ASGPR-binding compounds that degrade extracellular proteins

Abstract

Compounds and compositions are described that have an asialoglycoprotein receptor (ASGPR) binding ligand conjugated to an extracellular protein binding ligand that selectively degrades target extracellular proteins in vivo to treat disorders mediated by the extracellular proteins.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 62 / 968,802, filed on 31 January 2020, and U.S. Provisional Patent Application No. 63 / 063,015, filed on 7 August 2020, which, in whole, constitute a part of this specification by reference.

[0002] [References] The text file is named "19121-001WO1_Seq_Listing_ST25", was created on January 29, 2021, has a size of 19311KB, and its entire contents constitute part of this specification.

[0003] The present invention provides compounds and compositions having an asialoglycoprotein receptor (ASGPR)-binding ligand bound to an extracellular protein-binding ligand, which selectively degrades target extracellular proteins in vivo to treat extracellular protein-mediated disorders. [Background technology]

[0004] Historically, therapeutic strategies involving protein inhibition have utilized small molecule inhibitors that bind to the enzyme pocket or at allosteric sites. These non-enzymatic proteins are difficult to control, and some have been considered "drug-unavailable."

[0005] Intracellular proteolysis is a naturally occurring, highly regulated, and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins within a cell is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of virtually all intracellular processes. Numerous companies and institutions have designed intracellular proteolytic molecules that utilize this natural process to degrade disease-mediating proteins within cells by linking ligands to the proteins to be degraded in the UPP.Examples include Patent Document 1, "Targeting the Von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the Vhl / Hif-1alpha Interaction," allocated to Yale University, GlaxoSmithKline, and Cambridge EntA122-1erprise Limited of the University of Cambridge; Non-Patent Document 1, "Imide Based Modulators of Proteolysis and Associated Methods of Use," allocated to Arvinas Inc.; and "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target Brd4." Non-patent document 2 titled "Brd4)", Non-patent document 3 titled "Catalytic in Vivo Protein Knockdown by Small-Molecule Protacs", Non-patent document 4 titled "Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging", Non-patent document 5 titled "Modular Protac Design for the Degradation of Oncogenic Bcr-Abl", Non-patent document 6 titled "Small-Molecule Protacs: New Approaches to Protein Degradation", "Pharmaceutical Development.This can be found in Non-Patent Document 7, titled "Drug Development: Phthalimide Conjugation as a Strategy for in Vivo Targeted Protein Degradation," Patent Document 3, assigned to Arvinas Inc., titled "Imide Based Modulators of Proteolysis and Associated Methods of Use," and Patent Document 4, assigned to Arvinas Inc., titled "Estrogen-related Receptor Alpha Based PROTAC Compounds and Associated Methods of Use."

[0006] However, the ability of UPP to hijack intracellular processes and degrade proteins that are difficult or impossible to drug is not applicable to the degradation of extracellular proteins. Non-limited examples of extracellular proteins include immunoglobulins and cytokines, which may play a powerful role in causing or exacerbating serious diseases. Immunoglobulins include IgA, IgG, IgD, IgE, and IgM. Cytokines are cell signaling peptides secreted into the bloodstream that cannot pass through the cellular lipid bilayer into the cytoplasm, and include, for example, interferons, interleukins, chemokines, lymphokines, MIPs, and tumor necrosis factors. Cytokines are involved in autocrine, paracrine, and endocrine signaling. They mediate immunity, inflammation, and hematopoiesis. Cytokines are produced by immune cells (macrophages, B cells, T cells, and mast cells), endothelial cells, fibroblasts, and stromal cells.

[0007] Asialoglycoprotein receptor (ASGPR) is expressed primarily in parenchymal hepatocytes. 2+ It is a dependent lectin. The main role of ASGPR is to assist in the regulation of serum glycoprotein levels by mediating the endocytosis of desialylated glycoproteins (as shown below). The receptor binds ligands having terminal galactose or N-acetylgalactosamine. 3 -Hydroxyl group and C 4 - The hydroxyl group is Ca 2+ Joins to C. 2 The position of the N-acetyl is also considered important for binding activity.

[0008] [ka]

[0009] After binding to ASGPR, the asialoglycoprotein is removed by receptor-mediated endocytosis. The receptor and protein dissociate in the acidic endosomal compartment, and the protein is ultimately degraded by lysosomes. Whether or not the glycoprotein is bound, the receptor is taken up into the cell approximately every 15 minutes and constitutively returned from the endosome to the plasma membrane for reuse. However, the rate of intracellular translocation of the receptor is known to depend on the presence of the ligand. A 1998 study showed that the intracellular translocation rate of the protein in the absence of the ligand was less than one-third of the intracellular translocation rate of the ligand-receptor complex (Non-Patent Literature 8).

[0010] ASGPR is composed of two homologous subunits with 58% sequence identity, known as H1 and H2. Various ratios of H1 and H2 form functional homo-oligomers and hetero-oligomers with various conformations, but the most abundant conformation is a trimer consisting of two H1 subunits and one H2 subunit. ASGPR consists of a cytoplasmic domain, a transmembrane domain, a stalk region, and a carbohydrate recognition domain (CRD). Since both the H1 and H2 subunits are required to form the CRD, co-expression of both subunits is a prerequisite for endocytosis of the asialoclycoprotein. In 2000, the crystal structure of the CRD region was published, revealing three Ca 2+ The binding site was identified (Non-Patent Document 9).

[0011] Numerous publications describe ligands thought to bind to the CRD region of ASGPR. For example, Non-Patent Literature 10 describes the synthesis of a series of D-GalNAc derivatives in which the anomeric OH group is removed and the acetamide group is replaced by a 4-substituted 1,2,3-triazole moiety. The most potent compound is twice as potent as D-GalNAc in competitive NMR binding experiments. Non-Patent Literature 11 describes compounds derived from 2-azidogalactosyl analogs in which the anomeric position is occupied by either a β-methyl group or a β-4-methoxyphenyl group and the azide group is replaced by an amide or triazole. When the ligand binding activity was tested by surface plasmon resonance, many were potenter than parent N-acetylgalactosamine. d The value was shown.

[0012] Furthermore, studies have shown that receptor affinity for a ligand can be influenced by the ligand's valence. For example, Non-Patent Document 12 describes an assay that studies the ability of a particular analog to bind to rabbit liver cells, where IC 50 It was shown that the concentration range is approximately 1 mM for unbranched oligosaccharides and approximately 1 nM for tribranched oligosaccharides.

[0013] ASGPR is primarily expressed in hepatocytes, with minimal expression in cells outside the liver. Hepatocytes exhibit high exposure of ASGPR binding sites (approximately 100,000 to 500,000 binding sites per cell).

[0014] Patent Document 5 of NeoRx Corporation describes the use of a liver-directed system comprising a therapeutic agent having activity against liver disease or liver injury, which is bound to a director portion. In one embodiment, the director portion, which is galactose or a galactose derivative, directs the activator to the liver, where it acts as a therapeutic agent and is then removed from circulation with the assistance of the director portion.

[0015] Patent documents 6, 7, 8, 9, and 10, transferred to Pfizer Inc., describe in one embodiment certain bicyclic crosslinked ketal derivatives of GalNAc as targeting agents for the ASGPR receptor, conjugated to a linker and / or therapeutic agent, e.g., a small molecule, amino acid sequence, nucleic acid sequence, antibody, or fluorescent probe. The linker of the drug delivery system may be monovalent, divalent, or trivalent. The disclosure also includes methods for treating liver diseases or conditions, comprising administering a targeted drug delivery system. Several monovalent, divalent, and trivalent bicyclic crosslinked GalNAc-derived ASGPR targeting agents conjugated to fluorescent probes are disclosed in Non-Patent Document 13. One trivalent conjugate, in particular, showed selective hepatocyte targeting in in vivo in vivo distribution studies in mice.

[0016] Pfizer Inc. and the Board of Directors of the University of California jointly disclosed the use of a targeted drug delivery system containing a specific ASPGR-targeting ligand covalently bound to a ribonucleoprotein or endonuclease in CRISPR gene editing, as described in Patent Document 11.

[0017] Pfizer also developed PK2, a targeted drug delivery system in which doxorubicin is linked to an N-(2-hydroxypropyl)methacrylamide copolymer containing galactosamine as a targeting agent via a lysosome-degradable tetrapeptide sequence. In a Phase 1 clinical trial to determine selectivity, toxicity, and pharmacokinetic profiles, the drug was demonstrated to target primary hepatocellular carcinomas in patients with primary or metastatic liver cancer (Non-Patent Literature 14).

[0018] Non-patent document 15 describes paclitaxel conjugates covalently linked to one, two, or three GalNAc units via short linkers. These analogs exhibited cytotoxicity against human hepatocyte cancer cells and showed high affinity for ASGPR via surface plasmon resonance.

[0019] Pfizer Inc. and Wave Life Sciences Ltd. jointly disclosed the use of selected ASGPR ligands attached to oligonucleotides in PCT applications Patent Document 12 and Patent Document 13. Patent Document 12 describes the use of APOC3 oligonucleotide attached to an ASGPR-targeting ligand for selective delivery to the liver, and Patent Document 13 describes the use of PNPLA3 oligonucleotide attached to an ASGPR-targeting ligand. PCT application Patent Document 14, assigned to Wave Sciences Ltd., describes a composition comprising an oligonucleotide for RNA interference, in one embodiment, the oligonucleotide attached to an ASGPR-targeting ligand.

[0020] The targeted delivery of antisense oligonucleotides (ASOs) that bind to and regulate complementary RNA to hepatocytes via ASGPR-targeting ligands was studied in Non-Patent Literature 16. When monovalent, divalent, and trivalent GalNAc were conjugated to single-stranded and double-stranded ASOs, it was found that the divalent and trivalent GalNAc-conjugated ASO systems bound to ASGPR with the strongest affinity.

[0021] Examples of ASGPR-targeted therapies using modified glycoproteins as targeting agents are reviewed in Non-Patent Document 17. In addition to certain characteristics related to drug delivery, including linker length and scaffold spatial geometry, a number of developed polyvalent ligands are discussed.

[0022] Yale University has filed two PCT applications, Patent Document 15 and Patent Document 16, describing the use of a specific ASGPR-targeting ligand covalently bound to a circulating protein-binding moiety. When the circulating protein-binding moiety binds to a circulating protein, the complex travels to the liver, where it is recognized by ASGPR and degraded via the endolysosomal pathway. Patent Document 15 describes a circulating protein-binding moiety that may target macrophage migration inhibitory factors (MIFs) and / or immunoglobulin G (IgG). Patent Document 16 describes the targeting of numerous circulating proteins, including CD40L, TNF-α, PCSK9, VEGF, TGF-β, uPAR, PSMA, IL-2, GP120, TSP-1, and CXCL-2, using a drug delivery system that includes a circulating protein-binding moiety covalently bound to a targeting ligand that is an ASGPR-targeting ligand.

[0023] The Board of Trustees of Leland Stanford Junior University filed a PCT application for Patent Document 17, which describes the use of compounds that bind to lysosome-targeting molecules such as ASGPR and degrade cell surface molecules or extracellular molecules. Compounds related to the disclosure in Patent Document 17 are described in an article in Non-Patent Document 18. A related paper from Bertozzi's group was published online in ChemRxiv in July 2020 as a preprint titled "Lysosome Targeting Chimeras (LYTACs) That Engage a Liver-Specific Asialoglycoprotein Receptor for Targeted Protein Degradation."

[0024] While some progress has been made in the field of targeted degradation of disease-mediating extracellular proteins, much remains unfulfilled. There is still an unmet need for further chemical compounds and approaches to treat medical disorders mediated by extracellular proteins. [Prior art documents] [Patent Documents]

[0025] [Patent Document 1] U.S. Patent Application Publication No. 2014 / 0356322 [Patent Document 2] International Publication No. 2015 / 160845 [Patent Document 3] U.S. Patent Application Publication No. 2016 / 0058872 [Patent Document 4] U.S. Patent Application Publication No. 2016 / 0045607 [Patent Document 5] U.S. Patent No. 5,985,826 [Patent Document 6] U.S. Patent No. 9,340,553 [Patent Document 7] U.S. Patent No. 9,617,293 [Patent Document 8] U.S. Patent No. 10,039,778 [Patent Document 9] U.S. Patent No. 10,376,531 [Patent Document 10] U.S. Patent No. 10,813,942 [Patent Document 11] U.S. Patent Application Publication No. 2017 / 0137801 [Patent Document 12] International Publication No. 2018 / 223073 [Patent Document 13] International Publication No. 2018 / 223081 [Patent Document 14] International Publication No. 2018 / 223056 [Patent Document 15] International Publication No. 2019 / 199621 [Patent Document 16] International Publication No. 2019 / 199634 [Patent Document 17] International Publication No. 2020 / 132100 [Non-patent literature]

[0026] [Non-Patent Document 1] Buckley et al. (J. Am. Chem. Soc. 2012, 134, 4465-4468) [Non-Patent Document 2] Lu et al. (Chem. Biol. 2015, 22, 755-763) [Non-Patent Document 3] Bondeson et al. (Nat. Chem. Biol. 2015, 11, 611-617) [Non-Patent Document 4] Gustafson et al.(Angewandte Chemie, International Edition in English 2015, 54, 9659-9662) [Non-Patent Document 5] Lai et al.(Angewandte Chemie, International Edition in English 2016, 55, 807-810)

Non-licensed Document 6

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Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-Patent Document 17

Non-Patent Document 18

Summary of the Invention

[0027] Novel compounds that degrade extracellular proteins mediating diseases, their pharmaceutically acceptable salts and compositions, starting materials and intermediates for such compounds, and methods of use and production thereof are provided. The present invention focuses on a novel modification at the C 2 position of the ASGPR ligand called R 2 herein. These modifications include molecules having a C 2 substituent in the "downward" configuration corresponding to the stereochemistry of galactose, and molecules having a C 2 substituent in the "upward" configuration corresponding to the stereochemistry of talose. It has been found that incorporating an ASGPR ligand having the R 2 group specified herein with the stereochemistry of either galactose or talose into the structure results in advantageous extracellular protein degrader molecules.

