhao, et al., J. Chromatogr.
  • [CPBM] is a CD40L-targeting motif according to the chemical structure:
  • [CPBM] is a TNF alpha-targeting motif according to chemical structure: or [CPBM] is a PCSK9-targeting motif according to the chemical structure:
  • [CPBM] is a VEGF-targeting motif according to the chemical structure: [CPBM] is a TGF beta-targeting motif according to the chemical structure: [CPBM] is a TSP-1 targeting motif according to the chemical structure: , or [CPBM] is a soluble uPAR targeting motif according to the chemical structure: [CPBM] is a soluble PSMA targeting motif according to the chemical structure: [CPBM] is a IL-2 targeting motif according to the chemical structure: [CPBM] is a GP120-targeting motif according to the chemical structure: .
  • [CRBM] is an [ASGPRBM] is a group according to the chemical structure: where X is 1-4 atoms in length and is at each occurrence independently selected from the group consisting of O, S, N(R N1 ), and C(R N1 )(R N1 ) such that: if X is 1 atom in length, X is O, S, N(R N1 ), or C(R N1 )(R N1 ), if X is 2 atoms in length, no more than 1 atom of X is O, S, or N(R N1 ), if X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S or N(R N1 ); where R N1 is H or a C 1 -C 3 alkyl group optionally substituted with from 1-3 halogen groups; R1 and R3 are each independently H, -(CH2)KOH, -(CH2)KOC1-C4 alkyl,
  • each alkyl, vinyl, or alkynyl in R 1 and R 3 is optionally substituted with from 1-3 fluorines (F).
  • K is independently at each occurrence an integer from 0-4.
  • R1 and R3 are each independently a group, which is optionally substituted with 1-3 halogen groups, 1 to 3 C 1 -C 4 alkyl groups, or O-C 1 -C 4 alkyl groups, in which each of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently at each occurrence and integer from 0-4; or R 1 and R 3 are each independently a group according to the chemical structure: , where R 7 is O-C 1 -C 4 alkyl, which is optionally substituted with from 1 to 3 halo groups or 1 to 2 hydroxy groups, and K' is independently at each occurrence an integer from 0-4; or R 7 is a -NR N3 R N4 group independently at each occurrence an integer from 0
  • any of the alkyl groups described herein as being optionally substituted by 1-3 halogen groups are substituted by 1, 2, or 3 fluorine (F) atoms.
  • [CRBM] is a LRP1 (Low density lipoprotein receptor-related protein 1 or alpha-2-macroglobulin receptor) peptide binding group according to the peptide sequence (it is noted that in each case where a peptide is used, the amino end or the carboxylic acid end of the peptide is preferably linked, and 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): Ac-VKFNKPFVFLNleIEQNTK-NH 2 SEQ ID NO: 19 (See, Toldo, Stefano, et al.
  • Nle is neorleucine
  • VKFNKPFVFLMIEQNTK SEQ ID NO:20 See, Toldo, Stefano, et al. JACC: Basic to Translational Science 2.5 (2017): 561-574.
  • TWPKHFDKHTFYSILKLGKH-OH SEQ ID NO: 21 See, Sakamoto, Kotaro, et al. Biochemistry and biophysics reports 12 (2017): 135-139.
  • Angiopep-2 TFFYGGSRGKRNNFKTEEY-OH SEQ ID NO:22 (See, Sakamoto, Kotaro, et al.
  • Rap22 EAKIEKHNHYQKQLEIAHEKLR SEQ ID NO: 25 (Ruan, Huitong, et al. "A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery.” Journal of Controlled Release 279 (2016): 306-315.)
  • ANG TFFYGGSRGKRNNFKTEEY SEQ ID NO:26 (Kim, Jong Ah, et al.
  • [CRBM] is a LDLR (low density lipoprotein receptor) binding group according to the peptide sequence: VH4127: cM“Thz”RLRG“Pen” (cyclized c-Pen) SEQ ID NO:27 (See, Molino, Yves, et al. The FASEB Journal 31.5 (2017): 1807-1827) where Pen is Penicillamine and Thz is thiazolidine-4-carboxylic acid, VH434: CMPRLRGC (cyclized C-C) SEQ ID NO:28 (Molino, Yves, et al.
  • VH101 HLDCMPRGCFRN (cyclized C-C) SEQ ID NO:29 David, Marion, et al. PloS one 13.2 (2016): e0191052
  • VH202 CQVKSMPRC (cyclized C-C) SEQ ID NO:30 (David, Marion, et al. PloS one 13.2 (2018): e0191052)
  • VH203 CTTPMPRLC (cyclized C-C) SEQ ID NO:31 (David, Marion, et al.
  • VH4106 Ac- D -“Pen”M”Thz”RLRGC-NH 2 (cyclized Pen-C) SEQ ID NO:47 (Jacquot, Bryan, et al. Molecular pharmaceutics 13.12 (2016): 4094-4105), where Pen is penacillamine and Thz is thiazolidine-4-carboxylic acid, VH4127: Pr-cM”Thz”RLRG”Pen-NH 2 (cyclized c-Pen) SEQ ID NO:48 (Jacquot, Nicolas, et al.
  • Pen is Penicillamine
  • Thz is thiazolidine-4-carboxylic acid
  • Pip is pipecolic acid
  • Sar is sarcosine
  • [CRBM] is a Fc ⁇ RI binding group according to the peptide sequence: Cp22: TDT C LMLPLLLG C DEE (cyclized C-C) SEQ ID NO:53, Bonetto, Stephane, et al. The FASEB Journal23.2 (2009): 575-585, Cp21: DPI C WYFPRLLG C TTL (cyclized C-C) SEQ ID NO:54, Bonetto, Stephane, et al.
  • FASEB Journal23.2 (2009): 575-585, or [CRBM] is a FcRN binding moiety according to the peptide sequence: SYN746: Ac-NH-QRFCTGHFGGLYPCNGP-CONH2 (cyclized C-C) SEQ ID NO:70 (Mezo, Adam R., et al. Proceedings of the National Academy of Sciences 105.7 (2008): 2337-2342.), SYN1327: Ac-NH-RF-Pen-TGHFG-Sar-NMeLeu-YPC-CONH2 (cyclized C-C) SEQ ID NO:71 (Mezo, Adam R., et al.
  • Pen Penacillamine
  • Sar is a sarcosine
  • NMeLeu is N-methylleucine
  • SYN1436 succinic anhydride N-N dimerized SYN1327 (each cyclized C-C) (Mezo, Adam R., et al. Proceedings of the National Academy of Sciences 105.7 (2008): 2337-2342.)
  • [CRBM] is a Transferrin Receptor binding group according to the peptide sequence: Tf1: CGGGPFWWWP SEQ ID NO:72 (Santi, Melissa, et al.
  • PP1-13 Arteriosclerosis, thrombosis, and vascular biology 32.4 (2012): 971-978
  • PP1-13 LERFLRCWSDAPA SEQ ID NO:81
  • PP1-11 RFLRCWSDAPA SEQ ID NO:82
  • PP1-9 LRCWSDAPA SEQ ID NO:83
  • PP1-7 CWSDAPA SEQ ID NO:84 (Segers, Filip ME, et al. Arteriosclerosis, thrombosis, and vascular biology 32.4 (2012): 971-978.)
  • 4F DWFKAFYDKVAEKFKEAF SEQ ID NO:85 (Neyen, Claudine, et al.
  • [CON] is a connector moiety (including a [MULTICON]) as otherwise described herein; and [LINKER] is a linking moiety as otherwise described herein which links [CPBM] to the [CRBM] group and optionally contains one or more connector moieties (which optionally connect(s) more than one chemical moiety to provide said linking moiety or which connects said linking moiety to said [CPBM] group or said [CRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • X of the [CRBM]/[ASGPRBM] group is often -O-C(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 ) or C(R N1 )(R N1 )-C(R N1 )(R N1 ) when X is 2 atoms in length, X is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-O-C(R N1 )(R N1 )-, -O-C(R N1 )(R N1 )(R N1
  • R N1 is H.
  • X of the [CRBM]/[ASGPRBM] group is OCH2 or CH2O and R N1 is preferably H.
  • the [CRBM]/[ASGPRBM] group is a group according to the chemical structure: where R1, R2 and R3 are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • the [CRBM]/[ASGPRBM] group is a group according to the chemical structure: where R A is C 1 -C 3 alkyl optionally substituted with 1-5 halogen groups; ZA is -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) residues, or -C(O)(CH2)IMNRM, where IM and R M are the same as above; and Z B is absent, (CH 2 ) IM , C(O)-(CH 2 ) IM -, or C(O)-(CH 2 ) IM -NR M, where IM and R M are the same as above.
  • R 1 and R 3 are each independently a group according to the chemical structure: are as defined herein.
  • preferred compounds include the compounds which are presented in FIGURES 1, 7 and 13, as well as FIGURES 29-88.
  • additional compounds are presented in FIGURES 16-66 and include final compounds set forth therein and intermediates which are used to make final compounds pursuant to the present disclosure.
  • R1 and R3 of the [CRBM]/[ASGPRBM] group include those moieties which are presented in FIGURE 68 hereof.
  • R 2 of the [CRBM]/[ASGPRBM] group include those moieties which are presented in FIGURE 69 hereof.
  • the [CPBM]/[IgGBM] group is a peptide moiety according to the chemical structure for FcIII or FcIII-4c: .
  • the present disclosure is directed to a pharmaceutical composition 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 bioactive agent.
  • the present disclosure is directed to a method of treating a disease state or condition where a circulating protein is related to or contributes to a disease state and or condition or the symptomology associated with the disease state or condition.
  • the method of treatment according to the present disclosure comprises administering to a patient or subject in need of therapy 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 Protein associated with the disease state and/or condition from the circulation of the patient or subject.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • Alzheimer’s disease atherosclerosis
  • heart disease heart disease
  • stroke and cancer including leukemia
  • the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition 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 bioactive agent.
  • the present disclosure is directed to a method of treating a disease state or condition where a circulating protein is related to the symptomology associated with the disease state or condition.
  • 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), among numerous others as described herein.
  • the method comprises administering to a patient or subject in need of therapy 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.
  • FIG.1 shows representative compounds according to the present disclosure. Note that the figure discloses compound 3w (negative control for MIF inhibition), MIF-NVS- PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1, MIF-AcF3-2 and MIF-AcF3-3.
  • 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.
  • FIG.2 shows fluorescence polarization data of MIF-FITC binding to human MIF, indicating that our MIF-binding moiety binds MIF.
  • Bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3, and NVS-PEG3-GN3 bound competitively with MIF-FITC, indicating that the bifunctional molecules maintain the ability to bind human MIF.
  • FIG.3 shows that bifunctional molecules are able to deplete human MIF from the supernatant of culture HepG2 cells.
  • FIG.4 shows that MIF internalized by HepG2 cells is trafficked to lysosomes.
  • FIG.5 shows that MIF-GN3 mediates the depletion of injected human MIF from mice.
  • FIG.6 shows that MIF-GN3 is able to delay tumor growth in a mouse model of prostate cancer.
  • FIG.7 shows molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind to anti-DNP IgG and ASGPR.
  • FIG.8 shows that DNP-GN3 and DNP-AcF3-3 mediate the formation of a ternary complex between HepG2 cells and anti-DNP.
  • FIG.9 shows that DNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa 488- labeled anti-DNP by HepG2 cells.
  • FIG.10 shows that DNP-GN3 and DNP-AcF3-3 mediate the localization of alexa 568 labeled anti-DNP to late endosomes and lysosomes.
  • FIG.11 shows that DNP-AcF3-3 mediates the degradation of alexa 488-labeled anti- DNP in HepG2 cells.