[0028]

Chemical Formula

[0029] By attaching a ligand for an extracellular protein to a selected ASGPR ligand via covalent bonding or covalent linkage, the selected extracellular protein can be degraded using the extracellular proteolytic compounds described herein. Extracellular proteins that can be targeted by the present invention include, but are not limited to, immunoglobulins such as IgA, IgG, IgD, IgE, and IgM, and their derivatives that retain the same basic functions, as well as cytokines such as interferons, interleukins, chemokines, lymphokines, MIPs, and tumor necrosis factor. In certain embodiments, the extracellular protein is selected from IgA, IgG, IgE, TNF(α or β), IL-1b, IL-2, IFN-γ, IL-6, VGEF, TGF-b1, and PCSK-9. In other non-limiting embodiments, proteins of the complement system, including factor B, factor D, factor H, and CC5, are targeted for degradation.

[0030] Galactose-based molecules New C 2 It has been found that substituted galactose stereochemical sugars are useful ligands for ASGPR. These molecules can be used as ASGPR ligands, or linked to extracellular protein targeting ligands, to recruit extracellular proteins and degrade them in the liver.

[0031] In particular, Formulas I, II, III, IV, V, VI, VII, or VIII: [ka] TIFF0007849881000004.tif173170 (in the formula, X 1 O, S, N(R) 6 ), and C(R 4 )(R 4 ) are 1 to 5 adjacent atoms independently selected from, where X 1 When X is a single atom 1 is O, S, N(R6 ), or C(R 4 )(R 4 ) and X 1 When X has two atoms 1 One or fewer atoms are O, S, or N(R) 6 ) and X 1 X when there are 3, 4, or 5 atoms. 1 Two or fewer atoms are O, S, or N(R) 6 ) and R 2 teeth, (i) aryl, heterocyclic, and heteroaryl compounds each containing one or two heteroatoms independently selected from N, O, and S, each optionally substituted with one, two, three, or four substituents, (ii) [ka] (iii) Each of the -NRs is optionally substituted with one, two, three, or four substituents. 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 )2, -NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ,and, (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 , Selected from, R 10 are alkenyl, allyl, alkinyl, -NR 6-alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, each R 10 It is optionally substituted with one, two, three, or four substituents, or R 10 These are aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 Alkyl-NR 6 R 8 , NR 8 -NR 6 -C(O)R 3 , NR 8 -S(O)2-R 3 , alkenyl, allyl, alkinyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, each R 10 It is optionally substituted with one, two, three, or four substituents. In a particular embodiment, R 10 teeth, [ka] Selected from, In a particular embodiment, R 10 teeth, [ka] Selected from, R 1 and R 5is independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 、C0-C6 alkyl-C(S)R 3 、C0-C6 alkyl-S(O)2R 3 、C0-C6 alkyl-N(R 8 )-C(O)R 3 、C0-C6 alkyl-N(R 8 )-S(O)R 3 、C0-C6 alkyl-N(R 8 )-C(S)R 3 、C0-C6 alkyl-N(R 8 )-S(O)2R 3 、C0-C6 alkyl-O-C(O)R 3 、C0-C6 alkyl-O-S(O)R 3 、C0-C6 alkyl-O-C(S)R 3 、-N=S(O)(R 3 )2、C0-C6 alkyl N3, and C0-C6 alkyl-O-S(O)2R 3 is selected from, each of which is optionally substituted with one, two, three, or four substituents, R 3 is independently, in each case, hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 、and -NR 8 R 9 is selected from, R 4Independently, in each case, hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 6 , -NR 6 R 7 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 6 and R 7 Independently, in each case, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 8 and R 9 Independently, in each case, is selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic. The ring is a 3- to 8-membered fused cyclic group optionally substituted with one, two, three, or four substituents. Examples of ring groups, where permitted by their valency, include carbocyclic groups (e.g., cyclopropane, cyclohexane, or cyclohexene), heterocyclic groups (e.g., oxetane, piperazine), aryl groups (e.g., phenyl), or heteroaryl groups (e.g., pyridine, furan, or pyrrole). Each linker A The ASGPR ligand and linker B A bond or part that connects two things by a covalent bond, Linker B is a linker A A bond or portion that covalently connects the extracellular protein-targeting ligand to the extracellular protein, An extracellular protein targeting ligand is a chemical moiety that binds to the disease-modifying extracellular protein being targeted, and When a compound is "arbitrarily substituted," the compound may be alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR, if permitted by valency. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] Compounds of (which may be substituted with one or more groups selected from, where any substituent is selected such that a stable compound is obtained) or pharmaceutically acceptable salts thereof are provided.

[0032] In alternative embodiments, when the compound is "optionally substituted," the compound may be alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR, if permitted by valency. 6 F, Cl, Br, I, -NR 6 R 7 Heteroalkyl, heterocyclic, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR 3 -S(O)(NR 6 )R 3 , -NR 8 C(O)R 3 -C(O)NR 6 R 7 , -C(O)OR 3 , -C(O)R 3 ,-SF5, [ka] It may be substituted with one or more groups selected from, where any substituent is chosen such that a stable compound is produced.

[0033] In one embodiment, the extracellular protein-targeting ligand is not an oligomer.

[0034] In another embodiment, neither the extracellular protein nor the extracellular protein-targeting ligand directly mediates intracellular gene editing such as CRISPR.

[0035] In an alternative embodiment of the present invention, R 2 NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl, or -NR 6 -When it is aryl, the extracellular protein targeting ligand does not contain oligonucleotides. In certain embodiments of the present invention, R 2 R 10 , NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl, or -NR 6 -When it is aryl, the extracellular protein-targeting ligand does not contain oligonucleotides.

[0036] Formulas I-Bi, II-Bi, III-Bi, IV-Bi, V-Bi, VI-Bi, VII-Bi, or VIII-Bi: [ka] TIFF0007849881000011.tif198170TIFF0007849881000012.tif127170 (in the formula, Linker C Each linker A It is a chemical group that links to an extracellular protein-targeting ligand, and Compounds of (all other variants as defined herein) or pharmaceutically acceptable salts thereof are provided.

[0037] Formulas I-Tri, II-Tri, III-Tri, IV-Tri, V-Tri, VI-Tri, VII-Tri, or VIII-Tri: [ka] TIFF0007849881000014.tif211170TIFF0007849881000015.tif185170TIFF0007849881000016.tif183170 (in the formula, Linker D Each linker A It is a chemical group that links to an extracellular protein-targeting ligand, and Compounds of (all other variants as defined herein) or pharmaceutically acceptable salts thereof are also provided.

[0038] When used herein, anchoring bonds may optionally be linked to an extracellular protein-targeting ligand and a linker. B Linker C , or linker D It is defined as a chemical bond between any of the following:

[0039] Formula IX, Formula X, Formula XI, Formula XII, or Formula XIII: [ka] (In the formula, R L R 5 and linker E Selected from, R L2 R 6 and linker E Selected from, X 1 O, S, N(R) 6 ), and C(R 4 )(R 4 ) are 1 to 5 adjacent atoms independently selected from, where X 1 When X is a single atom 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 When X has two atoms 1 One or fewer atoms are O, S, or N(R) 6 ) and X 1 X when there are 3, 4, or 5 atoms. 1 Two or fewer atoms are O, S, or N(R) 6 ) and R 2A teeth, (i) aryl, heterocyclic, and heteroaryl compounds each containing one or two heteroatoms independently selected from N, O, and S, each optionally substituted with one, two, three, or four substituents, (ii) [ka] and, (iii) -NH-S(O)-R molecules each optionally substituted with one, two, three, or four substituents 3 , -NR 8 -C(S)-R 3 , -NH-S(O)(NR 6 )-R 3 , and -N=S(O)(R 3 )-NR 6 R 7 , Selected from, In an alternative embodiment, R 2A teeth, [ka] Selected from, In an alternative embodiment, R 2A R 10 Selected from, R 1 and R 5 These are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0~C6 alkyl-S(O)2R 3 , C0~C6 alkyl-N(R 8 )-C(O)R 3 , C0~C6 alkyl-N(R 8 )-S(O)R 3 , C0~C6 alkyl-N(R 8 )-C(S)R 3 , C0~C6 alkyl-N(R 8 )-S(O)2R 3 C0-C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, and C0-C6 alkyl-OS(O)2R 3 Selected from, each optionally substituted with one, two, three, or four substituents, R 3 Independently, in each case, hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 8, or -NR 8 R 9 Selected from, R 4 Independently, in each case, hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 6 , -NR 6 R 7 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 6 and R 7 Independently, in each case, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 8 and R 9 Independently, in each case, is selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic. The ring is a 3- to 8-membered fused cyclic group optionally substituted with one, two, three, or four substituents. Examples of ring groups, where permitted by their valency, include carbocyclic groups (e.g., cyclopropane, cyclohexane, or cyclohexene), heterocyclic groups (e.g., oxetane or piperazine), aryl groups (e.g., phenyl), or heteroaryl groups (e.g., pyridine, furan, or pyrrole). Linker E teeth, [ka] And, R 30 Cl, Br, I, -NR 6 H, -OH, -N3, -SH, [ka] -C(O)N(CH3)OCH3, -B(OR 6 )(OR 7 ), complex algebra, -NR 6 COR 3 , -OCOR 3 , and -COR 3 Selected from, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 These are independently linked in each case: alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-,-P(O)(OR 6 )O-, -P(O)(OR 6 )-,-P(O)(NR 6 R 7 )NR 6 -, -P(O)(NR 6 R 7 )-, amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, -[-(CH2)2-O-] n -,-[O-(CH2)2] n -,-[O-CH(CH3)C(O)] n -,-[C(O)-CH(CH3)-O] n -,-[O-CH2C(O)] n -,-[C(O)-CH2-O] n - Selected from the group consisting of fatty acids and unsaturated acids, each of which is R 21It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in each case. R 21 Independently, in each case, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Selected from the group consisting of haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocyclic compounds, or R 21 Independently, in each case, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, -SR 3 , -C(O)OR 3 -C(O)NR 6 NR 7 , -OR 3 , [ka] Compounds of (selected from the group consisting of and heterocycles) or pharmaceutically acceptable salts thereof are provided.

[0040] Talocose-based molecules Specific C 2 It was also found that substituted sugars in talose stereochemistry are useful ligands for ASGPR. These molecules can be used as ASGPR ligands, or linked to extracellular protein targeting ligands, to recruit extracellular proteins and degrade them in the liver.

[0041] In particular, formulas Id, II-d, III-d, IV-d, Vd, or VI-d: [ka] (In the formulas, for compounds of formula Id, formula II-d, formula III-d, formula IV-d, formula Vd, and formula VI-d, R 2 teeth, (i) aryl, heterocyclic, and heteroaryl compounds each containing one or two heteroatoms independently selected from N, O, and S, each optionally substituted with one, two, three, or four substituents, (ii) [ka] (iii) Each of the -NRs is optionally substituted with one, two, three, or four substituents. 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 )2, -NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ,and, (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 ,and, (v)R 200 , Selected from, R 200 -NR 8 -C(O)-R3 or, R 200 -NR 8 -C(O)-R 3 , -NR 6 -alkyl, -OR 8 , heteroaryls (e.g., including triazoles and tetrazoles), NR 8 -S(O)2-R 3 , or -NR 6 -heteroalkyl, each R 200 The substituents are arbitrarily substituted with one, two, three, or four substituents. When a compound is "arbitrarily substituted," those compounds may be alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR, if permitted by valency. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] Compounds of or pharmaceutically acceptable salts thereof are provided (which may be substituted with a group selected from, where any substituent is selected so as to result in a stable compound).

[0042] In alternative embodiments, when the compounds are "optionally substituted," those compounds may be alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR, if permitted by valency. 6 F, Cl, Br, I, -NR 6 R 7 Heteroalkyl, heterocyclic, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR 3 -S(O)(NR 6 )R 3, -NR 8 C(O)R 3 -C(O)NR 6 R 7 , -C(O)OR 3 , -C(O)R 3 ,-SF5, [ka] It may be substituted with a group selected from, where any substituent is selected such that a stable compound is produced, All other variables are as defined herein.

[0043] In certain embodiments, mixtures containing equimolar mixtures of galactose-based stereochemistry and talose-based stereochemistry, but not limited to these, are used in medical therapy. For example, compounds of formula I and the corresponding compounds of formula Id may be used in any mixture that yields a desired therapeutic outcome. More generally, any mixture of formulas I through XVI and formulas Id through XVI-d (any of which may exist in one-part, two-part, or three-part configurations).

[0044] Formulas Id-Bi, II-d-Bi, III-d-Bi, IV-d-Bi, Vd-Bi, or VI-d-Bi: [ka] TIFF0007849881000028.tif213170TIFF0007849881000029.tif130170(In the formula, for compounds of formula Id-Bi, formula II-d-Bi, formula III-d-Bi, formula IV-d-Bi, formula Vd-Bi, and formula VI-d-Bi, R 2 teeth, (i) aryl, heterocyclic, and heteroaryl compounds each containing one or two heteroatoms independently selected from N, O, and S, each optionally substituted with one, two, three, or four substituents, (ii) [ka] (iii) Each of the -NRs is optionally substituted with one, two, three, or four substituents. 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 )2, -NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ,and, (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 ,and, (v)R 200 , Selected from, R 200 -NR 8 -C(O)-R 3 And, Compounds of all other variants (as defined herein) are provided.

[0045] Formula Id-Tri, Formula II-d-Tri, Formula III-d-Tri, Formula IV-d-Tri, Formula Vd-Tri, or Formula VI-d-Tri: [ka] TIFF0007849881000032.tif206170TIFF0007849881000033.tif199170TIFF0007849881000034.tif94170(In the formulas, for compounds of formula Id-Tri, formula II-d-Tri, formula III-d-Tri, formula IV-d-Tri, formula Vd-Tri, and formula VI-d-Tri, R 2 teeth, (i) aryl, heterocyclic, and heteroaryl compounds each containing one or two heteroatoms independently selected from N, O, and S, each optionally substituted with one, two, three, or four substituents, (ii) [ka] (iii) Each of the -NRs is optionally substituted with one, two, three, or four substituents. 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 )2, -NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ,and, (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 ,and, (v)R 200 , Selected from, R 200 -NR 8 -C(O)-R 3 And, Compounds of (all other variants as defined herein) or pharmaceutically acceptable salts thereof are provided.

[0046] Formula IX-d, Formula Xd, Formula XI-d, Formula XII-d, Formula XIII-d, Formula XIV-d: [ka] Compounds or pharmaceutically acceptable salts thereof are provided.

[0047] In one embodiment of the present invention, the extracellular protein targeting ligand is a small organic molecule (i.e., a non-biologic) that binds appropriately to the protein so that it can be transported to the liver, a residue of a pharmaceutically active compound that binds to the target extracellular protein (e.g., compounds of a type that will be reviewed as a drug by the FDA's CDER, or approved drugs or drugs in the clinical stage), or a peptide, protein, or biologic, or a binding fragment thereof, that binds appropriately to the protein so that it can be transported to the liver and, in some embodiments, does not contain oligonucleotides or aptamers. Numerous exemplary, non-limiting examples of extracellular protein targeting ligands are shown in Figure 1. The present invention focuses, for example, on the degradation of circulating extracellular proteins that mediate diseases such as immune disorders, inflammation, hematopoietic / blood disorders (including those caused by or exacerbated by angiogenesis), and tumors and cancers with abnormal cell proliferation. In a typical embodiment of the present invention, neither the extracellular protein nor the extracellular protein targeting ligand directly mediates intracellular gene editing such as CRISPR.

[0048] In one embodiment of the present invention, R 2 NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O)2-alkenyl, -NR 8-S(O)2-alkynyl, -NR 6 -heteroaryl, or -NR 6 -When it is an aryl ligand, the extracellular protein targeting ligand does not contain oligonucleotides or aptamers.

[0049] The ASGPR-binding extracellular protein degrader of the present invention can be administered in any manner in which the degrader typically binds to an extracellular protein in the bloodstream, which is then transported to ASGPR-containing hepatocytes in the liver, where it is taken up and degraded. Therefore, examples of methods for delivering the degrader of the present invention include, but are not limited to, oral, intravenous, buccal, sublingual, subcutaneous, and nasal administration. [Brief explanation of the drawing]

[0050] [Figure 1A] This figure shows a non-restrictive list of extracellular protein targeting ligands that target immunoglobulin A (IgA). [Figure 1B] This figure shows a non-restrictive list of extracellular protein targeting ligands that target immunoglobulin G (IgG). [Figure 1C-1G] This figure shows a non-restrictive list of extracellular protein targeting ligands that target immunoglobulin E (IgE). [Figure 1H-1M] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target tumor necrosis factor α (TNF-α). [Figure 1N] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-1 (IL-1). [Figure 10-1S] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-2 (IL-2). [Figure 1T-1W] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-6 (IL-6). [Figure 1X-1AA]This figure shows a non-restrictive list of extracellular protein targeting ligands that target interferon-γ (IFN-γ). [Figure 1BB-1KK] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target vascular endothelial growth factor (VEGF). [Figure 1LL] This figure shows a non-restrictive list of extracellular protein targeting ligands that target transforming growth factor β (TGF-β1). [Figure 1MM-1PP] This figure shows a non-restrictive list of extracellular protein targeting ligands that target proprotein convertase subtilisin / kexin type 9 (PCSK-9). [Figure 1QQ-1SS] This figure shows a non-restrictive list of extracellular protein targeting ligands that target carboxypeptidase B2 (CPB2). [Figure 1TT-1UU] This figure shows a non-restrictive list of extracellular protein targeting ligands that target cholinesterase (ChE). [Figure 1VV-1WW] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target CC motif chemokine ligand 2 (CCL2). [Figure 1XX-1BBB] This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor VII (factor VII). [Figure 1CCC-1FFF] This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor IX (Factor IX). [Figure 1GGG] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target CD40 ligand (CD40L). [Figure 1HHH-1JJJ] This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor Xa (factor Xa). [Figure 1KKK-1MMM] This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor XI (Factor XI). [Figure 1NNN-1OOO]This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor XII (factor XII). [Figure 1 PPP-1QQQ] This figure shows a non-restrictive list of extracellular protein targeting ligands that target coagulation factor XIII (factor XIII). [Figure 1RRR-1UUU] This figure shows a non-restrictive list of extracellular protein targeting ligands that target fibroblast growth factor 1 (FGF1). [Figure 1VVV-1XXX] This figure shows a non-restrictive list of extracellular protein targeting ligands that target fibroblast growth factor 2 (FGF2). [Figure 1YYY-1ZZZ] This figure shows a non-restrictive list of extracellular protein targeting ligands that target fibronectin (FN1). [Figure 1AAAA-1BBBB] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-5 (IL-5). [Figure 1CCCC] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-8 (IL-8). [Figure 1DDDD-1EEEE] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-10 (IL-10). [Figure 1FFFF-1GGGG] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-21 (IL-21). [Figure HHHH-1IIII] This figure shows a non-restrictive list of extracellular protein targeting ligands that target interleukin-22 (IL-22). [Figure 1JJJJ-1NNNN] This figure shows a non-restrictive list of extracellular protein targeting ligands that target kallikrein 1. [Figure 1000] This figure shows a non-restrictive list of extracellular protein targeting ligands that target lipoprotein lipase (LPL). [Figure 1PPPP-1QQQQ]This figure shows a non-restrictive list of extracellular protein targeting ligands that target matrix metalloproteinase-1 (MMP1). [Figure 1RRRR-1DDDDD] This figure shows a non-restrictive list of extracellular protein targeting ligands that target macrophage migration inhibitors (MIFs), also known as glycosylation inhibitors (GIFs), L-dopachrome isomerase, or phenylpyruvate tautomerase. [Figure 1EEEEE-1GGGGG] This figure shows a non-restrictive list of extracellular protein targeting ligands that target neutrophil elastase (NE). [Figure 1HHHHH-1IIIII] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target prothrombin. [Figure 1JJJJJ-1NNNNN] This figure shows a non-restrictive list of extracellular protein targeting ligands that target plasma kallikrein (KLKB1). [Figure 1OOOOO-1SSSSS] This figure shows a non-restrictive list of extracellular protein targeting ligands that target plasminogen (PLG). [Figure 1TTTTT-1XXXXX] This figure shows a non-restrictive list of extracellular protein targeting ligands that target plasminogen activator inhibitor-1 (PAI-1), endothelial plasminogen activator inhibitor, or serpin E1. [Figure 1YYYYY-1AAAAAA] This figure shows a non-restrictive list of extracellular protein targeting ligands that target phospholipase A2, such as type 1B or group 1B (PLA2, PA21B, PLA2G1B, PLA2-IB). [Figure 1BBBBBB-1DDDDDD] This figure shows a non-restrictive list of extracellular protein targeting ligands that target phospholipase A2, such as type IIA or group IIA (PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA). [Figure 1EEEEEE-1NNNNNN] This figure shows a non-restrictive list of extracellular protein-targeting ligands that target placental growth factor (PGF). [Figure 1000-1QQQQQQ]This figure shows a non-restrictive list of extracellular protein targeting ligands that target plasminogen activators, tissue types (tPA, PLAT). [Figure 1RRRRRR] This figure shows a non-restrictive list of extracellular protein targeting ligands that target transforming growth factor β2 (TGF-β2, TGFB2). [Figure 1SSSSSS] This figure shows a non-restrictive list of extracellular protein targeting ligands that target thrombospondin 1 (TSP1, TSP-1, THBS1). [Figure 1TTTTTT-1XXXXXX] This figure shows a non-restrictive list of extracellular protein targeting ligands that target urokinase or urokinase-type plasminogen activators (UPAs, uPAs). [Figure 2] This figure shows a non-restrictive list of exemplary extracellular protein targeting ligands that target complement factor B. [Figure 3A-3B] This figure shows a non-restrictive list of exemplary extracellular protein targeting ligands that target complement factor D. [Figure 4] This figure shows a non-restrictive list of exemplary extracellular protein targeting ligands that target complement factor H. [Figure 5] This figure shows a non-restrictive list of exemplary extracellular protein targeting ligands that target complement component 5. [Figure 6] This figure shows a non-restrictive list of exemplary extracellular protein-targeting ligands that target TNF-α. [Figure 7] This figure shows a non-restrictive list of exemplary extracellular protein-targeting ligands that target Factor XI. [Figure 8] This figure shows a non-limiting list of exemplary formulas of the present invention. [Modes for carrying out the invention]

[0051] Novel compounds for degrading disease-mediated extracellular proteins, pharmaceutically acceptable salts and compositions thereof, as well as starting materials and intermediates for such compounds, and methods for their use and preparation are provided. The present invention is described herein by R 2 The C of the ASGPR ligand called 2 We are focusing on novel modifications at the position. These modifications include C in the "downward" configuration corresponding to the stereochemistry of galactose. 2 A molecule with substituents and C in an "upward" configuration corresponding to the stereochemistry of talos. 2 Examples include molecules having substituents. R, as specified herein, having the stereochemistry of either galactose or talose. 2 It was found that incorporating an ASGPR ligand containing the group into the structure yields a favorable extracellular protein degrader molecule.

[0052] I. The galactose-based ASGPR-binding extracellular protein degrader of the present invention When used in the embodiments 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.

[0053] When used in the embodiments herein, 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.

[0054] When used in the embodiments herein, 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.

[0055] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0056] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0057] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0058] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0059] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0060] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0061] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0062] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0063] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0064] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0065] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0066] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0067] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0068] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0069] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0070] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0071] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0072] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0073] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000056.tif88170.

[0074] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000058.tif174170.

[0075] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000060.tif123170.

[0076] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000062.tif197170, TIFF0007849881000063.tif219170, and TIFF0007849881000064.tif127170.

[0077] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0078] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0079] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0080] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0081] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0082] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0083] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0084] In one embodiment of the present invention, an extracellular proteolytic compound is provided in which the ASGPR ligand is a ligand described herein. [ka] In this embodiment, the ASGPR ligand is located at the C1 or C5 position (R 1 or R 5 ) are linked in any of the following to form a degradable compound, for example, ASGPR ligand, [ka] In that case, non-limiting examples of ASGPR-binding compounds intended by this embodiment include: [ka] Alternatively, these may be in two-part or three-part forms, or pharmaceutically acceptable salts thereof.