  • FIG.12 shows that DNP-GN3 mediates the depletion of anti-DNP from mouse serum.
  • FIG.13 shows the structures of IgG-degrading molecules IBA-GN3, Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3.
  • FIG.14 shows that FcIII-GN3 mediates the uptake of human IgG into HepG2 cells.
  • FIG.15 shows that FcIII-GN3 mediates the localization of IgG to late endosomes in HepG2 cells.
  • FIGs.16-18 show the synthesis of PEG linkers used in several molecules outlined in this disclosure.
  • FIGs.19-21 show the synthesis of ASGPR-binding precursors and ligands used in several molecules in this disclosure.
  • FIGs.22-26 show the synthesis of valency linkers used in several molecules in this disclosure.
  • FIGs.27-28 show the synthesis of MIF ligands used in several bifunctional molecules.
  • FIG.29 describes the synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3.
  • FIG.30 describes the synthesis of bifunctional molecules MIF-GN3 and MIF-PEGn- GN3.
  • FIG.31 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing one bicyclic ASGPR AcF3 ligands.
  • FIG.32 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing two bicyclic ASGPr AcF3 ligands.
  • FIG.33 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing three bicyclic ASGPr ligands.
  • FIG.34 shows the synthesis of DNP-GN3.
  • FIG.35 shows the synthesis of DNP-AcF3-3.
  • FIG.36 shows the synthetic scheme used to obtain IBA-GN3.
  • FIG.37 shows the synthesis of triazine-GN3.
  • FIG.38 shows the synthetic scheme used to access FcIII-GN3.
  • FIG.39 shows the synthetic scheme used to access FcIII-4c-GN3.
  • FIGs.40-43 describe the synthesis of bifunctional molecules targeting MIF and ASGPr, containing three bicyclic ASGPR ligands with different substitutions on the 2-amine of the sugar.
  • FIG.44 shows the synthesis of compound MIF-18-3.
  • FIG.45 shows the synthesis of compound MIF-31-3.
  • FIG.46 shows the synthesis of compound MIF-15-3.
  • FIG.47 shows the synthesis of compound MIF-19-3.
  • FIG.48 shows the synthesis of compound MIF-16-3
  • FIG.49 shows the synthesis of compound MIF-20-3
  • FIG.50 shows the synthesis of compound MIF-14-3
  • FIG.51 shows the synthesis of compound MIF-21-3
  • FIGs.52-66 show the synthesis of a number of MIF-binding compounds with various ASGPRBM moieties.
  • FIG.67 shows exemplary IgGBM groups each of which is covalently attached to a [CON] group, a [LINKER] group or a [ASGPRBM] group through an amine group, preferably a primary or secondary alkyl amine group which is optionally substituted on the amine group with a C 1 -C 3 alkyl group.
  • FIG.68 shows exemplary R1 and R3 substituents on ASGPRBM groups as otherwise described herein.
  • FIG.69 shows exemplary R 2 substituents on ASGPRBM groups as otherwise described herein.
  • FIG.70 shows the synthesis of CD40L-binding bifunctional molecule BIO8898- GN3.
  • FIG.71 shows the synthesis of TNF-alpha binding bifunctional molecule c87-GN3.
  • FIG.72 shows the synthesis of TNF-alpha binding bifunctional molecule 4e-GN3.
  • FIG.73 shows the synthesis of TNF-alpha binding bifunctional molecule Cpd1-GN3.
  • FIG.74 shows the synthesis of TNF-alpha binding bifunctional molecule SP307- GN3.
  • FIG.75 shows the synthesis of TNF-alpha binding bifunctional molecule YCWSQYLCY-GN3.
  • FIG.76 shows the synthesis of PCSK9 binding bifunctional molecule SBC110424- GN3.
  • FIG.77 shows the synthesis of PCSK9 binding bifunctional molecule SBC110076- GN3.
  • FIG.78 shows the synthesis of PSCK9 binding bifunctional molecule TVFTSWEEYLDWV-GN3.
  • FIG.79 shows the synthesis of VEGF binding bifunctional molecule VEPNCDIHVMWEWECFERL-GN3.
  • FIG.80 shows the synthesis of VEGF binding bifunctional molecule VEGFSM-GN3.
  • FIG.81 shows the synthesis of TGF-beta binding bifunctional molecule KRFK-GN3.
  • FIG.82 shows the synthesis of TGF-beta binding bifunctional molecule TGFBSM- GN3.
  • FIG.83 shows the synthesis of TSP-1 binding bifunctional molecule LSKL-GN3.
  • FIG.84 shows the synthesis of soluble uPAR binding bifunctional molecule uPAR- GN3.
  • FIG.85 shows the synthesis of soluble PSMA binding bifunctional molecule PSMA- GN3.
  • FIG.86 shows the synthesis of IL-2 binding bifunctional molecule IL2-GN3.
  • FIG.87 shows the synthesis of GP120 binding bifunctional molecule BMS378806- GN3.
  • FIG.88 shows the synthesis of GP120 binding bifunctional molecule CPD7-GN3.
  • FIG.89 lists a table of possible target proteins with their indications, examples of in vitro assays, and known binding molecules.
  • FIG.90 includes proposed derivatization sites for several ligands that bind target circulating proteins.
  • DETAILED DESCRIPTION In accordance with the present disclosure there may be employed conventional chemical synthetic and pharmaceutical formulation methods, as well as pharmacology, molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are well-known and are otherwise explained fully in the literature.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, stereoisomers and where applicable, optical isomers (enantiomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof.
  • compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, within context, to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents, linkers and connector molecules and variables associated with same, among others, are described.
  • the use of a bond presented as ----- signifies that a single bond is present or absent, depending on the context of the chemistry described, including the attachment of the bond to another moiety.
  • the use of a bond presented as ------- signifies that a single bond or a double bond is intended depending on the context of the chemistry described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder.
  • patient or “subject” is used throughout the specification within context to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment (prophylaxis, including especially as that term is used with respect to reducing the likelihood of metastasis of an existing cancer), with the compositions according to the present disclosure is provided.
  • treatment including prophylactic treatment (prophylaxis, including especially as that term is used with respect to reducing the likelihood of metastasis of an existing cancer)
  • prophylactic treatment prophylaxis, including especially as that term is used with respect to reducing the likelihood of metastasis of an existing cancer
  • the term patient refers to that specific animal.
  • Compounds according to the present disclosure are useful for the treatment of numerous disease states including autoimmune diseease states and/or conditions and inflammatory disease states and/or conditions as well as cancer, including especially for use in reducing the likelihood of metastasis or recurrence of a cancer.
  • the term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result, whether that result relates to the inhibition of the effects of a disease state (e.g.
  • autoimmune disease such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among others, atherosclerosis, heart disease or stroke, among numerous others or a cancer, including leukemia) on a subject or the treatment or prophylaxis of a subject for secondary conditions, disease states or manifestations of disease states as otherwise described herein.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • leukemia erythematosus
  • This term subsumes all other effective amount or effective concentration terms (including the term “therapeutically effective”) which are otherwise described in the present application.
  • a disease state or condition for which a MIF protein may be removed refers to any action providing a benefit to a patient at risk for a disease state or condition for which a MIF protein may be removed, such as an autoimmune disease including rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among others, atherosclerosis, heart disease, stroke and cancer (including leukemia) including recurrence and/or metastasis of cancer, improvement in the condition through lessening or suppression of at least one symptom of the disease state or condition, inhibition of one or more manifestations of the disease state (e.g., plaque formation, heart disease, cancer growth, reduction in cancer cells or tissue), prevention, reduction in the likelihood or delay in progression of a disease state or condition or manifestation of the disease state or condition, especially including plaque formation in atheroslerosis, deterioration of tissue and inflammation in rheumatoid arthritis, further damage to cardiovascular tissue in heart disease, further damage to central nervous tissue
  • RA
  • Treatment encompasses both prophylactic and therapeutic treatment, depending on the context of the treatment.
  • prophylactic when used, means to reduce the likelihood of an occurrence or the severity of an occurrence within the context of treatment of disease state or condition, as otherwise described hereinabove.
  • the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about/approximately are meant to cover any normal fluctuations in a value appreciated by one of ordinary skill in the relevant.
  • circulating protein binding moiety which term includes “macrophage migration inhibitory factor binding moiety” or “MIFBM”, “immunoglobulin G binding moiety” or “IgGBM” refers to a chemical moiety on one end of the bifunctional compounds according to the present disclosure which is capable of binding to a circulating protein (such as MIF, IgG, CD40L, TNFalpha, PCSK9, VEGf, TGFbeta, TSP-1, uPAR, PSMA and IL-2 which aer associated with or contribute to a disease state or condition as otherwise described herein.
  • MIFBM macrophage migration inhibitory factor binding moiety
  • IgGBM immunoglobulin G binding moiety
  • the CPBM is capable of binding to the circulating protein, forming a complex with the present compounds, and delivering the bound protein to a hepatocyte or other cell whereupon the other end of the bifunctional molecule which contains a cellular receptor binding moiety (CRBM) such an asialoglycoprotein receptor binding moiety (ASGPRBM) or as otherwise described herein can bind to the surface of a hepatocyte or other cell, respectively.
  • CRBM cellular receptor binding moiety
  • ASGPRBM asialoglycoprotein receptor binding moiety
  • the bifunctional molecule to which is bound circulating protein is internalized by the cell through a phagocytosis/endocytosis mechanism whereupon the cell will destroy the protein via a lysosomal degradation or other degradation pathway.
  • immunoglobulin G binding moiety or “IgGBM” is used to describe a moiety which binds to circulating IgG immunoglobulin, forming a complex with bifunctional molecules according to the present disclosure to be ultimately destroyed in hepatocytes.
  • MIFBM and IgGBM and other cell binding moieties are used synonymously.
  • Exemplary MIFBMs for inclusion in bifunctional compounds according to the present disclosure include moieties found in bifunctional chemical structures which appear in Figure 1, attached hereto.
  • MIFBMs include moieties according to the chemical structures: wherein X M is -(CH 2 ) IM, -O-(CH 2 ) IM , S-(CH 2 ) IM , NR M -(CH 2 ) IM, C(O)-(CH 2 ) IM -, a PEG (polyethylene glycol) group containing from 1 to 8 ethylene glycol residues or a - C(O)(CH2)IMNRM group; RM is H or a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups; IM is an integer from 0-6. In various embodiments, IM is 1.
  • CPBM groups such as IgGBM and various previously described moieties which bind to CD40L, TNFalpha, PCSK9, VEGf, TGFbeta, TSP-1, uPAR, PSMA and Il-2 are set forth hereinabove. These bind to the respective circulating proteins, thus forming a complex with the bifunctional compounds according to the present disclosure and the bifunctional compounds complexed with the bound circulating proteins can be bound to cellular receptors on cells which can take up the complexed compounds using phagocytosis/endocytosis mechanisms of the cell and remove the proteins through a degradation process.
  • CPBM which are peptides which bind to IgGBM, CD40L, TNFalpha, PCSK9, VEGf, TGFbeta, TSP-1, uPAR, PSMA and Il-2 are covalently linked to other portions of the bifunctional molecules according to the present disclosure through the terminal amine or carboxylic acid group of the peptide.
  • the carboxylic acid is amidated to form a non-reactive amide group, often with a free amine group (substituted with two H’s) or an amine group which alkylated with at least one C1-C10 alkyl group, more often at least one C1-C3 alkyl group so that the free amine on the other end of the peptide may be used to covalently link to other portions of the bifunctional molecule.
  • the amine terminus is rendered non-reactive by end-capping the amine group with a C 2 -C 10 acyl group, preferably a C 2 -C 4 acyl group, so that the carboxylic acid group may be reacted, often with an amine to form an amide.
  • cellular receptor binding moiety refers to a moiety of the bifunctional compounds according to the present disclosure which is capable of binding to a receptor on a cell capable of degrading circulating proteins pursuant to the present disclosure herein.
  • moieties which bind to asialoglycoprotein receptor, LRPR, LDLR, Rc ⁇ RI, FcRN, Transferrin Receptor or Macrophage Scavenger Receptor (e.g., membrane receptors of degradation cells) as otherwise described herein.
  • Many of these binding moieties are peptides which are covalently linked to other portions of the bifunctional compounds according to the present disclosure through a terminal amine or carboxylic acid group.
  • the carboxylic acid is amidated to form a non-reactive amide group, often with a free amine group (substituted with two H’s) or an amine group which alkylated with at least one C 1 -C 10 alkyl group, more often at least one C1-C3 alkyl group so that the free amine on the other end of the peptide may be used to covalently link to other portions of the bifunctional molecule.
  • the amine terminus is rendered non-reactive by end-capping the amine group with a C 2 -C 10 acyl group, preferably a C 2 -C 4 acyl group, so that the carboxylic acid group may be reacted, often with an amine to form an amide.
  • asialoglycoprotein receptor binding moiety (“ASGPRBM”) refers to a binding moiety which binds to hepatocyte asialoglycoprotein receptor. This binding moiety is also a component of the presently claimed bifunctional compounds as a CRBM group which is covalently bound to the CPBM group moiety through a CON group, a linker or directly.
  • the ASGPRBM group selectively binds to hepatocyte asialoglycoprotein receptor on the surface of hepatocytes. It is through this moiety that bifunctional compounds complexed with circulating protein bind to hepatocytes. Once bound to the hepatocyte, the circulating protein is taken into the hepatocytes or other cells via a phagocytosis mechanism wherein the circulating protein is degraded through lysosomal degradation.
  • Exemplary ASGPRBM groups for use in compounds according to the present disclosure include moieties according to the chemical structures: where X is 1-4 atoms in length and is at each occurrence independently selected from the group consisting of O, S, N(R N1 ), and C(R N1 )(R N1 ) such that: if X is 1 atom in length, X is O, S, N(R N1 ), or C(R N1 )(R N1 ), if X is 2 atoms in length, no more than 1 atom of X is O, S, or N(R N1 ), if X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S or N(R N1 ); where R N1 is H or a C1-C3 alkyl group optionally substituted with from 1-3 halogen groups; R 1 and R 3 are each independently H, -(CH 2 ) K OH, -(CH 2 ) K OC 1
  • each alkyl, vinyl, or alkynyl in R1 and R3 is optionally substituted with from 1-3 fluorines (F).
  • K is independently at each occurrence an integer from 0-4.
  • R 1 and R 3 are each independently a group, which is optionally substituted with 1-3 halogen groups, 1 to 3 C1-C4 alkyl groups, or O-C1-C4 alkyl groups, in which each of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently at each occurrence and integer from 0-4; or
  • R1 and R3 are each independently a group according to the chemical structure: , where R 7 is O-C1-C4 alkyl, which is optionally substituted with from 1 to 3 halo groups or 1 to 2 hydroxy groups, and K' is independently at each occurrence an integer from 0-4; or R 7 is a -NR N3 R N4 group independently at each occurrence an integer from 0-4; or
  • 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. [CON] is a connector moiety (including a [MULTICON]) as otherwise described herein; and [LINKER] is a linking moiety as otherwise described herein which links [CPBM] to the [CRBM] group and optionally contains one or more connector moieties (which optionally connect(s) more than one chemical moiety to provide said linking moiety or which connects said linking moiety to said [CPBM] group or said [CRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • [CON] is a connector moiety (including a [MULTICON]) as otherwise described herein
  • [LINKER] is a linking moiety as otherwise described herein which links [CPBM] to the [CRBM] group and optionally contains one or more connector moieties (which optionally connect(s) more than one chemical moiety to provide said linking moiety or
  • X is -O-C(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 ) or C(R N1 )(R N1 )-C(R N1 )(R N1 ) when X is 2 atoms in length, X is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-O-C(R N1 )(R N1 )-, -O-C(R N1 )(R N1 )-O-, -O-C(R N1 )(R N1
  • R N1 is H.
  • X is OCH 2 or CH 2 O and R N1 is H.
  • the [CRBM]/[ASGPRBM] group is a group according to the chemical structure: where R 1 , R 2 and R 3 are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • the [CRBM]/[ASGPRBM] group is a group according to the chemical structure: where R A is -C 1 -C 3 alkyl optionally substituted with 1-5 halogen groups; ZA is -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) units, or -C(O)(CH2)IMNRM, where IM and R M are the same as above; and ZB is absent, (CH2)IM, C(O)-(CH2)IM-, or C(O)-(CH2)IM-NRM, where IM and RM are the same as above.
  • Z A is a PEG group containing 1-4 ethylene glycol units. In various embodiments, Z A is a PEG group containing 2-4 ethylene glycol units. In various embodiments, R A is C1-C3 alkyl optionally substituted with 1-5 fluorine atoms. In various embodiments, R A is -CH 3 optionally substituted with 1-3 fluorine atoms. In various embodiments, R A is -CH 2 CH 3 optionally substituted with 1-3 fluorine atoms; Note that the [CRBM][ASGPRBM] group set forth above may also be represented as follows:
  • neoplasia or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • Neoplasms include, without limitation, morphological irregularities in cells in tissue of a subject or host, as well as pathologic proliferation of cells in tissue of a subject, as compared with normal proliferation in the same type of tissue. Additionally, neoplasms include benign tumors and malignant tumors (e.g., colon tumors) that are either invasive or noninvasive.
  • Malignant neoplasms are distinguished from benign neoplasms in that the former show a greater degree of anaplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis.
  • neoplasms or neoplasias from which the target cell of the present disclosure may be derived include, without limitation, carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bowel, 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 diseases; sarcomas, particularly Ewing's sarcoma
  • neoplasms may be treated using compounds according to the present disclosure.
  • Representative common cancers to be treated with compounds according to the present disclosure include, for example, prostate cancer, metastatic prostate cancer, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing’s sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms’ tumor, neuroblastoma, hairy cell leuk
  • the present disclosure has general applicability treating virtually any cancer in any tissue, thus the compounds, compositions and methods of the present disclosure are generally applicable to the treatment of cancer and in reducing the likelihood of development of cancer and/or the metastasis of an existing cancer.
  • the cancer which is treated is metastatic cancer, a recurrent cancer or a drug resistant cancer, especially including a multiple drug resistant cancer.
  • metastatic cancer may be found in virtually all tissues of a cancer patient in late stages of the disease, typically metastatic cancer is found in lymph system/nodes (lymphoma), in bones, in lungs, in bladder tissue, in kidney tissue, liver tissue and in virtually any tissue, including brain (brain cancer/tumor).
  • the present disclosure is generally applicable and may be used to treat any cancer in any tissue, regardless of etiology.
  • tumor is used to describe a malignant or benign growth or tumefacent.
  • autoimmune disease refers to a disease or illness that occurs when the body tissues are attacked by its own immune system.
  • the immune system is a complex organization within the body that is designed normally to "seek and destroy" invaders of the body, including infectious agents.
  • MIF levels are often elevated.
  • the present disclosure seeks to inhibit or lower elevated MIF levels in patients with autoimmune disease (as well as inflammatory diseases and conditions and cancer) and by decreasing MIF levels, ameliorate many of the symptoms and secondary effects of these disease states and conditions.
  • autoimmune diseases which often exhibit high expressed levels of MIF including, for example, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vtiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among numerous others.
  • autoimmune diseases which may be treated by compounds and pharmaceutical compositions according to the present disclosure includes Addison's Disease, Autoimmune polyendodrine syndrome (APS) types 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Grave's disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, coeliac disease, Crohns' disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APlS), aplastic anemia, autoimmune hemolytica anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglulinemia, Evans sndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult
  • inflammatory disease is used to describe a disease or illness with acute, but more often chronic inflammation as a principal manifestation of the disease or illness.
  • Inflammatory diseases include diseases of neurodegeneration (including, for example, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease; other ataxias), diseases of compromised immune response causing inflammation (e.g., dysregulation of T cell maturation, B cell and T cell homeostasis, counters damaging 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, Sjogren’s disease; hyperglycemic disorders, diabetes (I and II), affecting lipid metabolism islet function and/or structure, pancreatic ⁇ -cell death and related hyperglycemic disorders, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g.
  • dyslipidemia e.g. hyperlipidemia as expressed by obese subjects, elevated low-density lipoprotein (LDL), depressed high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome, liver disease, renal disease (apoptosis in plaques, 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 associated conditions such as cardiac and neurological (both central and peripheral) manifestations including stroke, age-associated dementia and sporadic form of Alzheimer's disease, and psychiatric conditions including depression), stroke and spinal cord injury, arteriosclerosis, among others.
  • dyslipidemia e.g. hyperlipidemia as expressed by obese subjects, elevated low-density lipoprotein (LDL), depressed high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome, liver disease, renal disease (apoptosis in plaques
  • linker refers to a chemical entity including a complex linker connecting a circulating protein binding moiety (CPBM) to the cellular receptor binding moiety (CRBM) including an asialoglycoprotein receptor binding moiety (ASGPRBM), optionally through at least one (preferably one or two) connector moiety [CON] through covalent bonds in compounds according to the present disclosure.
  • CPBM circulating protein binding moiety
  • CRBM cellular receptor binding moiety
  • ASGPRBM asialoglycoprotein receptor binding moiety
  • the linker between the two active portions of the molecule ranges from about 5 ⁇ to about 50 ⁇ or more in length, about 6 ⁇ to about 45 ⁇ in length, about 7 ⁇ to about 40 ⁇ in length, about 8 ⁇ to about 35 ⁇ in length, about 9 ⁇ to about 30 ⁇ in length, about 10 ⁇ to about 25 ⁇ in length, about 7 ⁇ to about 20 ⁇ in length, about 5 ⁇ to about 16 ⁇ in length, about 5 ⁇ to about 15 ⁇ in length, about 6 ⁇ to about 14 ⁇ in length, about 10 ⁇ to about 20 ⁇ in length, about 11 ⁇ to about 25 ⁇ in length, etc.
  • Linkers which are based upon ethylene glycol units and are between 2 and 15 glycol units, 1 and 8 glycol units, 1, 2, 3, 4, 5, and 6 glycol units in length may be preferred, although the length of certain linkers may be far greater.
  • the CPBM group and the CRBM/ASGPRBM group may be situated to advantageously take advantage of the biological activity of compounds according to the present disclosure which bind to receptors, including asialoglycoprotein receptors on hepatocytes and other cells resulting in the selective and targeted degradation of circulating proteins within the lysosomal degradation mechanism or other degradation mechanism of the hepatocytes.
  • linker component The selection of a linker component is based on its documented properties of biocompatibility, solubility in aqueous and organic media, and low immunogenicity/antigenicity. Although numerous linkers may be used as otherwise described herein, a linker based upon polyethyleneglycol (PEG) linkages, polypropylene glycol linkages, or polyethyleneglycol-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.) may be favored as a linker because of the chemical and biological characteristics of these molecules.
  • PEG polyethyleneglycol
  • polyethylene (PEG) linkages of between 2 and 15 ethylene glycol units is preferred.