[0085] In any of the embodiments herein describing the ASGPR ligand used in a degrader, the ASGPR ligand is typically C 5 Location (for example, adjacent C which can be used for connection purposes) 6 The linker is linked to the extracellular protein targeting ligand at the carbon hydroxyl moiety or other functional moiety. 1 When linked via a position, the carbon is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group. Typically, ASGPR ligands are C 3 Position or C 4They are not linked at these positions because these sites chelate with calcium for ASGPR binding in the liver.

[0086] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0087] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from TIFF0007849881000077.tif106170.

[0088] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0089] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0090] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from TIFF0007849881000081.tif131170.

[0091] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0092] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0093] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0094] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0095] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0096] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0097] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0098] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0099] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0100] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0101] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0102] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0103] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0104] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0105] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0106] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0107] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0108] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0109] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0110] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0111] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000103.tif204170.

[0112] In certain embodiments, the compound of the present invention is [ka] That is the case.

[0113] In certain embodiments, the compound of the present invention is [ka] That is the case.

[0114] II. The present invention provides a talose-based ASGPR-binding extracellular protein degrader. In certain embodiments, the compound of the present invention is [ka] Selected from.

[0115] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0116] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0117] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0118] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0119] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0120] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0121] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0122] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0123] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0124] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0125] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0126] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0127] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0128] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0129] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0130] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0131] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0132] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0133] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0134] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0135] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0136] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0137] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0138] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0139] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0140] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0141] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0142] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0143] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0144] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0145] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000138.tif179170 and TIFF0007849881000139.tif93170.

[0146] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0147] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0148] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0149] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0150] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0151] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0152] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0153] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0154] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0155] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0156] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0157] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0158] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0159] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0160] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0161] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0162] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0163] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0164] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0165] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0166] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0167] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0168] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0169] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0170] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0171] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0172] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0173] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0174] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0175] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0176] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0177] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0178] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0179] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0180] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0181] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0182] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0183] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0184] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0185] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0186] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0187] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0188] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0189] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0190] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000185.tif207170 and TIFF0007849881000186.tif124170.

[0191] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000188.tif199170, TIFF0007849881000189.tif192170, and TIFF0007849881000190.tif91170.

[0192] In one embodiment of the present invention, an extracellular proteolytic compound is provided in which the ASGPR ligand is a ligand described herein. [ka] In this embodiment, the ASGPR ligand is located at the C1 or C5 position (R 1 or R 5) are linked in any of the following to form a degradable compound, for example, ASGPR ligand, [ka] In that case, non-limiting examples of ASGPR-binding compounds intended by this embodiment include: [ka] Alternatively, these may be in two-part or three-part forms, or pharmaceutically acceptable salts thereof.

[0193] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0194] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0195] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0196] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0197] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0198] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0199] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0200] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0201] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0202] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0203] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0204] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0205] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0206] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0207] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0208] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0209] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0210] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0211] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0212] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0213] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0214] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0215] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0216] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0217] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0218] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0219] In certain embodiments, the compound of the present invention is [ka] (In the formula, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), each R 2 The group is selected from one, two, three, or four independent substituents described herein (for example, optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl).

[0220] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0221] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0222] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0223] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0224] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0225] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0226] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0227] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0228] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000230.tif99170.

[0229] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from TIFF0007849881000232.tif197170.

[0230] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0231] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0232] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from TIFF0007849881000236.tif61170.

[0233] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0234] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0235] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0236] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0237] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0238] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0239] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0240] In certain embodiments, the ASGPR ligand useful for incorporation into the compound of the present invention is [ka] Selected from.

[0241] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0242] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0243] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000248.tif60170.

[0244] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007849881000250.tif205170.

[0245] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0246] In certain embodiments, the compound of the present invention is [ka] Selected from.

[0247] III. Embodiments of ASGPR Ligands R 1 Embodiment In a particular embodiment, R 1 It is hydrogen.

[0248] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0249] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0250] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0251] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0252] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0253] In a particular embodiment, R 1 teeth, [ka] That is the case.

[0254] In a particular embodiment, R 1 This is a heteroalkyl group optionally substituted with one, two, three, or four substituents.

[0255] In a particular embodiment, R 1 This is a C0-C6 alkyl-cyano compound optionally substituted with one, two, three, or four substituents.

[0256] In a particular embodiment, R 1 This is an alkyl group optionally substituted with one, two, three, or four substituents.

[0257] In a particular embodiment, R 1 This is an alkenyl optionally substituted with one, two, three, or four substituents.

[0258] In a particular embodiment, R 1 This is an alkynyl molecule optionally substituted with one, two, three, or four substituents.

[0259] In a particular embodiment, R 1 This is a haloalkyl group optionally substituted with one, two, three, or four substituents.

[0260] In a particular embodiment, R 1 It is F.

[0261] In a particular embodiment, R 1 It is Cl.

[0262] In a particular embodiment, R 1 It is Br.

[0263] In a particular embodiment, R 1 This is an aryl molecule optionally substituted with one, two, three, or four substituents.

[0264] In a particular embodiment, R 1 This is an arylalkyl compound optionally substituted with one, two, three, or four substituents.

[0265] In a particular embodiment, R 1This is a heteroaryl compound optionally substituted with one, two, three, or four substituents.

[0266] In a particular embodiment, R 1 This is a heteroarylalkyl compound optionally substituted with one, two, three, or four substituents.

[0267] In a particular embodiment, R 1 It is a heterocycle optionally substituted with one, two, three, or four substituents.

[0268] In a particular embodiment, R 1 This is a heterocycloalkyl compound optionally substituted with one, two, three, or four substituents.

[0269] In a particular embodiment, R 1 This is a haloalkoxy optionally substituted with one, two, three, or four substituents.

[0270] In a particular embodiment, R 1 These are -O-alkenyl, -O-alkynyl, C0~C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0~C6 alkyl-S(O)2R 3 , C0~C6 alkyl-N(R 8 )-C(O)R 3 , C0~C6 alkyl-N(R 8 )-S(O)R 3 , C0~C6 alkyl-N(R 8 )-C(S)R 3 , C0~C6 alkyl-N(R 8 )-S(O)2R 3 C0-C6 alkyl-OC(O)R 3C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, or C0-C6 alkyl-OS(O)2R 3 Each of these is optionally substituted with one, two, three, or four substituents.

[0271] R 2 Embodiment In a particular embodiment, R 2 This is an aryl molecule optionally substituted with one, two, three, or four substituents.

[0272] In a particular embodiment, R 2 It is a heterocycle optionally substituted with one, two, three, or four substituents.

[0273] In a particular embodiment, R 2 This is a heteroaryl compound containing one or two heteroatoms independently selected from N, O, and S, which are optionally substituted with one, two, three, or four substituents.

[0274] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0275] In a particular embodiment, R 2 It is a heterocycle optionally substituted with one, two, three, or four substituents.

[0276] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 8 -S(O)-R 3 That is the case.

[0277] In a particular embodiment, R2 -NR is optionally substituted with one, two, three, or four substituents. 8 -C(S)-R 3 That is the case.

[0278] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 8 -S(O)(NR 6 )-R 3 That is the case.

[0279] In a particular embodiment, R 2 -N=S(O)(R) is a molecule that is arbitrarily substituted with one, two, three, or four substituents. 3 )2.

[0280] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 8 C(O)NR 9 S(O)2R 3 That is the case.

[0281] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 8 -S(O)2-R 10 That is the case.

[0282] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 8 -C(NR 6 )-R 3 That is the case.

[0283] In a particular embodiment, R 2 It is hydrogen.

[0284] In a particular embodiment, R 2 R 10 That is the case.

[0285] In a particular embodiment, R 2 is alkyl-C(O)-R 3 That is the case.

[0286] In a particular embodiment, R 2 is -C(O)-R 3 That is the case.

[0287] In a particular embodiment, R 2 It is an alkyl group.

[0288] In a particular embodiment, R 2 It is a haloalkyl compound.

[0289] In a particular embodiment, R 2 is -OC(O)R 3 That is the case.

[0290] In a particular embodiment, R 2 -NR 8 -C(O)R 10 That is the case.

[0291] In a particular embodiment, R 2 This is an alkenyl optionally substituted with one, two, three, or four substituents.

[0292] In a particular embodiment, R 2 This is an allyl optionally substituted with one, two, three, or four substituents.

[0293] In a particular embodiment, R 2 This is an alkynyl molecule optionally substituted with one, two, three, or four substituents.

[0294] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 6 -It is Alkenil.

[0295] In a particular embodiment, R 2 This is an -O-alkenyl optionally substituted with one, two, three, or four substituents.

[0296] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 6 - It is Alkinil.

[0297] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 6 -It is a heteroaryl compound.

[0298] In a particular embodiment, R 2 -NR is optionally substituted with one, two, three, or four substituents. 6 - It is Ariel.

[0299] In a particular embodiment, R 2 It is an -O-heteroaryl compound optionally substituted with one, two, three, or four substituents.

[0300] In a particular embodiment, R 2 This is an -O-aryl compound optionally substituted with one, two, three, or four substituents.

[0301] In a particular embodiment, R 2 This is an -O-alkynyl molecule optionally substituted with one, two, three, or four substituents.

[0302] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0303] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0304] In a particular embodiment, R 2 teeth, [ka] (wherein R is any substituent as defined herein) selected from:

[0305] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0306] In a particular embodiment, R 2A teeth, [ka] (wherein R is any substituent as defined herein) selected from:

[0307] In a particular embodiment, R 2A teeth, [ka] Selected from.

[0308] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0309] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0310] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0311] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0312] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0313] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0314] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0315] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0316] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0317] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0318] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0319] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0320] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0321] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0322] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0323] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0324] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0325] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0326] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0327] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0328] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0329] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0330] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0331] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0332] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0333] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0334] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0335] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0336] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0337] In a particular embodiment, R2 or R 2A teeth, [ka] Selected from.

[0338] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0339] In a particular embodiment, R 2 teeth, [ka] Selected from.

[0340] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0341] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0342] In a particular embodiment, R 2 This is a spiro-type heteroalgebra, for example, [ka] That is the case.

[0343] In a particular embodiment, R 2 This refers to silicon-containing heterocycles, for example, [ka] That is the case.

[0344] In a particular embodiment, R 2 This has been replaced with SF5, for example, [ka] That is the case.

[0345] In a particular embodiment, R 2 It is substituted with a sulfoxime, for example, [ka] That is the case.

[0346] R 10 Embodiment In a particular embodiment, R 10 It is selected from biring complex algebras.

[0347] In a particular embodiment, R 10 It is selected from spirocyclic heteroalgebras.

[0348] In a particular embodiment, R 10 -NR 6 - Selected from a complex algebra.

[0349] In a particular embodiment, R 10 teeth, [ka] Selected from.

[0350] In a particular embodiment, R 10 teeth, [ka] Selected from.

[0351] In a particular embodiment, R 10 teeth, [ka] Selected from.

[0352] In a particular embodiment, R 10 teeth, [ka] Selected from.

[0353] Ring embodiment In a particular embodiment, the ring is [ka] Selected from.

[0354] R 30 Embodiment In one embodiment, R 30 teeth, [ka] Selected from.

[0355] R 200 Embodiment In a particular embodiment, R 200 teeth, [ka] That is the case.

[0356] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0357] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0358] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0359] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0360] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0361] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0362] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0363] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0364] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0365] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0366] In a particular embodiment, R 200 teeth, [ka] That is the case.

[0367] IV. Embodiments of the Linker In a non-limiting embodiment, the linker A and linker B Independently, [ka] (In the formula, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 These are independently linked in each case: alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-,-P(O)(R 3 )O-, -P(O)(R 3 )-, divalent residues of natural or unnatural amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, -CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2]n -,-[-(CH2)2-O-] n -,-[O-(CH2)2] n -,-[O-CH(CH3)C(O)] n -,-[C(O)-CH(CH3)-O] n -,-[O-CH2C(O)] n -,-[C(O)-CH2-O] n - Selected from the group consisting of divalent residues of fatty acids, and divalent residues of saturated or unsaturated monocarboxylic acids or dicarboxylic acids, each of which is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in each case. R 21 Independently, in each case, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Selected from the group consisting of haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocyclic compounds, The remaining variables are selected from (as defined herein).

[0368] In one embodiment, the linker A It is a bond and a linker B teeth, [ka] That is the case.

[0369] In one embodiment, the linker B It is a bond and a linker A teeth, [ka] That is the case.

[0370] In one embodiment, the divalent residue of the amino acid is [ka] (In the formula, amino acids may be oriented in either direction, and amino acids may be L-form, D-form, or a mixture thereof) are selected from the following.

[0371] In one embodiment, the divalent residue of the dicarboxylic acid undergoes a nucleophilic addition reaction: [ka] It is generated from.

[0372] Non-limiting embodiments of the divalent residue of a dicarboxylic acid produced by a nucleophilic addition reaction include: [ka] These are some examples.

[0373] In one embodiment, the divalent residue of the dicarboxylic acid undergoes a condensation reaction: [ka] It is generated from.

[0374] Non-limiting embodiments of the divalent residues of the dicarboxylic acid produced by condensation include: [ka] These are some examples.