  • one or more additional groups e.g., methylene groups, amide groups, keto groups, amine groups, etc., with methylene groups or amide groups being preferred
  • methylene groups or amide groups may be covalently attached at either end of the linker group to attach to a CRBM/ASGPRBM group, a [CON] group, another linker group or a CPBM group.
  • Alternative linkers may include, for example, polyamino acid linkers of up to 100 amino acids (of any type, preferably D- 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 connecting groups (preferably 1 or 2 connecting groups at one or both ends of the polyamino acid linker).
  • polyamino acid linkers of up to 100 amino acids (of any type, preferably D- 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
  • Preferred linkers include those according to the chemical structures: or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 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 ; where Ra is H, C1-C3 alkyl or alkanol or forms a cyclic ring with R 3 (proline) and R 3 is a side chain derived from a D- or L amino acid (preferably a naturally occurring L-amino acid) preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or
  • a linker according to the present disclosure comprises a polyethylene glycol linker containing from 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 is bonded a lysine group or other amino acid moiety at one or both ends of the linker (which can consist of between 1 and 10 amino acids which can bind the CPBM and/or the CRBM/ASGPRBM group.
  • Still other linkers comprise amino acid residues (D or L) which are bonded to CPBM and/or CRBM/ASGPRBM moieties as otherwise described herein.
  • the amino acid has anywhere from 1-15 methylene groups separating the amino group from the acid (acyl) group in providing a linker to the MIFBM and/or the ASGPRBM group, wherein the linker contains 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 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5 amino acid groups linked together through peptide linkages to form the linker.
  • This linker is represented by the chemical structure: , where R am is H or a C 1 -C 3 alkyl optionally substituted with one or two hydroxyl groups; na is 1-15, 1-12, 1-10, 1-8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; 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 51 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.
  • the linker is according to the chemical formula: , where Z and Z’ are each independently a bond, -(CH 2 ) i -O, -(CH 2 ) i -S, -(CH 2 ) i -N-R, wherein said -(CH 2 ) i group, if present in Z or Z’, is bonded to a connector (CON), CPBM or CRBM/ASGPRBM; each R is H, or a C1-C3 alkyl or alkanol group; each R 2 is independently H or a C1-C3 alkyl group; each Y is independently a bond, O, S or N-R; 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; D is a bond, with the proviso that Z, Z’ and D
  • linkers which are included herein include linkers according to the chemical structure: where 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 each n” is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 2, 3, 4 or 5).
  • Linkers also can comprise two or more linker segments (based upon the linkers described above) which are attached directly to each other or through [CON] groups forming a complex linker.
  • linkers which include a [CON] group connecting a first and second (PEG) linker group include the following structures: or where 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 each n” is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 3).
  • Each of these linkers can also contain alkylene groups containing from 1 to 4 methylene groups at the distal ends of each linker group in order to facilitate connection of the linker group.
  • linkers which include a connector group [CON] include groups which are represented by the chemical formula: PEG-[CON]-PEG, wherein each PEG linker is independently a polyethylene glycol group containing from 1-12 ethylene glycol units and [CON] is a connector group as otherwise set forth herein.
  • [CON] is: .
  • the term “connector”, symbolized in the generic formulas by “CON” or [CON] is used to describe a chemical moiety which is optionally included in bifunctional compounds according to the present disclosure which forms from the reaction product of an activated linker with a CPBM moiety (which also is preferably activated for covalently bonding the linker with the moiety) or a CRBM/ASGPRBM group with an activated linker.
  • the connector group is often the resulting moiety which forms from the facile condensation of two or more separate chemical fragments which contain reactive groups which can provide connector groups as otherwise described to produce bifunctional or multifunctional compounds according to the present disclosure. It is noted that a connector may be distinguishable from a linker in that the connector is the result of a specific chemistry which is used to provide bifunctional compounds according to the present disclosure wherein the reaction product of these groups results in an identifiable connector group or part of a connector group which is distinguishable from the linker group, although in certain instances, the connector group is incorporated into and integral with the linker group as otherwise described herein.
  • a connector group may be linked to a number of linkers to provide multifunctionality (i.e., more than one CPBM moiety and/or more than one CRBM/ASGPRBM moiety) within the same molecule. It is noted that there may be some overlap between the description of the connector group and the linker group such that the connector group is actually incorporated or forms part of the linker, especially with respect to more common connector groups such as amide groups, oxygen (ether), sulfur (thioether) or amine linkages, urea or carbonate –OC(O)O- groups or as otherwise described herein.
  • a connector may be connected to CPBM, CRBM/ASGPRBM or a linker at positions which are represented as being linked to another group using the symbol: .
  • any of an CRBM/ASGPRBM, a linker or a CPBM group may be bonded to such a group.
  • the linker may be at one or more positions of a moiety where an open valence is present.
  • suitable [CON] connector groups which are used in the present disclosure include the following chemical groups:
  • X 2 is CH 2 , O, S, NR 4 , C(O), S(O), S(O) 2 , -S(O) 2 O, -OS(O) 2 , or OS(O) 2 O;
  • X 3 is O, S, NR 4 ;
  • R 4 is H, a C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group;
  • R 1 is H or a C1-C3 alkyl group (preferably H); and n'' is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 3); or the connector group [CON] is a group according to the chemical structure: , where R 1CON , R 2CON , and R 3CON are each independently H, -(CH2)MC1, - (CH 2 ) MC1a C(O)
  • MC1 is 1 or 2. In various embodiments, MC1a is 0, 1, or 2.
  • the triazole group, indicated above, may be a preferred connector group.
  • An additional preferred connector group is: , which is linked to at least one CPBM and/or at least one CRBM/ASPRGBM (preferably 3 CRBM/ASPRGBM moieties). This connector group may be used to form GN 3 as otherwise described herein. It is noted that each connector may be extended with one or more methylene groups to facilitate connection to a linker group, another CON group, a CPBM group or a CRBM/ASGPRBM group. It is noted that in certain instances, within context the diamide group may also function independently as a linker group.
  • the present disclosure is directed to compounds which are useful for removing circulating proteins which are associated with a disease state or condition in a patient or subject according to the general chemical structure of Formula II:
  • Formula II The term "Extracellular Protein Targeting Ligand” as used herein is interchangeably used with the term CPBM (cellular protein binding moiety).
  • ASGPR Ligand as used herein is interchangeably used with an asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.
  • each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER- 2] to [CPBM] or to [CRBM].
  • [LINKER-2] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and/or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER-2] optionally itself contains one or more [CON] or [MULTICON] group(s);
  • k’ is an integer from 1 to 15;
  • j’ is an integer from 1 to 15;
  • h and h’ are each independently an integer from 0 to 15;
  • iL is an integer from 0 to 15; with the proviso that at least one of h, h’ and iL is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • a [MULTICON] group can connect one or more of a [CRBM] or [CPBM] to one or more of a [LINKER-2].
  • [LINKER-2] has a valency of 1 to 10.
  • [LINKER-2] has a valency of 1 to 5.
  • [LINKER-2] has a valency of 1, 2 or 3.
  • the [LINKER-2] includes one or more of Linker A , Linker B , Linker C , Linker D , and/or combinations thereof as defined herein.
  • 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.
  • 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.
  • 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.
  • X 1 is 1 to 5 contiguous atoms independently selected from O, S, N(R b ), and C(R 4 )(R 4 ), wherein if X 1 is 1 atom then X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ), if X 1 is 2 atoms then no more than 1 atom of X 1 is O, S, or N(R 6 ), if X 1 is 3, 4, or 5 atoms then no more than 2 atoms of X 1 are O, S, or N(R 6 ); R 3 at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and, heteroaryl, heterocycle,
  • the compound of Formula II has one of the following structures:
  • the ASGPR ligand is linked at either the C 1 or C 5 (R 1 or R 5 ) position to form a degrading compound. In various embodiments, the ASGPR ligand is linked at C 6 position to form a degrading compound.
  • non- limiting examples of ASGPR binding compounds of Formula II include: or the bi- or tri- substituted versions thereof or pharmaceutically acceptable salts thereof, where the bi- or tri- substitution refers to the number additional galactose derivatives attached to a linker moiety.
  • an ASGPR ligand is typically linked through to the Extracellular Protein Targeting Ligand in the C 5 position (e.g., which can refer to the adjacent C 6 carbon hydroxyl or other functional moiety that can be used for linking purposes).
  • the linker and Extracellular Protein Targeting Ligand is connected through the C 1 position, then that carbon is appropriately functionalized for linking, for example with a hydroxyl, amino, allyl, alkyne or hydroxyl-allyl group.
  • the ASGPR ligand is not linked in the C 3 or C 4 position, because these positions chelate with the calcium for ASGPR binding in the liver.
  • an ASGPR ligand useful for incorporation into a compound of Formula II is selected from:
  • the compound of Formula II is selected from:
  • the compound of Formula II is selected from:
  • the compound of Formula II is an Extracellular Protein degrading compound in which the ASGPR ligand is a ligand as described herein .
  • the ASGPR ligand is linked at either the C1 or C5 (R 1 or R 5 ) position to form a degrading compound.
  • the ASGPR ligand is linked at C6.
  • non- limiting examples of ASGPR binding compounds of Formula II include:
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR b COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • R 2 is selected from -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and-NR 6 -(6-membered heteroaryl), each of which R 2 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.
  • the compound of Formula II is selected from:
  • an ASGPR ligand useful for incorporation into a compound of Formula II is selected from:
  • R 1 is hydrogen. 1 In certain embodiments, in the compound of Formula II, R is In certain embodiments, in the compound of Formula II, R 1 is 1 In certain embodiments, in the compound of Formula II, R is 1 In certain embodiments, in the compound of Formula II, R is In certain embodiments, in the compound of Formula II, R 1 is In certain embodiments, in the compound of Formula II, R 1 is C0-C6alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.
  • R 1 is alkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is F. In certain embodiments, in the compound of Formula II, R 1 is Cl. In certain embodiments, in the compound of Formula II, R 1 is Br.
  • R 1 is aryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is heteroaryl alkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is heterocycle optionally substituted with 1, 2, 3, or 4 substituents.
  • R 1 is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.
  • R 1 is -O-alkenyl, -O-alkynyl, C0-C6alkyl-OR 6 , C0-C6alkyl-SR 6 , C0-C6alkyl-NR 6 R 7 , C0-C6alkyl-C(O)R 3 , C0-C6alkyl-S(O)R 3 , C0-C6alkyl-C(S)R 3 , C0-C6alkyl-S(O)2R 3 , C0-C6alkyl-N(R 8 )-C(O)R 3 , C0-C6alkyl-N(R 8 )- S(O)R 3 , C 0 -C 6 alkyl-N(R 8 )-C(S)R 3 , C 0 -C 6 alkyl-N(R 8 )-S(O) 2 R 3 C 0 -C 6 alkyl-O-C(O)R 3 ,
  • R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is heterocycle optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is heterocycle optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is -NR 8 C(O)NR 9 S(O) 2 R 3 optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is -NR 8 -S(O)2-R 10 optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is -NR 8 -C(NR 6 )-R 3 optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is hydrogen.
  • R 2 is R 10 , In certain embodiments, in the compound of Formula II, R 2 is alkyl-C(O)-R 3 . In certain embodiments, in the compound of Formula II, R 2 is -C(O)-R 3 . In certain embodiments, in the compound of Formula II, R 2 is alkyl. In certain embodiments, in the compound of Formula II, R 2 is haloalkyl. In certain embodiments, in the compound of Formula II, R 2 is -OC(O)R 3 . In certain embodiments, in the compound of Formula II, R 2 is -NR 8 -C(O)R 10 .
  • R 2 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is allyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -NR 6 -alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is -NR 6 -alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -NR 6 -heteroaryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -NR 6 -aryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R 2 is -O-aryl optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is -O-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.
  • R 2 is selected from and In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from R is an optional substituent as defined herein. In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2A is selected from wherein R is an optional substituent as defined herein. In certain embodiments, in the compound of Formula II, R 2A is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from
  • R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from
  • R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II
  • R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is selected from In certain embodiments, in the compound of Formula II, R 2 is a spirocyclic heterocycle, for example, and without limitation, In certain embodiments, in the compound of Formula II, R 2 is a silicon containing heterocycle, for example, and without limitation, .
  • R 2 is substituted with SF5, for example, and without limitation, in the compound of Formula II, R 2 is substituted with a sulfoxime, for example, and without limitation, in certain embodiments, in the compound of Formula II, R 10 is selected from bicyclic heterocycle. In certain embodiments, in the compound of Formula II, R 10 is selected from spirocyclic heterocycle. In certain embodiments, in the compound of Formula II, R 10 is selected from -NR 6 - heterocycle.
  • R 10 is selected from In certain embodiments, in the compound of Formula II, R 10 is selected from In certain embodiments, in the compound of Formula II, R 10 is selected from In certain embodiments, in the compound of Formula II, R 10 is selected from . In certain embodiments, in the compound of Formula II, Cycle is selected from
  • R 30 is selected from: In certain embodiments, in the compound of Formula II, R 200 is I n certain embodiments, in the compound of Formula II, R is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is In certain embodiments, in the compound of Formula II, R 200 is ertain embodiments, in the compound of Formula II, R 20 In c 0
  • Linker A is bond and Linker B is In certain embodiments, in the compound of Formula II, Linker B is bond and Linker A is In certain embodiments, in the compound of Formula II, a divalent residue of an amino acid is selected from
  • a divalent residue of a dicarboxylic acid is generated from a nucleophilic addition reaction:
  • Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a nucleophilic addition reaction include:
  • a divalent residue of a dicarboxylic acid is generated from a condensation reaction:
  • Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a condensation include:
  • Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include:
  • Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include: Non-limiting embodiments of a divalent residue of a saturated monocarboxylic acid is selected from butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH 2 ) 5 CH 2 -), capric acid (-OC(O)(CH 2 ) 8 CH 2 -), lauric acid (- OC(O)(CH 2 ) 10 CH 2 -), myristic acid (-OC(O)(CH 2 ) 12 CH 2 -), pentadecanoic acid (- OC(O)(CH2)13CH2-), palmitic acid (-OC(O)(CH2)14CH2-), stearic acid (-OC(O)(CH2)16CH2-), behenic acid (-OC(O)(CH2)20CH2-), and lignoceric acid (-OC(O)(CH
  • Non-limiting embodiments of a divalent residue of a fatty acid is selected from linoleic acid (-C(O)(CH 2 ) 7 (CH) 2 CH 2 (CH) 2 (CH 2 ) 4 CH 2 -), docosahexaenoic acid (-C(O)(CH 2 ) 2 (CHCHCH 2 ) 6 CH 2 -), eicosapentaenoic acid (- C(O)(CH2)3(CHCHCH2)5CH2-), alpha-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-) stearidonic acid (-C(O)(CH 2 ) 4 (CHCHCH 2 ) 4 CH 2 -), y-linolenic acid (- C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (- C(O)(CH2)3,(CHCHCH2)4(CH2)4CH2-), docosatetraenoic
  • Linker C is selected from: wherein: R 22 is independently at each occurrence selected from the group consisting of 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 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; and the remaining variables are as defined herein.
  • Linker D is selected from: wherein: R 32 is independently at each occurrence selected from the group consisting of alkyl, N + X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; X- is an anionic group, for example Br- or Cl -; and all other variables are as defined herein.
  • Linker A is selected from: wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments, in the compound of Formula II, Linker A is selected from:
  • Linker B is selected from: In certain embodiments, in the compound of Formula II, Linker B is selected from:
  • Linker B in the compound of Formula II, is selected from:
  • Linker B , Linker C , or Linker D is selected from: wherein tt and ss are as defined herein. In certain embodiments, in the compound of Formula II, Linker B , Linker C , or Linker D is selected from:
  • each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein.
  • Linker B , Linker C , or Linker D is selected from:
  • each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 23, or 4 of any combination of halogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence: and tt and ss are as defined herein.
  • Linker B , Linker C , or Linker D is selected from:
  • each heteroaryl and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein.
  • Linker A is selected from: In certain embodiments, in the compound of Formula II, Linker A is selected from: In certain embodiments, in the compound of Formula II, Linker A is selected from:
  • Linker A is selected from: In certain embodiments, in the compound of Formula II, Linker B is selected from: In certain embodiments, in the compound of Formula II, Linker B is selected from:
  • Linker B is selected from:
  • Linker B is selected from:
  • Linker C is selected from: In certain embodiments, in the compound of Formula II, Linker C is selected from:
  • Linker C is selected from:
  • Linker C is selected from: In certain embodiments, in the compound of Formula II, Linker C is selected from:
  • Linker C is selected from:
  • Linker C is selected from:
  • Linker D is selected from:
  • Linker D is selected from:
  • LinkerD is selected from: In certain embodiments, in the compound of Formula II, Linker D is selected from: In certain embodiments, in the compound of Formula II, Linker D is selected from:
  • Linker D is selected from: In certain embodiments, in the compound of Formula II, Linker D is selected from:
  • the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from
  • Linker A is selected from: In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from, in the compound of Formula II, the Linker A is selected from:
  • the Linker A is selected from
  • the Linker A is selected from
  • the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from
  • the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker A is selected from In certain embodiments, in the compound of Formula II, the Linker B is selected from In certain embodiments, in the compound of Formula II, the Linker B is selected from In certain embodiments, in the compound of Formula II, the Linker B is selected from In certain embodiments, in the compound of Formula II, the Linker B is selected from wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R 21 .
  • Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from:
  • the Linker B is selected from: In certain embodiments, in the compound of Formula II, the Linker B is selected from:
  • Linker B -Linker A is selected from: In certain embodiments, in the compound of Formula II, Linker B -Linker A is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from:
  • the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from:
  • the Linker C is selected from: wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R 21 . In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from: In certain embodiments, in the compound of Formula II, the Linker C is selected from:
  • the Linker C is selected from: In certain embodiments, in the compound of Formula II, Linker C -(Linker A ) 2 is selected from: In certain embodiments, in the compound of Formula II, Linker C -(Linker A )2 is selected from: In certain embodiments, in the compound of Formula II, Linker C -(Linker A ) 2 is selected from: In certain embodiments, in the compound of Formula II, Linker C -(Linker A ) 2 is selected from:
  • Linker D is selected from:
  • Linker D is selected from: wherein each is optionally substituted with 1, 2, 3, or 4 substituents are selected from R 21 .
  • Linker B -(Linker A ) is selected from
  • Linker C -(Linker A ) is selected from
  • Linker D -(Linker A ) is selected from
  • R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, 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 5 is independently selected from hydrogen, heteroalkyl, , C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C 0 -C 6 alkyl- OR 6 , C 0 -C 6 alkyl-SR 6 , C 0 - C6alkyl-NR 6 R 7 , C0-C6alkyl-C(O)R 3 , C0-C6alkyl-S(O)R 3 , C0-C6alkyl- C(S)R 3 , C0-C6alkyl- S(O) 2 R 3 , C 0 -C 6 alkyl-N(R 8 )
  • R 6 and R 7 are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroaryl alkyl, alkenyl, alkynyl, and, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 .
  • R 8 and R 9 are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.
  • the compound of Formula II has the structure of Formula II- A.
  • a compound of Formula II-A having the structure: Formula II-A wherein: [CPBM] is a Circulating Protein Binding Moiety which 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; [ASGPBM] is an asialoglycoprotein receptor binding moiety having the structure selected from each [CON] is an optional connector chemical moiety which, when present, connects the [LIN] to [CPBM] or to [ASGPBM]; [LIN] is [LINKER] or [LINKER-2], each of which is a chemical moiety having a valency from 1 to 15, which covalently attaches to one or more [ASGPBM] or [CPBM] groups, optionally through a [CON], wherein the [LIN] optionally itself contains one or more [CON] groups; Z B is absent, (CH 2 ) IM , C(O)-(CH 2 ) IM -, or C
  • IM is independently at each occurrence an integer from 0 to 6
  • K is independently at each occurrence an integer from 0 to 4
  • 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; with the proviso that at least one of h, h’, and i L is at least 1, or a salt, stereoisomer, or solvate thereof.
  • the ASGPR binding moieties can be any of the moieties described in: Reshitko, G. S., 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, A.
  • the ASGPR binding moiety can be a moiety having the structure of M1, M2, M3, or M4, or a combination thereof.
  • X is independently at each occurrence O, NH, or S.
  • compounds of Formula I or Formula II can have one, two, or three ASGPR binding moieties with the structure of M1, M2, M3, or M4. M3 M4.
  • ASGPR binding moieties M1 to M4 can be conjugated to any suitable [CON], [Linker], or [Linker-2] as described herein and in Congdon, M.
  • the ASGPR binding moiety can be a moiety having the structure of M5: , M5.
  • each R is independently at each occurrence R 1 or R 2 , .
  • compounds of Formula I or Formula II contain an ASGPR binding moiety with the structure of M5.
  • each R in M5 is R1.
  • each R in M5 is R2.
  • ASGPR binding moiety M5 can be conjugated/bonded to any suitable [CON], [Linker], or [Linker-2] as described herein and in Reshitko, G. S., et al., “Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor,” Bioconjugate Chem, doi: 10.1021/acs.bioconjchem.0c00202. 3.
  • the ASGPR binding moiety can be the galactose behenic acid ester-derived moiety M7: In the structure M7, Y is OH or NHAc.
  • the ASGPR binding moiety can be the agarose behenic acid ester-derived moiety M8: .
  • ASGPR binding moieties M7 and M8 can be conjugated to any suitable [CON], [Linker], or [Linker-2] as described herein and in Dhawan, V., et al., “Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting – Synthesis and comparative in silico and in vitro assessment,” Carbohydrate Research 509 (2021) 108417, doi: 10.1016/j.carres.2021.108417. 4.
  • the ASGPR binding moiety can be any of the compounds 2- 18 below:
  • R is CH2OAc, COOH, or CH2OH.
  • Compounds 2-18 can be conjugated/bonded to any suitable [CON], [Linker], or [Linker-2] as described herein and in Majouga, A. G., et al., “Identification of Novel Small-Molecule ASGP-R Ligands,” Current Drug Delivery, 2016, 13, 1303-1312, doi: 10.2174/1567201813666160719144651; Olshanova, A.
  • compounds 2-13 can be attached to a CON], [Linker], or [Linker-2] through or by reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone, or aromatic halogen contained in compounds 2-18.
  • Suitable reaction modes for attaching compounds 2-18 to a [CON], [Linker], or [Linker-2] as described herein include, but are not limited to, substitution (e.g.
  • Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.
  • an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group
  • a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester such as an alkyl and aryl sulfide group
  • sulfur-containing group such as an alkyl and aryl sulfide group
  • Non-limiting examples of organic groups include OR, OOR, OC(O)N(R) 2 , CN, CF 3 , OCF 3 , R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, 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, (CH 2 ) 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)SO 2 R, N(R)SO 2 N(R) 2
  • substituted refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms.
  • the substitution can be direct substitution, whereby the hydrogen atom is replaced by a functional group or substituent, or an indirect substitution, whereby an intervening linker group replaces the hydrogen atom, and the substituent or functional group is bonded to the intervening linker group.