[0375] A non-limiting embodiment of the divalent residue of a saturated dicarboxylic acid is: [ka] These are some examples.

[0376] A non-limiting embodiment of the divalent residue of a saturated dicarboxylic acid is: [ka] These are some examples.

[0377] Non-limiting embodiments of the divalent residue of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), and lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 Selected from CH2-).

[0378] Non-limiting embodiments of the divalent fatty acid residue include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, pauric acid, oleic acid, elaidic acid, gondoiic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid: [ka] These are some examples.

[0379] Non-limiting embodiments of the divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), and γ -Linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3,(CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), pauric acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondouic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadolic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)7CH2-), Mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), Myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and Erucic acid (-C(O)(CH2) 11 Selected from CHCH(CH2)7CH2-).

[0380] In a particular embodiment, the linker C teeth, [ka] (In the formula, R 22 These are independently alkyl, -C(O)N-, -NC(O)-, -N-, and -C(R) in each case. 21)-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 ) Selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, each of which is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original, and The remaining variables are selected from (as defined herein).

[0381] In a particular embodiment, the linker D teeth, [ka] (In the formula, R 32 These are, independently, alkyl and N in each case. + X - Selected from the group consisting of -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, each is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. X - This is an anionic group, for example, Br - or Cr - And, All other variables are selected from those defined herein.

[0382] In a particular embodiment, the linker A teeth, [ka] (In the formula, each heteroaryl, heterocyclic, cycloalkyl, and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence.)

[0383] In a particular embodiment, the linker A teeth, [ka] (In the formula, each heteroaryl, heterocyclic, cycloalkyl, and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence.)

[0384] In a particular embodiment, the linker A teeth, [ka] (In the formula, each heteroaryl, heterocyclic, cycloalkyl, and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence.)

[0385] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0386] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0387] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] (wherein tt is independently selected from 1, 2, or 3, and ss is 3-tt)

[0388] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] (wherein tt and ss are as defined herein) are selected from the following:

[0389] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] TIFF0007849881000343.tif232170TIFF0007849881000344.tif226170TIFF0007849881000345.tif225170TIFF0007849881000346.tif47170 (wherein each heteroaryl, heterocyclic, cycloalkyl, and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein).

[0390] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] TIFF0007849881000348.tif208170 (wherein each heteroaryl, heterocyclic, cycloalkyl, and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein).

[0391] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] (wherein each heteroaryl and aryl may be optionally substituted with any combination of one, two, three, or four halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein)

[0392] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0393] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0394] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0395] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0396] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0397] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0398] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0399] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0400] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0401] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0402] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0403] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0404] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0405] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0406] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0407] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0408] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0409] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0410] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0411] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0412] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0413] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0414] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0415] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0416] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0417] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0418] In a particular embodiment, the linker A teeth, [ka] (In the formula, each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents selected from).

[0419] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0420] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0421] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0422] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0423] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0424] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0425] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0426] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0427] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0428] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0429] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0430] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0431] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0432] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0433] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0434] In a particular embodiment, the linker B teeth, [ka] (In the formula, each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents selected from).

[0435] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0436] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0437] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0438] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0439] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0440] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0441] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0442] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0443] In a particular embodiment, the linker B - Linker A teeth, [ka] Selected from.

[0444] In a particular embodiment, the linker B - Linker A teeth, [ka] Selected from.

[0445] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0446] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0447] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0448] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0449] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0450] In a particular embodiment, the linker C teeth, [ka] TIFF0007849881000409.tif221170TIFF0007849881000410.tif71170(In the formula, each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents selected from).

[0451] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0452] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0453] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0454] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0455] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0456] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0457] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0458] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0459] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0460] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0461] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0462] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0463] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0464] In a particular embodiment, the linker D teeth, [ka] (In the formula, each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents selected from).

[0465] In a particular embodiment, the linker B -(Linker A )teeth, [ka] Selected from.

[0466] In a particular embodiment, the linker C -(Linker A )teeth, [ka] Selected from.

[0467] In a particular embodiment, the linker D -(Linker A )teeth, [ka] Selected from.

[0468] V. Terminology for Compounds Compounds are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0469] Any compound of any of the formulas described herein includes, as individual embodiments, enantiomers, diastereomers, tautomers, racemates, rotational isomers, or mixtures thereof, unless otherwise indicated or excluded by the context, each as specifically described.

[0470] The terms "a" and "an" do not indicate a limitation of quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification by reference as if they were individually enumerated herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly rejected by the context. The use of example or illustrative words (e.g., "such as") is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention unless otherwise asserted. Unless otherwise specified, the technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention pertains.

[0471] The present invention includes compounds having isotopic substitution of at least one desired atom in an amount exceeding the natural abundance of the isotope, i.e., an enriched amount.

[0472] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 Each of I is an example. In one embodiment, isotope-labeled compounds are used in metabolic studies (e.g. 14 (using C), reaction dynamics studies (for example) 2 H or 3It can be used in detection or imaging techniques, including drug or substrate tissue distribution assays or radiotherapy for patients, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), using H. 18 1F-labeled compounds may be desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing the non-isotope labeling reagent with a readily available isotope labeling reagent, by following the procedures disclosed in the scheme or the examples and preparations below.

[0473] As a general example, though not limited to them, hydrogen isotopes, for example, deuterium ( 2 H) and tritium ( 3 H) can be optionally used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 C can be used. In one embodiment, isotope substitution affects the efficacy of a drug, such as pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, and T. max , C max This involves substituting hydrogen with deuterium at one or more positions on the molecule to improve performance, etc. For example, deuterium can bind to a carbon atom at the cleavage site during metabolism (α-deuterium dynamic isotope effect) or to a carbon atom adjacent to or near the cleavage site (β-deuterium dynamic isotope effect).

[0474] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, isotopes are enriched to 80%, 85%, 90%, 95%, or 99% or more at any position of the target. In certain embodiments, deuterium is enriched to 80%, 85%, 90%, 95%, or 99% at the desired position. Unless otherwise specified, enrichment at any point exceeds the natural abundance, and in one embodiment, the enrichment is sufficient to alter the properties of the detectable drug in humans.

[0475] In one embodiment, the substitution of a hydrogen atom with a deuterium atom is present within any of the variable groups. For example, if any of the variable groups are, for example, methyl, ethyl, or methoxy, or contain these by substitution, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, the variable group has the symbol "'" or "a", which can be deuterated in one embodiment. In certain other embodiments, if two substituents of the central core ring combine to form a cyclopropyl ring, the unsubstituted methylene carbon may be deuterated.

[0476] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one embodiment, the present invention includes active compounds in solvated form. The term "solvate" refers to a molecular complex of the compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing the compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent for crystallization can be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0477] A dash ("-") without a space between two letters or symbols is used to indicate the point at which a substituent is attached. For example, -(C=O)NH2 is attached via the carbon of the keto (C=O) group.

[0478] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced by a moiety selected from the indicated group, provided that the normal valence of the designated atom is not exceeded and the resulting compound is stable. For example, if the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is pyridone. Combinations of substituents and / or variable moieties are permitted only if such combinations result in a stable compound or a useful synthetic intermediate.

[0479] "Alkyl" refers to a branched, linear, or cyclic saturated aliphatic hydrocarbon group. In one embodiment, the alkyl contains 1 to about 12 carbon atoms, more generally 1 to about 6 carbon atoms, 1 to about 4 carbon atoms, or 1 to 3 carbon atoms. In one embodiment, the alkyl contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein refer to alkyl groups in which each element of the range described as a unique species is considered to be explicitly disclosed as an individual species. For example, the term C1-C6 alkyl, as used herein, refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and also to carbocyclic alkyl groups having 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as an independent species. For example, as used herein, the term C1-C4 alkyl refers to a linear or branched alkyl group having one, two, three, or four carbon atoms, and each of these is intended to be described as a separate species. nWhen alkyl is used herein in combination with another group, for example, as (C3-C7 cycloalkyl)C0-C4 alkyl or -C0-C4 alkyl(C3-C7 cycloalkyl), the indicated group, in this case cycloalkyl, is directly bonded by a single covalent bond (C0 alkyl) or attached by an alkyl chain, in this case one, two, three, or four carbon atoms. The alkyl may also be attached via other groups, such as a heteroatom, as in -O-C0-C4 alkyl(C3-C7 cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl.

[0480] When terms containing "alk" are used, it should be understood that "cycloalkyl" or "carbocyclic" can be considered part of the definition unless the context clearly excludes it. For example, though not limited to, terms such as alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenyloxy, and haloalkyl can all be considered to include alkyl in cyclic form unless the context clearly excludes it.

[0481] An "alkenyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. Non-limiting examples include C2-C8 alkenyls, C2-C7 alkenyls, C2-C6 alkenyls, C2-C5 alkenyls, and C2-C4 alkenyls. The designation used herein refers to alkenyl groups having each member in the range described above as a separate species for the alkyl moiety. Examples of alkenyls include, but are not limited to, ethenyl and propenyl.

[0482] "Alkynyl" refers to a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain, such as a C2-C8 alkynyl or a C2-C6 alkynyl. The designation used herein refers to an alkynyl group having each member in the range described above as a separate species for the alkyl moiety. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0483] An "alkoxy" is a specified alkyl group covalently bonded by an oxygen crosslink (-O-). Examples of alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group is a specified alkyl group having an indicated number of carbon atoms covalently bonded by a sulfur crosslink (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

[0484] "Haloalkyl" refers to both branched and linear alkyl groups substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyls include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0485] "Aryl" refers to an aromatic group containing only carbon atoms in one or more aromatic rings. In one embodiment, the aryl group contains one to three single or fused rings with 6 to 14 or 18 ring atoms and no heteroatoms as ring members. The term "aryl" includes groups in which a saturated or partially unsaturated carbocyclic group is fused with an aromatic ring. The term "aryl" also includes groups in which a saturated or partially unsaturated heterocyclic group is fused with an aromatic ring, provided that the attachment point is an aromatic ring. Such compounds may include aryl rings fused to a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated cyclic group containing any one, two or three heteroatoms independently selected from N, O, B, P, Si, and S to form a 3,4-methylenedioxyphenyl group. Examples of aryl groups include phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is a pendant group. An example of a pendant ring is a phenyl group substituted with another phenyl group.

[0486] The term "heterocyclic ring" refers to saturated and partially saturated heteroatom-containing ring groups in which the heteroatoms can be selected from N, S, and O. The term "heterocyclic ring" includes not only monocyclic rings with 3 to 12 members, but also bicyclic ring systems with 5 to 16 members (which may include condensed, bridging, or spiro bicyclic ring systems). Heterocyclic rings do not include rings containing -OO- or -SS- moieties. Examples of saturated heterocyclic groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl), saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic groups, though not limited to them, include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, and 1,2,3,4-tetrahydro Examples include dilo-isoquinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazoliol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. "Bicyclic heterocycles" include groups in which a heterocyclic group is fused with an aryl group and the attachment point is a heterocycle. "Bicyclic heterocycles" also include heterocyclic groups fused with or bridged with a carbocyclic group.For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen atoms or sulfur atoms.

[0487] An unrestricted example of a biring complex algebra is: [ka] These are some examples.

[0488] Unless otherwise specified or made clear from the context, the term “bicyclic heteroalgebra” includes cis-diastereomers and trans-diastereomers. Non-restrictive examples of chiral bicyclic heteroalgebras include: [ka] These are some examples.

[0489] In certain alternative embodiments, the term “heterocyclic” refers to saturated and partially saturated heteroatom-containing ring groups in which the heteroatoms can be selected from N, S, O, B, Si, and P.

[0490] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing one to three heteroatoms, or in some embodiments one, two, or three heteroatoms, selected from N, O, S, B, and P (typically selected from N, O, and S), with the remaining ring atom being carbon; or a stable bicyclic or tricyclic system containing at least one five-membered, six-membered, or seven-membered aromatic ring, containing one to three heteroatoms, or in some embodiments one to two heteroatoms, selected from N, O, S, B, or P, with the remaining ring atom being carbon. In one embodiment, the heteroatom is nitrogen only. In one embodiment, the heteroatom is oxygen only. In one embodiment, the heteroatom is sulfur only. Monocyclic heteroaryl groups typically have five or six ring atoms. In some embodiments, the bicyclic heteroaryl group is an 8- to 10-membered heteroaryl group, i.e., a group containing 8 or 10 ring atoms in which one 5-membered, 6-membered, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, and the attachment point is the aromatic ring. If the total number of S and O atoms in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group is not greater than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not greater than 1.Examples of heteroaryl groups include pyridinyl (e.g., including 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (e.g., including 4-hydroxypyridinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, ben Examples include, but are not limited to, zofuranil, cinnolinil, indazolyl, indolidinil, phthalazinil, pyridadinil, triazinil, isoindolyl, pteridinil, purinil, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, flazanil, benzoflazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, tetrahydrofuranil, and phlopyridinil. The heteroaryl group may be independently and optionally substituted with one or more substituents described herein. "Heteroaryloxy" is the heteroaryl group described herein, bonded to the group to be substituted via an oxygen (-O-) linker.