  • direct substitution is: RR-H RR-Cl, wherein 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 intervening linker group, and 'zz' is an integer from 0 to 100 inclusive. When zz is 0, LL is absent, and direct substitution results.
  • (LL) zz can be linear, branched, cyclic, acyclic, and combinations thereof.
  • a halogen e.g., F, Cl, Br, and I
  • an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters
  • a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups
  • a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other hetero
  • Non-limiting examples of substituents that can be bonded to a 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 (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH 2 C(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 , (CH 2 ) 0-2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(
  • alkyl refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • alkenyl refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms.
  • alkynyl refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 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) among others.
  • acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning herein.
  • a nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen
  • the group is termed a "haloacyl” group.
  • An example is a trifluoroacetyl group.
  • cycloalkyl refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • heterocycloalkyl refers to a cycloalkyl group as defined herein in which one or more carbon atoms in the ring are replaced by a heteroatom such as O, N, S, P, and the like, each of which may be substituted as described herein if an open valence is present, and each may be in any suitable stable oxidation state.
  • aryl refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined herein.
  • substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.
  • aralkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • heterocyclyl refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.
  • a heterocyclyl ring can 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 that include fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.
  • heteroaryl refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring designated C x-y can be any ring containing 'x' members up to 'y' members, including all intermediate integers between 'x' and 'y' and that contains one or more heteroatoms, as defined herein.
  • Heterocyclyl rings designated Cx-y can also be polycyclic ring systems, such as bicyclic or tricyclic ring systems.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, gu
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional 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), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydry
  • heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • arylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.
  • heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
  • the term "amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., 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-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group refers to a substituent of the form -NH 2 , - NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each, except for -NR3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
  • alkylamino includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • halo means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl examples include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • epoxy-functional or "epoxy-substituted” as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system.
  • epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- epoxyhexyl.
  • the term "monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • the term "hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.
  • hydrocarbyl refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (C a - Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms.
  • (C 1 -C 4 )hydrocarbyl means the hydrocarbyl group can be methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ), or butyl (C 4 ), and (C 0 -C b )hydrocarbyl means in certa embodiments there is no hydrocarbyl group.
  • the term "C 6-10 -5-6 membered heterobiaryl” means a C 6-10 aryl moiety covalently bonded through a single bond to a 5- or 6-membered heteroaryl moiety.
  • the C 6-10 aryl moiety and the 5-6-membered heteroaryl moiety can be any of the suitable aryl and heteroaryl groups described herein.
  • Non-limiting examples of a C6-10-5-6 membered heterobiaryl include .
  • the C6-10-5-6 membered heterobiaryl is listed as a substituent (e.g., as an "R" group)
  • the C 6-10 -5-6 membered heterobiaryl is bonded to the rest of the molecule through the C 6-10 moiety.
  • the term "5-6 membered- C6-10 heterobiaryl" is the same as a C6-10-5- 6 membered heterobiaryl, except that when the 5-6 membered- C6-10 heterobiaryl is listed as a substituent (e.g., as an "R” group), the 5-6 membered- C 6-10 heterobiaryl is bonded to the rest of the molecule through the 5-6-membered heteroaryl moiety.
  • the term "C6-10- C6-10 biaryl” means a C6-10 aryl moiety covalently bonded through a single bond to another C 6-10 aryl moiety.
  • the C 6-10 aryl moiety can be any of the suitable aryl groups described herein.
  • Non-limiting example of a C 6-10 - C 6-10 biaryl include biphenyl and binaphthyl.
  • pharmaceutically acceptable salt or “salt” is used throughout the specification to describe a salt form of one or more of the compositions herein which are presented to increase the solubility of the compound in saline for parenteral delivery or in the gastric juices of the patient’s gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art.
  • salts may be preferred as neutralization salts of carboxylic acids and free acid phosphate containing compositions according to the present disclosure.
  • the term “salt” shall mean any salt consistent with the use of the compounds according to the present disclosure.
  • the term “salt” shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents.
  • coadministration shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time.
  • Chimeric antibody- recruiting compounds according to the present disclosure may be administered with one or more additional anti-cancer agents or other agents which are used to treat or ameliorate the symptoms of cancer, especially prostate cancer, including metastatic prostate cancer.
  • additional anticancer agent refers to a compound other than the chimeric compounds according to the present disclosure which may be used in combination with a compound according to the present disclosure for the treatment of cancer.
  • anticancer agents which may be coadministered in combination with one or more chimeric compounds according to the present disclosure include, for example, antimetabolites, inhibitors of topoisomerase 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, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kina
  • a number of other agents may be co-administered with chimeric compounds according to the present disclosure in the treatment of cancer.
  • agents include active agents, minerals, vitamins and nutritional supplements which have shown some efficacy in inhibiting cancer tissue or its growth or are otherwise useful in the treatment of cancer.
  • active agents include active agents, minerals, vitamins and nutritional supplements which have shown some efficacy in inhibiting cancer tissue or its growth or are otherwise useful in the treatment of cancer.
  • one or more of dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids and phytoestrogens, including beta-sitosterol may be utilized in combination with the present compounds to treat cancer.
  • compounds according to the present disclosure which contain a CPBM binding moiety (CPBM) and CRBM/ASGPR binding moiety selectively bind to circulating proteins and through that binding, facilitate the introduction of the cellular protein into hepatocytes or other cells (degrading cells) which bind the CRBM/ASGPRBM selectively, where, the circulating protein, inside the hepatocyte or other degrading cell is degraded and removed from circulation.
  • CPBM CPBM binding moiety
  • ASGPRBM binds the CRBM/ASGPRBM
  • compositions comprising combinations of an effective amount of at least one compound disclosed herein, often a bi-functional chimeric compound (containing at least one MIFBM group or antibody binding moiety and at least one ASGPRBM) according to the present disclosure, and one or more of the compounds as otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present disclosure. These may be used in combination with at least one additional, optional anticancer agent as otherwise disclosed herein.
  • the compositions of the present disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations.
  • Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorb
  • compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, among others.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally (including via intubation through the mouth or nose into the stomach), intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • the pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this disclosure may also be administered topically, especially to treat skin cancers, psoriasis or other diseases which occur in or on the skin.
  • Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • Topically-acceptable transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components 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, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutical compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • benzyl alcohol or other suitable preservatives to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the amount of compound in a pharmaceutical composition of the instant disclosure that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration.
  • the compositions should be formulated to contain between about 0.05 mg to about 1.5 g, from 0.1 mg to 1 g, 0.5 mg to 750 mg, more often about 1 mg to about 600 mg, and even more often about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one additional compound which may be used to treat cancer, prostate cancer or metastatic prostate cancer or a secondary effect or condition thereof.
  • Methods of treating patients or subjects in need for a particular disease state or condition as otherwise described herein, especially cancer comprise administration of an effective amount of a pharmaceutical composition comprising therapeutic amounts of one or more of the novel compounds described herein and optionally at least one additional bioactive (e.g. anti-cancer, anti-inflammatory) agent according to the present disclosure.
  • compositions could be formulated so that a therapeutically effective dose of 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 of patient/day or in some embodiments, greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg/kg of the novel compounds can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.
  • a patient or subject e.g.
  • an inflammatory disease or cancer can be treated by administering to the patient (subject) an effective amount of a chimeric/bi-functional compound according to the present disclosure including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known pharmaceutical agents, preferably agents which can assist in treating autoimmune and/or inflammatory diseases or cancer, including metastatic cancer or recurrent cancer or ameliorating the secondary effects and/or symptoms associated with these disease states and/or conditions.
  • This treatment can also be administered in conjunction with other conventional therapies, such as radiation treatment or surgery for cancer.
  • the present compounds can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel, or solid form, or by aerosol form.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day.
  • a typical topical dosage will range from about 0.01-3% wt/wt in a suitable carrier.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of about 25-500 mg is often convenient.
  • the active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 ⁇ M. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed 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 excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
  • the active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active compound or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, anti-inflammatory agents, immunosuppressants, antibiotics, antifungals, or antiviral compounds.
  • one or more chimeric/bi-functional CPBM binding compound according to the present disclosure is co-administered with another anticancer agent and/or another bioactive agent, as otherwise described herein.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, 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 the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, prop
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • PBS physiological saline or phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled and/or sustained release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions or cholestosomes may also be pharmaceutically acceptable carriers.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound are then introduced into the container.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • FIGs.1, 7, and 13 attached hereto identify particular compounds according to the present disclosure which exhibit activity in binding to and reducing and/or eliminating unwanted circulating proteins for therapeutic and/or diagnostic purposes.
  • FIG.16 shows the synthesis of azide/amide carboxylic end capped PEG linker intermediates which may be condensed onto an alkynyl precursor (e.g.
  • FIG.17 describes a general method for conversion of PEG molecules into hydroxyl azides.
  • the PEG compound is tosylated (TsCl, DCM, in the presence of base) at reduced temperature and further reacted with sodium azide at elevated temperature in a non- nucleophilic solvent.
  • the final azidoalcohol is used in subsequent figures.
  • FIG.18 describes the synthesis of a mesylated azide from a starting PEG molecule employing the same synthetic steps to reach the intermediate azido alcohol. This is then treated with MsCl in pyridine to afford the final compound.
  • FIG.19 shows the synthesis of the GalNAc ASGPR ligand linked through PEG to a terminating amine. Pentaacetyl galactosamine is reacted with TMSOTf at elevated temperature in DCE to produce a bicyclic intermediate, which is then reacted with an azido alcohol to give an azide intermediate (TMSOTf, DCE). This molecule is then subjected to a Staudinger reduction to give an amine which is used in subsequent figures.
  • FIG.20 shows the synthesis of a higher affinity bicylic ASGPR ligand.
  • Galactose pentaacetate is treated with HBr/AcOH to give the brominated intermediate, which is treated with Zn and CuSO4 (water/AcOH) to give the galactal.
  • This is treated with ammonium cerium nitrate and sodium azide at reduced temperature (MeCN) to give the disubstituted intermediate compound.
  • This is then treated with strong base (NaOMe/MeOH) to give the triol azide intermediate.
  • This compound is silylated completely (TMSCl/pyr) then the primary alcohol is deprotected (potassium carbonate, MeOH, lowered temperature) and oxidized (Dess-Martin Periodinane, DCM).
  • FIG.21 shows the synthesis of a trifluoro-acetate derivative of the bicyclic ASGPR ligand.
  • the triol azide is reduced (Pd/C, MeOH) to give the intermediate amine, which is then peracylated with trifuloroacetic anhydride.
  • the esters are hydrolyzed with strong base (NaOMe/HOMe) to give the intermediate amide, which is protected using dimethoxypropane in the presence of camphorsulfonic acid in DMF at elevated temperature.
  • FIG.22 shows the synthesis of the MIF-targeting linker to a monovalent linker, which is synthesized through analogous methods as described in a previous figure.
  • the boc- protected methyl ester is deprotected with TFA in DCM, then coupled to the MIF-targeting carboxylic acid (HBTU, DIPEA, DMF). Subsequent hydrolysis with strong base (NaOH/dioxane/H2O) gives the MIF-targeting carboxylic acid.
  • FIG.23 shows the synthesis of the di-carboxylic acid MIF targeting motif, which is synthesized as described in previous figures.
  • FIG.24 shows the synthesis of a tris base-derived trivalent linker. Tris base is treated with di-t-butyl dicarbonate in the presence of base to give the boc protected triol, which is then reacted with acrylonitrile in the presence of base (dioxane/H2O) to give a trinitrile intermediate. This is then converted to the methyl ester through treatment with strong acid in methanol. The amine is then reacted with Cbz-glycine through a DCC-mediated amide formation, and deprotected to give a tricarboxylic acid that is used in subsequent figures.