[0491] "Heteroarylalkyl" refers to an alkyl group as described herein that is substituted with a heteroaryl group as described herein.

[0492] "Arylalkyl" refers to an alkyl group as described herein that is substituted with an aryl group as described herein.

[0493] "Hypercycloalkyl" refers to an alkyl group as described herein that is substituted with a heterocyclo group as described herein.

[0494] The term "heteroalkyl" refers to an alkyl, alkenyl, alkynyl, or haloalkyl moiety as defined herein, in which a CH2 group is substituted with a heteroatom or a carbon atom is substituted with a heteroatom, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron. In one embodiment, the sole heteroatom is nitrogen. In one embodiment, the sole heteroatom is oxygen. In one embodiment, the sole heteroatom is sulfur. In one embodiment, "heteroalkyl" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 20 carbon atoms. Non-limiting examples of heteroalkyl moieties include polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0495] When a portion of the compound is "arbitrarily substituted," that portion may be alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), or -OR, depending on the valency. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] It may be substituted with one or more groups selected from, where any substituent is chosen such that a stable compound is produced. For example, [ka] As long as a stable compound is produced, alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 F, Cl, Br, I, -NR 6 R7 , heteroalkyl, cyano, nitro, C(O)R 3 It can be substituted with one or two groups independently selected from the above, as long as a stable compound is produced. [ka] It can be replaced by only one base selected from. On the other hand, [ka] teeth, [ka] It can only be replaced by one or two elements selected from the set.

[0496] An unrestricted example of an arbitrarily substituted CH2 group is: [ka] These are some examples.

[0497] An unrestricted example of an arbitrarily substituted -S- group is: [ka] These are some examples.

[0498] "Dosage form" refers to the unit of administration of an active drug. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral forms, sublingual forms, topical forms, gels, mucosal forms, subcutaneous forms, intramuscular forms, parenteral forms, systemic forms, and intravenous forms. "Dosage form" may also include implants for controlled delivery.

[0499] A "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance, such as a carrier. The present invention includes pharmaceutical compositions of the described compounds.

[0500] A "pharmaceutical combination" is a combination of at least two active agents that can be administered together in a single dosage form or in separate dosage forms, and which are indicated to be used in combination to treat any of the disorders described herein.

[0501] A "pharmaceutically acceptable salt" is a derivative of the disclosed compound modified by the parent compound to produce an inorganic or organic salt, a pharmaceutically acceptable acid-addition salt, or a base-addition salt. Salts of the compound can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K), or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Salts of the compound further include solvates of the compound and salts of the compound.

[0502] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include, for example, human-ingestable salts of parent compounds formed from inorganic or organic acids, and quaternary ammonium salts. Examples of such salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitrate, as well as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) 1~4Examples include salts prepared from organic acids such as -COOH, or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0503] In the context of the present invention, the term "carrier" refers to a diluent, excipient, or vehicle that delivers the active compound.

[0504] "Pharmacologically acceptable excipients" generally mean excipients that are safe, ingestible by humans, and not inappropriate for administration to a host (usually humans) biologically or otherwise, and that are useful in the preparation of pharmaceutical compositions / combinations. In one embodiment, excipients acceptable for veterinary use are used.

[0505] "Patient," "host," or "subject" refers to a human or non-human animal that requires treatment or prevention of any of the disorders specifically described herein. Typically, the host is a human. "Patient," "host," or "subject" also refers to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc.

[0506] The "therapeutic effective dose" of the compound, pharmaceutical composition, or combination of the present invention means an amount that, when administered to a host, is effective in producing a therapeutic effect such as improvement of symptoms or reduction or mitigation of the disease itself. In another embodiment, a prophylactic dose may be administered to prevent or minimize the risk of disease mediated by extracellular target proteins.

[0507] "alkyl" embodiment In one embodiment, "alkyl" is C1-C 10 These are alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0508] In one embodiment, the "alkyl" has one carbon atom.

[0509] In one embodiment, the "alkyl" has two carbon atoms.

[0510] In one embodiment, the "alkyl" has three carbon atoms.

[0511] In one embodiment, the "alkyl" has four carbon atoms.

[0512] In one embodiment, the "alkyl" has five carbon atoms.

[0513] In one embodiment, the "alkyl" has six carbon atoms.

[0514] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0515] Further non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0516] Further non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0517] Further non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0518] Further non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0519] In alternative embodiments, the "alkyl" group is optionally substituted.

[0520] In an alternative embodiment, the "alkenyl" group is optionally substituted.

[0521] In an alternative embodiment, the "alkynyl" group is optionally substituted.

[0522] Embodiments of "haloalkyl" In one embodiment, "haloalkyl" is C1-C 10 Haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1-C2 haloalkyl.

[0523] In one embodiment, "haloalkyl" has one carbon.

[0524] In one embodiment, "haloalkyl" has one carbon and one halogen.

[0525] In one embodiment, "haloalkyl" has one carbon and two halogens.

[0526] In one embodiment, "haloalkyl" has one carbon and three halogens.

[0527] In one embodiment, "haloalkyl" has two carbons.

[0528] In one embodiment, "haloalkyl" has three carbons.

[0529] In one embodiment, "haloalkyl" has four carbons.

[0530] In one embodiment, "haloalkyl" has five carbons.

[0531] In one embodiment, "haloalkyl" has six carbons.

[0532] As a non-limiting example of "haloalkyl", [ka] These are some examples.

[0533] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0534] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0535] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0536] "Heteroaryl" Embodiment Non-exclusive examples of a five-membered "heteroaryl" group include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0537] As a further non-restrictive example of a 5-membered "heteroaryl" group, [ka] These are some examples.

[0538] In one embodiment, the "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0539] As a non-limiting example of a six-membered "heteroaryl" group containing one or two nitrogen atoms, [ka] These are some examples.

[0540] In one embodiment, the "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0541] Non-restrictive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[0542] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0543] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0544] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0545] In one embodiment, the "heteroaryl" is a 10-membered bicyclic aromatic group comprising one or two atoms selected from nitrogen, oxygen, and sulfur.

[0546] Non-restrictive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0547] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0548] "Hybrid Algebra" Embodiment In one embodiment, "heterocyclic ring" refers to a ring having one nitrogen atom and three, four, five, six, seven, or eight carbon atoms.

[0549] In one embodiment, “heterocyclic ring” refers to a ring having one nitrogen atom, one oxygen atom, and three, four, five, six, seven, or eight carbon atoms.

[0550] In one embodiment, "heterocyclic ring" refers to a ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[0551] In one embodiment, "heterocyclic ring" refers to a ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[0552] In one embodiment, “heterocyclic” refers to a ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[0553] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[0554] Further non-restrictive examples of "heterocyclic rings" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[0555] Further non-restrictive examples of "heterocyclic compounds" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0556] Further non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0557] Additional, non-restrictive examples of "heterocyclic rings" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group lies on the heterocyclic ring.

[0558] for example, [ka] This is a "heterocyclic" group.

[0559] however, [ka] This is an "aryl" group.

[0560] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0561] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0562] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0563] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0564] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0565] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0566] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0567] Ariel In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0568] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0569] In one embodiment, "aryl" is a six-carbon aromatic group fused to a heterocycle, with the attachment point being an aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group is on an aromatic ring.

[0570] for example, [ka] This is an "aryl" group.

[0571] however, [ka] This is a "heterocyclic" group.

[0572] "Arylalkyl" Embodiment Non-specific examples of "arylalkyl" include: [ka] These are some examples.

[0573] In one embodiment, "arylalkyl" is, [ka] That is the case.

[0574] In one embodiment, "arylalkyl" refers to a two-carbon alkyl group substituted with an aryl group.

[0575] Non-specific examples of "arylalkyl" include: [ka] These are some examples.

[0576] VI. Extracellular proteins and targeted ligands A wide range of known and characterized extracellular proteins may induce, regulate, or exacerbate diseases in vivo, including abnormal cell proliferation such as tumors and cancers, autoimmune diseases, inflammation, and age-related diseases. For example, extracellular proteins such as growth factors, cytokines, and chemokines bind to cell surface receptors and often initiate abnormal signaling in numerous diseases, including cancer and inflammation.

[0577] Extracellular protein degraders described herein or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable compositions thereof can be used to treat disorders mediated by selected target proteins bound to a targeted ligand. The degraders described herein can target and lysosomal degrade specific extracellular target proteins that mediate pathological disorders. Selected extracellular target proteins can modulate disorders in humans through mechanisms of action such as modification of biological pathways, pathogenic signaling, or regulation of signal cascades or cell entry. In one embodiment, the target protein is a protein that is not drug-worthy in the classical sense, in that it does not have a binding pocket or active site that can be inhibited or otherwise bound and cannot be readily allosterically controlled. In another embodiment, the target protein is a drug-worthy protein in the classical sense, but for therapeutic purposes, protein degradation is preferred over inhibition. The extracellular target protein is recruited together with a targeted ligand, which is a ligand for the extracellular target protein. Typically, the targeted ligand binds to the target protein non-covalently. In alternative embodiments, the target protein is covalently bound to the targeting ligand in a manner that may be irreversible or reversible.

[0578] Accordingly, in some embodiments, methods are provided for treating a host with an extracellular target protein-mediated disorder, comprising administering to a host, typically a human, an effective amount of a degrader targeting the extracellular protein described herein or a pharmaceutically acceptable salt thereof, in an optionally pharmaceutically acceptable composition.

[0579] The extracellular target protein can be any amino acid sequence to which a degrader containing a targeting ligand can bind, and through its degradation, a beneficial therapeutic effect is obtained. In one embodiment, the target protein is a non-endogenous peptide, such as one derived from a pathogen or toxin. In another embodiment, the target protein may be an endogenous protein that mediates the damage. The endogenous protein may be either a normal or abnormal form of the protein. For example, the target protein may be an extracellular mutant protein, or a protein in which partial or complete gain-of-function or loss-of-function is encoded by nucleotide polymorphisms, for example. In some embodiments, the degrader targets an abnormal form of the protein rather than its normal form.

[0580] A targeted ligand is a ligand that covalently or noncovalently binds to a target protein selected to be lysosomal degraded. A targeted ligand is a small molecule or portion (e.g., a peptide, nucleotide, antibody fragment, aptamer, biomolecule, or other chemical structure) that binds to a target protein, where the target protein is a mediator of disease in the host, as detailed below. Exemplary targeted ligands are shown in Figure 1.

[0581] Anchor connection Extracellular protein target ligands ("EPTLs") are covalently bound to linkers in ASGPR-binding extracellular protein degrader compounds via anchoring bonds (chemical bonds between the EPTL and either linker B, linker C, or linker D). These bonds can be located anywhere on the ligand that does not unacceptably hinder the EPTL's ability to bind to extracellular protein targets. Anchoring bonds are shown in Figure 1 as an example of an extracellular protein target ligand. [ka] It is represented as follows.

[0582] Many of the exemplary extracellular proteins targeted by the medical therapies described below have characteristic structural information in the Known Protein Data Bank ("PDB"), a database of three-dimensional structural information for large biomolecules such as proteins and nucleic acids. The PDB contains X-ray crystallographic and other information submitted by scientists worldwide and is freely accessible. See, for example, www.rcsb.org, www.wwpdb.org, and www.uniprot.org. ** Alternatively, using the PDB codes provided in the databank itself, and the technical reference materials shown herein or otherwise published, a person skilled in the art can determine a suitable location where the EPTL can be linked to the ASGPR binding site via anchoring to linker B, linker C, or linker D. For many of these proteins, published reference materials describe how a wide range of ligands bind to the target protein, and from this information a reasonable anchoring site can be determined.

[0583] For example, a person skilled in the art can use available visualization tools, including those available on the PDB website, to determine the site where an extracellular protein-targeting ligand docks to an extracellular protein. A person skilled in the art can also import crystal structures and selected target extracellular protein-targeting ligands into modeling software (including, for example, PyMOL, Glide, Maestro, RasMol, Visual Molecular Dynamics, Jmol, and AutoDock) to determine which portion of the extracellular protein-targeting ligand binds to the extracellular protein. In this case, the ASGPR ligand binds via linker and anchor junctions at a site that does not excessively negatively affect binding to the extracellular protein.

[0584] Non-restrictive examples of extracellular target proteins Immunoglobulin A (IgA) In some embodiments, the target protein is human immunoglobulin A (IgA). IgA is an antibody that plays a crucial role in mucosal immune function. The amount of IgA produced in relation to mucosa is greater than the combined total of all other types of antibodies. IgA has two subclasses (IgA1 and IgA2) and can be produced as both monomers and dimers. The dimeric form of IgA is the most common. In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89) expressed on immune effector cells to initiate an inflammatory response. Ligation of FcαRI by IgA-containing immune complexes leads to antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils, phagocytosis by monocytes, macrophages, and neutrophils, and induction of respiratory burst activity by polymorphonuclear leukocytes. Abnormal IgA expression is associated with numerous autoimmune and immune-mediated disorders, including IgA nephropathy, celiac disease, Henoch-Schönein purpura (HSP), linear IgA bullous dermatosis, and IgA pemphigus.