  • FIG.25 describes the synthesis of an ASGPR-targeting moiety employing three GalNAc ASGPR ligands.
  • the tricarboxylic acid is reacted with amine-terminated protected GalNAc (amide bond formation in the presence of HBTU and DIPEA), then deprotected by reduction (Pd/C, solvent) and treatment with strong base (NaOMe/MeOH).
  • FIG.26 shows the synthesis of the tri-carboxylic acid MIF targeting motif, which is synthesized as described in previous figures.
  • FIG.27 shows the synthesis of the MIF NVS alkyne precursor which can be reacted with an azido reactant containing a carboxylic acid (as set forth in subsequent figures) to provide MIF-NVS-carboxylic acid capped reactants to produce bifunctional compounds according to the present disclosure.
  • FIG.28 shows the synthesis of the MIF-targeting moiety terminating in a carboxylic acid.2-chloroquinolin-6-ol is reacted with ethyl 4-bromobutanoate in the presence of base (DMF, elevated temperature) to give an aryl chloride that then undergoes Sonogashira coupling at elevated temperature with ethynyltrimethylsilane.
  • DMF base
  • the intermediate silylated compound is deprotected with TBAF (DCM/THF).
  • DCM/THF TBAF
  • a click reaction then forms a triazole between the alkyne intermediate and in situ synthesized 4-azido-2-fluorophenol to give an ethyl ester intermediate that is hydrolyzed with strong base (NaOH/dioxane) to give the carboxylic acid that is used in subsequent figures.
  • FIG.29 describes the synthesis of the bifunctional molecule MIF-NVS-PEGn-GN3 through HBTU-mediated coupling in DMF of the ASPGR-targeting amine and the MIF targeting carboxylic acid prepared by first forming the MIF-targeting carboxylic acid by condensing the reactant azido PEG-carboxylic acid onto the MIF moiety containing a alkyne terminated PEG group.
  • FIG.30 describes the synthesis of bifunctional molecules MIF-GN3 and MIF-PEGn- GN3 through HATU-mediated coupling (DMF, DIPEA) of ASGPR-targeting amine and MIF-targeting carboxylic acid.
  • FIG.31 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing one bicyclic ASGPR AcF3 ligands.
  • MIF-binding mono-carboxylic acid is treated with HBTU, DIPEA, the amine terminated ligand, and DMF to give the amide, which is then deprotected with 1M HCl to give the final compound.
  • FIG.32 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing two bicyclic ASGPr ligands. It is synthesized as described above.
  • FIG.33 describes the synthesis of the bifunctional molecule targeting MIF and ASGPR, containing three bicyclic ASGPr ligands. It is synthesized as described above.
  • FIG.34 shows the synthesis of DNP-GN3.2,4-dinitro chlorobenzene was treated with an amino carboxylic acid in the presence of weak base to give the di-nitro analine carboxylic acid intermediate. Further steps were carried out as described for previous molecules.
  • FIG.35 shows the synthesis of DNP-AcF3-3, which was carried out with methods analogous previous compounds.
  • FIG.36 shows the synthetic scheme used to obtain IBA-GN3. Pentaethylene glycol was treated with tosyl chloride in the presence of base to give the mono-tosylated alcohol, which was then treated with sodium azide at elevated temperature to give the azidoalcohol.
  • Cyanuric chloride was treated with (4- (methoxycarbonyl)phenyl)methanaminium in THF and diisopropylethlamine at -78o C to give the mono-substituted product. This was then treated with cyclohexylmethanamine at room temperature to afford the second substitution. The final substitution was accomplished under elevated temperature with (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amine to give the trisubstituted triazine.
  • FIG.38 shows the synthetic scheme used to access FcIII-GN3.
  • the hexynyl peptide was prepared using standard solid phase peptide synthesis techniques. The peptide was removed from Rink resin using Reagent L, then oxidized using ammonium bicarbonate buffer (pH8-9) in MeOH under air to give the cyclic peptide.
  • FIG.39 shows the synthetic scheme used to access FcIII-4c-GN3, which was accomplished using methods described above.
  • FIGs.40-43 describe the synthesis of bifunctional molecules targeting MIF and ASGPr, containing three bicyclic ASGPR ligands with different substitutions on the 2-amine of the sugar. They are synthesized through analagous methods described above as set forth in the attached figures.
  • FIG.44 shows the synthesis of compound MIF-18-3. Tri-acyl galactal was deprotected with ammonia in methanol, then tri-benzyl protected with benzylbromide in the presence of base.
  • the alkene was hydrolyzed overnight with HCl in THF/H2O, then oxidized with PCC to give an aldehyde.
  • Sodium azide was then added alpha to the carbonyl with KHMDS and TIBSN3 at lowered temperature.
  • the intermediated was then treated with p- OMePhMgBr in THF and toluene to give an intermediate alcohol, which was then reduced using Et3SiH in the presence of BF3-Et2O at reduced temperature.
  • the resulting azide was then reduced with Lindlar’s catalyst under a hydrogen atmosphere to give the corresponding amine, which was acylated with trifluoroacetic acid in pyridine.
  • FIG.45 shows the synthesis of compound MIF-31-3.
  • Galactosamine hydrochloride was fully protected with acetic anhydride, then treated with allyl alcohol in the presence of BF3 ehtrate to give the allyl intermediate.
  • Treatment with pivaloyl chloride in pyridine gave a di-Piv protected intermediate, which was treated with triflic anhydride and subsequently subjected to hydrolysis in water at elevated temperature.
  • FIG.46 shows the synthesis of compound MIF-15-3, which was synthesized using procedures analogous to compounds described above.
  • FIG.47 shows the synthesis of compound MIF-19-3. The molecule is synthesized through a late stage triazole-forming click reaction between the triazide and propionic acid in methanol in the presence of THPTA, copper sulfate, water, and sodium ascorbate. All other reactions are performed as described above.
  • FIG.48 shows the synthesis of compound MIF-16-3, which was synthesized using procedures analogous to compounds described above.
  • FIG.49 shows the synthesis of compound MIF-20-3, which was synthesized using procedures analogous to compounds described above.
  • FIG.50 shows the synthesis of compound MIF-14-3, which was synthesized using procedures analogous to compounds described above.
  • FIG.51 shows the synthesis of compound MIF-21-3, which was synthesized using procedures analogous to compounds described above.
  • FIG.52 shows the synthesis of compounds MIF-NVS-PEGN-GN3. PEG compounds were treated with tosyl chloride in the presence of base, then subsequently treated with sodium azide at elevated temperature to give azido alcohols. These intermediates were oxidized using Jones reagent to give carboxylic acid azides.
  • diethylene glycol was treated with base and propargyl bromide to give an alkynyl alcohol, which was then tosylated in the presence of base and subsequently treated with sodium iodide to give an iodinated intermediate.
  • This iodinated compound was then treated with 4-N-boc-aminophenol in the presence of base, which gave an ether intermediate that was treated with hydrochloric acid in dioxane to give an amino alkyne.
  • This amine was reacted with 2-hydroxy-4-(tert- butyldimethylsiloxy) benzaldehyde in the presence of sodium borohydride to give the cyclic intermediate, which was then treated with TBAF in THF to give the resulting alcohol.
  • FIGs.53-66 show the synthesis of a number of MIF-binding compounds with various ASGPRBM moieties. These are synthesized through methods analogous to those laid out above.
  • FIGs.70-88 show the synthesis of a number of further bifunctional compounds according to the present disclosure. Examples Proper protein section and turnover is a necessary process for maintaining homeostasis.
  • Newly synthesized proteins targeted for secretion are first trafficked to the endoplasmic reticulum, where they are post-translationally modified with N-linked glycan chains terminating in sialic acids.
  • terminal sialic acid residues are removed by circulating endogenous glycosydases.
  • This natural protein aging process unmasks galactose and N-acetylgalactose (GalNAc) residues, which bind the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes.
  • the ASGPR is a C-type lectin that removes aged circulating proteins with exposed GalNAc residues from circulation by trafficking them to lysosomes.
  • GalNAc residues displayed on the protein surface are necessary for high-affinity binding to – and subsequent endocytosis by – ASGPR.
  • these proteins are endocytosed, they are released from the ASGPR through depletion of calcium from the endosome and changes in binding site amino acid protonation changes due to a decrease in pH; the ASGPR is recycled back to the hepatocyte surface.
  • Endocytosed proteins are trafficked to late endosomes, which are fused with lysosomes. Lysosomal proteases then degrade endocytosed proteins, permanently removing them from circulation.
  • Non-glycosylated proteins are not known to be natural target for the ASGPR.
  • MIF macrophage inhibitory factor
  • MIF-AcF2 and MIF-AcF3 have been reported previously as high affinity binders for the ASGPR.
  • FIGURE 1 shows representative compounds according to the present disclosure. Note that the figure discloses compound 3w (negative control for MIF inhibition), MIF- NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1, MIF-AcF3-2 and MIF-AcF3- 3 .
  • 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. In an experiment the results of which are shown in FIGURE 2, A.
  • bifunctional molecules WJ-PEG4-GN3, WJ-PEG2- GN3, and NVS-PEG3-GN3 bound competitively with MIF-FITC, indicating that the bifunctional molecules maintain the ability to bind human MIF.
  • bifunctional molecules were able to deplete human MIF from the supernatant of culture HepG2 cells.
  • human MIF 100 nM was added to cell culture media in the presence of negative control MIF inhibitor 3w as well as bifunctional molecules MIF-NVS-PEGn-GN3, MIF- GN3, MIF-PEGn-Gn3, MIF-AcF3-1, MIF-AcF3-2, and MIF-AcF3-3. All molecules utilized a known MIF-binding ligand. Experiments were performed in 96 well plates (approximate surface area .3 cm 2 ).
  • HepG2 cells were grown to 90% confluency in RPMI media, then washed with PBS (2x) and treated with serum-free media (optimem + .1% BSA, + Pen/Strep) containing 100 nM huMIF (Cayman Chemical) and compounds (when applicable).
  • Compounds were diluted from 1mM stock solutions in DMSO. After 24 hours, a sample of the supernatant (2 uL) was collected, diluted 1:100, and analyzed for MIF content by sandwich ELISA (and incubated for 24 hours in the presence or absence of compound). Remaining MIF levels were determined by sandwich ELISA (biolegend monoclonal anti- MIF and biotinylated anti-MIF antibodies).
  • FIGURE 4 shows the results of an experiment to determine whether or not MIF internalized by HepG2 cells is trafficked to lysosomes.
  • cells were incubated with rhuMIF (Cayman) at a concentration of 100 nM with 200 nM MIF-GN3.
  • FIGURE 5 shows that MIF-GN3 mediates the depletion of injected human MIF from mice.
  • Human MIF has a half-life of approximately 40 minutes in mice.
  • human recombinant MIF (Cayman chemical) was co-injected into mice with an anti-DNP IgG, which was used as an injection positive control.
  • nude mice were injected with 5 ⁇ g recombinant human MIF and 200 ⁇ g anti-DNP IgG as an injection control (FIGURE 4).
  • MIF-GN 3 was then injected at the concentration shown and blood drawn every twenty minutes over the course of two hours.
  • Serum was diluted 1:100 and analyzed for MIF content by sandwich ELISA (biolegend monoclonal anti-MIF and biotinylated anti-MIF antibodies). The levels of the injected IgG were not significantly different between testing groups.
  • FIGURE 6 shows that MIF-GN3 is able to delay tumor growth in a mouse model of prostate cancer.
  • nude mice were engrafted with PC3 human prostate cancer cells. Treatment was then initiated immediately with either a non-bifunctional MIF inhibitor (3w), an anti-MIF antibody, or MIF-GN3.
  • FIGURE 7 shows molecules DNP-GN3 and DNP-AcF3-3, which are bifunctional molecules that bind to anti-DNP IgG and ASGPR. These compounds were used in several of the experiments as described below.
  • FIGURE 8 shows that DNP-GN3 and DNP-AcF3-3 mediate the formation of a ternary complex between HepG2 cells and anti-DNP, thus validating the bifunctional character of the molecules.
  • ASGPR-expressing HepG2 cells were incubated with bifunctional molecules and alexa-488 labeled anti-DNP (Thermo).
  • the readout is mean fluorescence intensity of the cell population. Fluorescence was measured using a flow cytometer.
  • the results presented in FIGURE 9 show that DNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa 488-labeled anti-DNP by HepG2 cells.
  • the assay carried out in this experiment was as is described above for MIF uptake. Readout is percentage of Alexa 488-positive cells after 6 hours. Fluorescence was measured using a flow cytometer.
  • FIGURE 10 shows that DNP-GN3 and DNP-AcF3-3 mediate the localization of alexa 568 labeled anti-DNP to late endosomes and lysosomes.
  • This experiment was carried out as described above for the MIF colocalization studies.
  • the experimental results presented in FIGURE 11 show that DNP-AcF3-3 mediates the degradation of alexa 488-labeled anti-DNP in HepG2 cells.
  • cells were incubated with 1 uM alexa 488-labeled anti-DNP (Thermo) and 200 nM DNP-AcF3-3.
  • FIGURE 12 shows the structures of IgG-degrading molecules IBA-GN3, Triazine- GN3, FcIII-GN3, and FcIII-4c-GN3.
  • FIGURE 14 shows that FcIII-GN3 mediates the uptake of human IgG into HepG2 cells. This experiment was performed as described above.
  • FIGURE 15 shows that FcIII-GN3 mediates the localization of IgG to late endosomes in HepG2 cells. Experiment performed as described above. Additional Biological Data for Compounds With Varying CRBM Groups Cells lines are chosen which express the cellular receptor at high levels. These cells are all known in the art and most are commercially available. Cells are treated with bifunctional molecule and target protein. Target proteins in cell supernatant and/or cell lysate are measured by ELISA. Molecules give time- and concentration- dependent uptake of target proteins as measured by ELISA.
  • target proteins are labeled with NHS-fluorophores and are taken up by cells. This uptake is time- and concentration-dependent. Uptake is measured by flow analysis, which counts cells according to their fluorescence. Uptake of the fluorophore- protein conjugate is correlated with increased cell brightness. Additionally, compounds are assayed for their ability to lead to localization of target protein to lysosomes. Cells are treated with target protein and compound, incubated for several hours (generally about 6-24 hours), and fixed using standard methods (paraformaldehyde, acetone). Lysosomes and target protein are localized using orthogonal primary antibodies (anti-Lamp2 and anti-target protein) and then fluorescently-labeled secondary antibodies are added.
  • orthogonal primary antibodies anti-Lamp2 and anti-target protein
  • GaINAc ASGPR ligand (Figure 15) Galactosamine pentaacetate (100 mg, .257 mmol) was dissolved in dichloroethane (1 mL) and stirred at room temperature before the addition of TMSOTf (70 ⁇ L, 86.0 mg, .387 mmol, 1.5 eq). The reaction was stirred at 50o for 90 minutes, then allowed to cool to room temperature and stirred for a further 12 hours. The reaction was poured into ice cold saturated sodium bicarbonate and extracted into DCM.
  • TMSOTf (55 ⁇ L, 67.5 mg, .304 mmol, .5 eq) was then added to the mixture, and the reaction 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 curde oil was purified on silica gel (50-100% EtoAc in DCM) to give compound 67 (245 mg, .486 mmol) in 80.1% yield.
  • Triphenylphosphine (1.40 g, 5.35 mmol, 1.5 eq) and water (257 ⁇ L, 14.28 mmol, 4 eq) were then added and the reaction stirred at room temperature under nitrogen for 36 hours. The solvent was removed and the crude product used in the next step without further purification. 4.
  • Tris Valent Glycine ( Figure 16) 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 stirred for 4 hours.
  • Methanesulfonyl chloride (3.14 g, 27.4 mmol, 1.2 eq) was then added and the reaction stirred for six hours under nitrogen. The mixture was then diluted into ethyl acetate, washed with water (3x), .5M HCl (2x), saturated sodium bicarbonate (1x), and brine (1x), dried over sodium sulfate, and evaporated to give compound 18 (5.71 g, 19.2 mmol) in 84% yield.
  • Trimetylsilylchloride (10.43 mL, 8.929 g, 82.18 mmol, 3.6 eq) was added dropwise and the mixture 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 the tri-TMS intermediate. Residual pyridine was removed by co- evaporating with toluene (3x). The intermediate was taken up into dry MeOH (45 mL) and cooled to 0o before potassium carbonate (40 mg) was added.
  • Dess-Martin periodane (9.82 g, 23.2 mmol, 1.2 eq) was added and the mixture 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.
  • Compound 6 was dissolved in molecular sieve-dried EtOH (100 mL).
  • Paraformaldehyde 36.50 g, 384.9 mmol, 20 eq
  • 21% sodium ethoxide solution (14.5 mL, 38.5 mmol, 2 eq) were added and the reaction stirred for 8 hours.
  • the solvent was evaporated and the product adsorbed onto silica.
  • Standard fmoc amino acids with sidechains protected using acid-labile protecting groups are utilized for all couplings.
  • Resin is Fmoc deprotected (20% piperidine in DMF, 2 x 3 minute incubations on rotator) and is coupled to the first amino acid (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) overnight.
  • the resin is then washed and treated with 10% acetic anhydride in pyridine to cap any unreacted amines (10 minutes on rotator).
  • the resulting resin-amino acid conjugate is Fmoc deprotected as described above and coupled to the next amino acids (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) for 40 minutes.
  • the resin is then capped as above.
  • Subsequent iterative deprotection, coupling and capping steps provide the final peptides.
  • ⁇ 2-[2-(Fmoc-amino)ethoxy]ethoxy ⁇ acetic acid is coupled to the peptide and Fmoc deprotected to give an N terminal amine.
  • Peptides are cleaved from resin using 90%TFA, 5% TIPS, 5% water (2hr treatment), ether precipitated, and purified using RPHPLC to 95% purity, then reacted with carboxylic acids to provide the bifunctional compounds.
  • these peptides are treated with succinic anhydride to afford a terminal carboxylic acid for coupling with amines; azidoacetic acid to generate a terminal alkyne; or 5-hexynoic acid to generate a terminal alkyne.
  • Copper-mediated cross coupling is used in the case of terminal azides or alkynes to give triazole-linked bifunctional molecules.
  • N-linked disulfide cyclized peptides, C-amide terminating, without amine-containing (sidechain) amino acids As above, but following cleavage from resin the peptides are then resuspended in PBS pH 8, MeOH/ammonium bicarbonate, or another acceptable buffer to provide the oxidized peptide containing a disulfide. Alternatively, iodine is used to oxidatively cyclize the peptides. N-linked non-cyclized peptides, C-amide terminating with amine-containing (sidechain) amino acids.
  • iodine is used to oxidatively cyclize the peptides.
  • Peptides are synthesized on 200 ⁇ mol scale using 2-chlorotrityl resin. Standard fmoc amino acids with sidechains protected using acid-labile protecting groups are utilized for all couplings. Between each deprotection, coupling, and capping reaction resin was washed 5x with DMF, 5x with DCM, and 5x with DMF. Resin is treated with 4 eq 2,4,6-collidine in DCM with the first amino acid (4 eq) of the sequence overnight.
  • the resin is then capped by treatment with methanol in DIPEA/DCM for 1hr at RT.
  • the amino acid is then deprotected (20% piperidine in DMF, 2 x 3 minute incubations on rotator) and is coupled to the first amino acid (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) overnight.
  • the resin is then washed and treated with 10% acetic anhydride in pyridine to cap any unreacted amines (10 minutes on rotator).
  • the resulting resin-amino acid conjugate is Fmoc deprotected as described above and coupled to the next amino acids (4 eq oxyma, 4 eq Fmoc-protected amino acid, 4 eq DIC in DMF) for 40 minutes.
  • the resin is then capped as above.
  • Subsequent iterative deprotection, coupling and capping steps provide the final peptides.
  • peptides are optionally capped with acetic anhydride, propionic anhydride, or another suitable activated acid.
  • Peptides are cleaved from resin using hexafluoroisopropanol (20%) in DCM for 1.5 hr at room temperature and ether precipitated.
  • Peptides are then purified using RPHPLC to 95% purity, then reacted with carboxylic acids to provide the bifunctional compounds.
  • these peptides are treated with N-boc- ethylenediamine and subsequently HCl/DCM to afford a terminal amine for coupling with carboxylic acids.
  • these peptides are treated with 3-azidopropan-1-amine under standard coupling conditions (HBTU, DIPEA, DMF) to generate a terminal azide.
  • these peptides are treated with 4-pentyn-1-amine under standard amide coupling conditions (HBTU, DIPEA, DMF) to give a C terminal alkyne.
  • Copper-mediated cross coupling is used in the case of terminal azides or alkynes to give triazole-linked bifunctional molecules.
  • C-linked disulfide cyclized peptides Without carboxylic acid-containing (sidechain) amino acids.
  • carboxylic acid-containing (sidechain) amino acids As above, but following cleaveage from resin the peptides are then resuspended in PBS pH 8, MeOH/ammonium bicarbonate, or another acceptable buffer to provide the oxidized peptide containing a disulfide.
  • iodine is used to oxidatively cyclize the peptides.
  • C-linked non-cyclized peptides With carboxylic acid-containing (sidechain) amino acids.
  • iodine is used to oxidatively cyclize the peptides.

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US12258332B2 (en) 2021-07-14 2025-03-25 Lycia Therapeutics, Inc. ASGPR cell surface receptor binding compounds and conjugates
WO2025219911A1 (en) * 2024-04-16 2025-10-23 Biohaven Therapeutics Ltd. Treatment of diseases with monoclonal antibody drugs and molecular degraders
WO2025248469A1 (en) * 2024-05-28 2025-12-04 Biohaven Therapeutics Ltd. TREATMENT OF IgG-RELATED DISEASES

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CA2997444A1 (en) * 2015-09-29 2017-04-06 Amgen Inc. Asgr inhibitors for reducing cholesterol levels
US12364766B2 (en) * 2018-04-09 2025-07-22 Yale University Bifunctional small molecules to target the selective degradation of circulating proteins
WO2019199621A1 (en) * 2018-04-09 2019-10-17 Yale University Bi-functional molecules to degrade circulating proteins
CN113301925A (zh) * 2018-12-19 2021-08-24 小利兰·斯坦福大学理事会 用于溶酶体靶向的双官能分子以及相关的组合物和方法
IL294515A (en) * 2020-01-31 2022-09-01 Avilar Therapeutics Inc Compounds bind asgpr to degrade extracellular proteins

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US12258332B2 (en) 2021-07-14 2025-03-25 Lycia Therapeutics, Inc. ASGPR cell surface receptor binding compounds and conjugates
WO2025219911A1 (en) * 2024-04-16 2025-10-23 Biohaven Therapeutics Ltd. Treatment of diseases with monoclonal antibody drugs and molecular degraders
WO2025248469A1 (en) * 2024-05-28 2025-12-04 Biohaven Therapeutics Ltd. TREATMENT OF IgG-RELATED DISEASES

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