[0585] The Protein Databank website provides not only the crystal structure of IgA, but also the crystal structures of IgA bound to various compounds searchable by 5E8E (Baglin, TP, et al., J. Thromb. Haemost., 2016, 14: 137-142) and 2QTJ (Bonner, A., et al., J. Immunol., 2008, 180: 1008-1018). Furthermore, Hatanaka T. et al. provide outstanding insights into the specificity and high binding affinity of IgA to the OPT-1 peptide (J Biol Chem., 2012, 287(51), 43126-43136).

[0586] Representative IgA-targeting ligands are shown in Figure 1.

[0587] Further representative IgA-targeting ligands include: MLKKIE (Jerlstrom et al. Infect. Immun. 1996 Jul; 64(7):2787-2793) Sequence ID 1, Opt-1 - HMVCLAYRGRPVCCFAL (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012) SEQ ID NO: 2, Opt-2 - HMVCLSYRGRPVCFSL(Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012) SEQ ID NO: 3, Opt-3 - HQVCLSYRGRPVCFST(Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012) SEQ ID NO: 4, QMRCLSYKGRRVCLWL (US Patent No. 9593147), Sequence ID No. 5, KRLCLQYKGSKVCFRL (US Patent No. 9593147), Sequence ID No. 6, RMRCLTYRGRRVCLEL (US Patent No. 9593147), Sequence ID No. 7 SMRCLQYRGSRVCLTL (US Patent No. 9593147), Sequence ID No. 8, HLRCLRYKGTRVCFSL (US Patent No. 9593147), Sequence ID No. 9 HVRCLSYKGREVCVQL (US Patent No. 9593147), Sequence ID No. 10. PRMCLFIYKGRRVCIPY (US Patent No. 9593147), Sequence ID No. 11, HMRCLHYKGRRVCFLL (US Patent No. 9593147), Sequence ID No. 12, HKRCLHYRGRMVCFLI (US Patent No. 9593147), Sequence ID No. 13, QKRCLKYKGSRVCFFL (US Patent No. 9593147), Sequence ID No. 14 HVRCLRYRGKNVCFLL (US Patent No. 9593147), Sequence ID No. 15, SDVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 16, RDVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 17, HDVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 18, SMVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 19. SAVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 20, SDVCLNYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 21, SDVCLHYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 22, SDVCLAYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 23, SDVCLRYRGRPVCFAV (US Patent No. 9593147), Sequence ID No. 24, SDVCLRYRGRPVCFQL (US Patent No. 9593147), Sequence ID No. 25, SDVCLRYRGRPVCFQA (US Patent No. 9593147), Sequence ID No. 26, HMVCLSYRGRPVCF (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 27, HMVCLSYRGRPVCFS (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 28, HQVCLSYRGQPVCFSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 29, HQVCLSYRGRPTCFSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 30, HQVCLSYRGRPVCYSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 31, HQVCLSYRGQPVCFST (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 32, HQVCLSYRGRPTCFST (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 33, HQVCLSYRGQPTCFST (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 34, These are some examples.

[0588] Immunoglobulin G (IgG) In some embodiments, the target protein is human immunoglobulin G (IgG). IgG accounts for approximately 75% of serum antibodies in humans. IgG is the most common type of antibody found in the blood circulation. IgG antibodies are large, globular proteins with a molecular weight of approximately 150 kDa, composed of four peptide chains. [6] IgG has a tetrameric quaternary structure because it contains two identical gamma (γ) heavy chains of approximately 50 kDa and two identical light chains of approximately 25 kDa. The two heavy chains are linked to each other and to the light chains by disulfide bonds. The resulting tetramer has two identical halves, which together form a Y-shape. Both ends of the branch contain identical antigen-binding sites. Various regions and domains of typical IgG are shown in the figure on the left. The Fc region of IgG has an N-glycosylation site that is highly conserved at asparagine 297 in the constant region of the heavy chain. The N-glycans attached to this site are mainly complex core-fucosylated bibranched structures. In addition, small amounts of these N-glycans also have bisected GlcNAc and α-2,6-linked sialic acid residues. The N-glycan composition in IgG is associated with several autoimmune diseases, infectious diseases, and metabolic diseases. Furthermore, IgG4 overexpression is generally associated with IgG4-related diseases involving multiple organs, including type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, Mikulicz's disease, Küttner tumor, inflammatory pseudotumor (in various parts of the body), mediastinal fibrosis and, in some cases, retroperitoneal fibrosis, aortitis, retroperitoneal fibrosis, proximal bile duct stenosis, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement, and pericarditis.

[0589] The Protein Databank website allows you to search for IgG crystal structures not only by 1H3X (Krapp, S., et al., J. Mol. Biol., 2003, 325: 979) and 5V43 (Lee, CH, et al., Nat. Immunol., 2017, 18: 889-898), but also by 5YC5 (Kiyoshi M., et al., Sci. Rep., 2018, 8: 3955-3955), 5XJE (Sakae Y., et al., Sci. Rep., 2017, 7: 13780-13780), 5GSQ (Chen, CL, et al., ACS Chem. Biol., 2017, 12: 1335-1345), and 1HZH (Saphire EO, et al.). Crystal structures of IgG bound to various compounds searchable by al. (Science, 2001, 293: 1155-1159) are also provided. Furthermore, Kiyoshi, M. et al. provide insights into the structural basis for how human IgG1 binds to its high-affinity human receptor FcγRI (Kiyoshi M., et al., Nat Commun., 2015, 6, 6866).

[0590] Representative IgG-targeting ligands are shown in Figure 1.

[0591] Further representative IgG targeting ligands include: [ka] (In the formula, X R is O, S, NH, or N-C1~C3 alkyl, and X M Examples include O, S, NH, or N-C1~C3 alkyl groups.

[0592] In other embodiments, the IgG-targeting ligand is [ka] Selected from.

[0593] In some embodiments, the IgG-targeting ligand has the following chemical structure: [ka] (In the formula, R N02 This is a group consisting of a dinitrophenyl group (which is arbitrarily linked via CH2, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O).

[0594] In certain embodiments, the IgG-targeting ligand is [ka] (In the formula, X 100 (Selected from O, CH2, NH, N-C1~C3alkyl, NC(O)C1~C3alkyl, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O).

[0595] In some embodiments, the IgG-targeting ligand has the following chemical structure: [ka] (wherein k'''' is 1 to 4 (preferably 2 to 3, most frequently 3)) a 3-indoleacetic acid group, or [ka] It is the basis.

[0596] In some embodiments, the IgG-targeting ligand is a peptide. Non-limiting examples of IgG-targeting ligand peptides include: PAM(RTY)4K2KG (Fassina, et al, J. Mol. Recognit. 1996, 9, 564-569) SEQ ID NO: 35 [ka] D-PAM (where all amino acids in the PAM sequence are D-amino acids) (Verdoliva, et al, J. Immunol. Methods, 2002, 271, 77-88) (RTY) 4K2KG Sequence ID No. 36 D-PAM-Φ (where all amino acids in the PAM sequence are D-amino acids, with further modifications including acetylation of four N-terminal arginines with phenylacetic acid) (Dinon, et al J. Mol. Recognit. 2011, 24, 1087-1094) (RTY) 4K2KG SEQ ID NO: 37 TWKTSRISIF(Krook, et al,.J. Immunol. Methods 1998, 221, 151-157) SEQ ID NO: 38, FGRLVSSIRY (Krook, et al, J. Immunol. Methods 1998, 221, 151-157) Sequence ID 39, Fc-III(DCAWHLGELVWCT-NH2)(DeLano et al, Science 2000, 287, 1279-1283) Sequence ID No. 40 [ka] FCBP-Ser DSAWHLGELWST (International Publication No. 2014 / 010813) Sequence ID No. 41, DCHKRSFWADNCT (see International Publication No. 2014 / 010813) Sequence ID No. 42, DCRTQFRPNQTCT (see International Publication No. 2014 / 010813), Sequence ID No. 43, DCQLCDFWRTRCT (see International Publication No. 2014 / 010813), Sequence ID No. 44, DCFEDFNEQRTCT (see International Publication No. 2014 / 010813), Sequence ID No. 45, DCLAKFLKGKDCT (see International Publication No. 2014 / 010813) Sequence ID 46, DCWHRRTHKTFCT (see International Publication No. 2014 / 010813) Sequence ID No. 47, DCRTIQTRSCT (see International Publication No. 2014 / 010813) Sequence ID 48, DCIKLAQLHSVCT (see International Publication No. 2014 / 010813) Sequence ID No. 49, DCWRHRNATEWCT (see International Publication No. 2014 / 010813), Sequence ID No. 50, DCQNWIKDVHKCT (see International Publication No. 2014 / 010813) Sequence ID 51, DCAWHLGELVWCT (see International Publication No. 2014 / 010813), Sequence ID 52, DCAFHLGELVWCT (see International Publication No. 2014 / 010813), Sequence ID No. 53, DCAYHLGELVWCT (see International Publication No. 2014 / 010813) Sequence ID 54, FcBP-1 PAWHLGELVWP (Kang, et al, J. Chromatogr. A 2016, 1466, 105-1 12) Sequence ID 55 [ka] FcBP-2 PDCAWHLGELVWCTP (Dias, et al, J. Am. Chem. Soc. 2006, 128, 2726-2732) Sequence ID No. 56; [ka] Fc-lll-4c CDCAWHLGELVWCTC (Gong, et al, Bioconjug. Chem. 2016, 27, 1569-1573) Sequence ID No. 57 [ka] EPIHRSTLTALL (Ehrlich, et al, J. Biochem. Biophys. Method 2001, 49, 443-454) SEQ ID NO: 58, APAR (Camperi, et al, Biotechnol. Lett. 2003, 25, 1545-1548) Sequence ID 59, FcRM(CFHH)2KG (Fc receptor mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242-1253) Sequence ID No. 60 [ka] HWRGWV (Yang, et al., J Peptide Res. 2006, 66, 110-137) Sequence ID 61, HYFKFD (Yang, et al, J. Chromatogr. A 2009, 1216, 910-918) Sequence ID 62, HFRRHL(Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104) SEQ ID NO: 63, HWCitGWV (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104) Sequence ID 64, HWmetCitGWmetV (US Patent No. 10,266,566), Sequence ID No. 65 D2AAG (small synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158-167) Sequence ID No. 66, DAAG (small synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158-167) SEQ ID NO: 67 Cyclo[(Nα-Ac)S(A)-RWHYFK-Lact-E](Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237) SEQ ID NO: 68, Cyclo[(Nα-Ac)-Dap(A)-RWHYFK-Lact-E](Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237) SEQ ID NO: 69, Cyclo[Link M-WFRHYK](Menegatti, et al, Biotechnol. Bioeng. 2013, 110, 857-870) Sequence ID No. 70, NKFRGKYK (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40) Sequence ID No. 71, NARKFYKG (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40) Sequence ID No. 72, FYWHCLDE (Zhao, et al, Biochem. Eng. J. 2014, 88, 1-11) Sequence ID No. 73, FYCHWALE (Zhao, et al, J Chromatogr. A 2014, 1355, 107-114) Sequence ID 74, FYCHTIDE (Zhao, et al., Z Chromatogr. A 2014, 1359, 100-111) Sequence ID 75, Dual 1 / 3(FYWHCLDE-FYCHTIDE)(Zhao, et al, J. Chromatogr. A 2014, 1369, 64-72) Sequence ID 76, RRGW (Tsai, et al, Anal. Chem. 2014, 86, 2931-2938) Sequence ID 77, KHRFNKD (Yoo and Choi, BioChip J. 2015, 10, 88-94) Sequence ID No. 78, CPSTHWK (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 79, NVQYFAV (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 80, ASHTQKS (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 81, QPQMSHM (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 82, TNIESLK (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 83, NCHKCWN (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 84, SHLSKNF (Sun et al. Polymers 2018, 10, 778) Sequence ID No. 85, These are some examples.

[0597] Immunoglobulin E (IgE) In some embodiments, the target protein is human immunoglobulin E (IgE). IgE is a type of immunoglobulin that plays an essential role in type I hypersensitivity, which can manifest in various allergic diseases such as allergic asthma, most types of sinusitis, allergic rhinitis, food allergies, and certain types of chronic urticaria and atopic dermatitis. IgE also plays a central role in responses to allergens such as anaphylactic drugs, bee stings, and antigen preparations used in desensitization immunotherapy.

[0598] On the Protein Data Bank website, not only the crystal structure of IgE searchable by 1F2Q (Garman, S.C., Kinet, J.P., Jardetzky, T.S., Cell, 1998, 95: 951-961), but also the crystal structures of IgE bound to various compounds searchable by 1F6A (Garman, S.C., et al., Nature, 2000, 406 259-266), 1RPQ (Stamos, J., et al., Structure, 2004, 12 1289-1301), 2Y7Q (Holdom, M.D., et al., Nat. Struct. Mol. Biol., 2011, 18 571), and 4GRG (Kim, B., et al., Nature, 2012, 491: 613-617) are provided. Furthermore, Wan et al. provided insights into the crystal structure of the Fc of IgE, revealing an asymmetrically curved conformation (Wan et al., Nat. Immunol., 2002, 3(7), 681-6), and Dhaliwal et al. provided insights into the crystal structure of IgE bound to the B cell receptor CD23, revealing the mechanism of reciprocal allosteric inhibition by the high-affinity receptor FcεRI (Dhaliwal, B., et al., Proc Natl Acad Sci U S A., 2012, 109(31), 12686-91).

[0599] Additional immunoglobulin-targeting ligands Additional non-limiting examples of extracellular targeting ligands include [Chemical formula] (where X M is -(CH2) 0~6 -O-(CH2) 0~6 S-(CH2) 0~6 NR M -(CH2) 0~6 C(O)-(CH2) 0~6, a PEG group containing 1 to 8, preferably 1 to 4, ethylene glycol residues, or -C(O)(CH2) 0~6 NR M It is a base, R M (where 0 to 6 is preferably 1, 2, 3, or 4, more preferably 1) is a C1-C3 alkyl group optionally substituted with H or one or two hydroxyl groups.

[0600] Further non-limiting examples of extracellular targeting ligands include: [ka] (wherein DNP is a 2,4-dinitrophenyl group), or chemical structure: [ka] (In the formula, Y' is H or NO2 (preferably H), X 101 O, CH2, S, NR 101 , S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O, and R 101 Examples of groups include H, C1-C3 alkyl groups, or -C(O)(C1-C3 alkyl) groups.

[0601] Further non-limiting examples of extracellular targeting ligands include: [ka] (In the formula, X 102 CH, O, NR 101 , or S, preferably O, R 101 is H or C1-C3 alkyl, and Z is a sugar group selected from a combination of monosaccharides, monosaccharides, disaccharides, oligosaccharides, more preferably monosaccharides including aldoses and ketoses, and disaccharides including disaccharides described herein. Examples of monosaccharide aldoses include monosaccharides such as aldotrioses (especially D-glyceraldehyde), aldotetroses (especially D-erythrose and D-threose), aldopentoses (especially D-ribose, D-arabinose, D-xylose, D-lyxose), and aldoxoses (especially D-allose, D-altrose, D-glucose, D-mannose, D-glucose, D-idosose, D-galactose, and D-talose). Examples of sugar ketoses include monosaccharides such as ketotriose (especially dihydroxyacetone), ketotetrose (especially D-erythrulose), ketopentose (especially D-ribulose and D-xylulose), ketohexose (especially D-psicose, D-fructose, D-sorbose, and D-tagatose), amino sugars including galactoseamine, sialic acid, and N-acetylglucosamine, and sulfosaccharides including sulfoquinovose.Exemplary disaccharides used in the present invention include, in particular, sucrose (which may optionally have N-acetylated glucose), lactose (which may optionally have N-acetylated galactose and / or glucose), maltose (which may optionally have N-acetylated glucose residues, one or both of which may have N-acetylated glucose residues), trehalose (which may optionally have N-acetylated glucose residues, one or both of which may have N-acetylated glucose residues), cellobiose (which may optionally have N-acetylated glucose residues, one or both of which may have N-acetylated glucose residues), nigerose (which may optionally have N-acetylated glucose residues, one or both of which may have N-acetylated glucose residues), isomaltose (which may optionally have N-acetylated glucose residues, one or both of which may have N-acetylated glucose residues), β,β-trehalose (which may optionally have N-acetylated glucose residues), sophorose (which may optionally have N-acetylated glucose residues), and Examples include (both may optionally have N-acetylated glucose residues), laminaribiose (one or both may optionally have N-acetylated glucose residues), gentiobiose (one or both may optionally have N-acetylated glucose residues), turanose (may optionally have N-acetylated glucose residues), maltulose (may optionally have N-acetylated glucose residues), palatinose (may optionally have N-acetylated glucose residues), gentiovirose (may optionally have N-acetylated glucose residues), mannoviobiose, melibiose (may optionally have N-acetylated glucose residues and / or galactose residues), melibiurose (may optionally have N-acetylated galactose residues), rutinose (may optionally have N-acetylated glucose residues), rutinulose, and xylobiose.

[0602] TNF-α In some embodiments, the target protein is human TNF-α (UniProtKB - P01375(TNFA_HUMAN)). TNF-α is a pro-inflammatory cytokine active in the body's immune response and in severe inflammatory diseases. TNF-α has been linked to numerous disorders, including, but is not limited to, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupus erythematosus, diabetes mellitus, and the induction of cachexia.

[0603] The Protein Databank website allows you to search for TNF-α crystal structures using 6RMJ (Valentinis, B., et al., Int. J. Mol. Sci., 2019, 20), 5UUI (Carrington et al., Biophys J., 2017, 113 371-380), 6OOY, 6OOZ, and 6OPO (O'Connell, J., et al., Nat. Commun., 2019, 10 5795-5795), as well as 5TSW (Cha, SS, J Biol Chem., 1998, 273 2153-2160), and also 5YOY (Ono et al., Protein Sci., 2018, 27 1038-1046), 2AZ5 (He., MM, et al., Science, 2005, Crystal structures of TNF-α bound to various compounds searchable by 310: 1022-1025), 5WUX (Lee, JU, Int J Mol Sci., 2017, 18), 5MU8 (Blevitt et al., J Med Chem., 2017, 60 3511-3517), 4Y6O (Feldman JL, et al., Biochemistry, 2015, 54 3037-3050), 3WD5 (Hu, S., et al., J Biol Chem, 2013, 288 27059-27067), and 4G3Y (Liang, SY, J Biol Chem., 2013, 288 13799-13807) are also provided.

[0604] Representative TNF-α-targeting ligands are shown in Figure 1. Further TNF-α-targeting ligands can be found, for example, in U.S. Patent No. 8,541,572 and J Chem Inf Model. 2017 May 22; 57(5): 1101-1111 (each of which is incorporated herein by reference).

[0605] IL-1 In some embodiments, the target protein is human interleukin-1 (IL-1) (UniProtKB - P01584(IL1B_HUMAN)). IL-1 is a potent pro-inflammatory cytokine. Initially discovered as a major endogenous pyrogen, it induces prostaglandin synthesis, neutrophil influx and activation, T cell activation and cytokine production, B cell activation and antibody production, and fibroblast proliferation and collagen production. IL-1 promotes Th17 differentiation of T cells and, in synergy with IL12 / interleukin-12, induces IFNG synthesis from T helper 1 (Th1) cells. IL-1 is thought to be associated with a number of autoinflammatory and autoimmune disorders, including, but not limited to, Blau syndrome, cryopyrin-associated periodic syndromes, familial Mediterranean fever, Magid syndrome, mevalonate kinase deficiency syndrome, suppurative arthritis-pyoderma gangrenosum-acne syndrome, tumor necrosis factor receptor-associated periodic syndromes, Behçet's disease, Sjögren's syndrome, gout and chondrocalcinosis, periodic fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis (or PFAPA) syndrome, rheumatoid arthritis, type 2 diabetes, acute pericarditis, chronic interstitial lung disease (ILD), and Still's disease.

[0606] The Protein Databank website allows you to search for IL-1 crystal structures using the following identifiers: 9ILB (Yu, B., et al., Proc Natl Acad Sci USA, 1999, 96 103-108), 1I1B (Finzel, BC, et al., J Mol Biol., 1989, 209 779-791), and 3O4O (Wang et al., Nat.Immunol., 2010, 11: 905-911), as well as 4G6J (Blech, M., et al., J Mol Biol., 2013, 425 94-111), 5BVP (Rondeau e al., MAbs, 2015, 7 1151-1160), and 3LTQ (Barthelmes, K., et al., J Am Chem.). Crystal structures of IL-1 bound to various searchable compounds are also provided (Soc., 2011, 133 808-819). Furthermore, Guy et al. provide insights into the crystal structure of a small antagonist peptide bound to interleukin-1 receptor type 1 (Guy et al., The Journal of Biological Chemistry, 2000, 275, 36927-36933).

[0607] Potential direct or indirect inhibitors of IL-1 are shown in Figure 1. Further IL-1 targeting ligands may be found, for example, in U.S. Patent No. 9,694,015 (each of which is incorporated herein by reference). Further binding ligands include lilonacept or its binding fragment (J Rheumatol. 2012;39:720-727 (2012)) and canakinumab or its binding fragment (J Rheumatol. 2004;31:1103-1111).

[0608] IL-2 In some embodiments, the target protein is human interleukin-2 (IL-2) (UniProtKB - P60568(IL2_HUMAN)). IL-2 is a potent pro-inflammatory cytokine. IL-2 is thought to be involved in host-versus-graft rejection and other autoimmune disorders.

[0609] The Protein Databank website allows you to search for IL-2 crystal structures not only by 1M4C and 1M47 (Arkin, MR, et al., Proc.Natl.Acad.Sci.USA, 2003, 100: 1603-1608), but also by 4NEJ and 4NEM (Brenke, R., et al.), 1QVN (Thanos, CD, et al., Proc Natl Acad Sci USA, 2006, 103 15422-15427), 1PW6 and 1PY2 (Thanos, CD, et al., J Am Chem Soc., 2003, 125 15280-15281), and 1NBP (Hyde, J., et al., Biochemistry, 2003, 42 Crystal structures of IL-2 bound to various compounds, searchable by 6475-6483), as well as 1M48, 1M49, 1M4A, 1M4B, and 1M4C (Arkin, MR, et al., Proc Natl Acad Sci USA, 2003, 100 1603-1608), are also provided. Furthermore, Stauber, DJ et al. provide insights into the paradigm of the IL-2 signaling complex: heterotrimeric cytokine receptor (Stauber, DJ, et al., PNAS, 2006, 103(8), 2788-2793).

[0610] Representative IL-2 targeting ligands are shown in Figure 1. Further IL-2 targeting ligands can be found, for example, in U.S. Patent Nos. 8802721, 9682976, 9708268, Eur J Med Chem 83: 294-306 (2014), J Med Chem 60: 6249-6272 (2017), and Nature 450: 1001-1009 (2007) (each of which is incorporated herein by reference).

[0611] IL-6 In some embodiments, the target protein is human interleukin-6 (IL-6) (UniProtKB - P05231(IL6_HUMAN)). IL-6 is a cytokine with a wide range of biological functions. IL-6 is a potent inducer of the acute phase response and plays a crucial role in the eventual differentiation of B cells into Ig-secreting cells. IL-6 is also involved in the differentiation of lymphocytes and monocytes. IL-6 also acts on B cells, T cells, hepatocytes, hematopoietic progenitor cells, and CNS cells and is required for the generation of T(H)17 cells. IL-6 is associated with numerous inflammatory diseases and cancers, including, but not limited to, Castleman disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large cell lung cancer, ovarian cancer, rheumatoid arthritis, and asthma.

[0612] The Protein Databank website allows you to search for IL-6 crystal structures not only by 1P9M (Boulanger, MJ, et al., Science, 2003, 300: 2101-2104), 1ALU (Somers et al., EMBO J., 1997, 16, 989-997), 1IL6 and 2IL6 (Xu, GY, et al., J Mol Biol., 1997, 268 468-481), and 1N26 (Varghese et al., Proc Natl Acad Sci US A., 2002, 99 15959-15964), but also by 4CNI (Shaw, S., et al., Mabs, 2014, 6: 773), and 4NI7 and 4NI9 (Gelinas et al., J Biol Chem. Crystal structures of IL-6 bound to various searchable compounds are also provided (2014, 289(12), 8720-8734). Furthermore, Gelinas et al. provide insights into the crystal structure of interleukin-6 complexed with modified nucleic acid ligands (Gelinas, AD, et al., J Biol Chem. 2014, 289(12), 8720-8734), and Somers et al. provide insights into the crystal structure of interleukin-6: its impact on novel forms of receptor dimerization and signaling.

[0613] Potential direct or indirect inhibitors of IL-6 are shown in Figure 1. Further potential direct or indirect inhibitors of IL-6 may be found, for example, in U.S. Patent No. 8901310, U.S. Patent No. 10189796, and U.S. Patent No. 9694015 (each of which is part of this specification by reference). In another embodiment, the extracellular targeting ligand for IL-6 is AvimarC326 or its binding fragment, as described in Nat Biotechnol 23, 1556-1561 (2005).

[0614] IFN-γ In some embodiments, the target protein is human interferon-γ (IFN-γ) (UniProtKB - Q14609 (Q14609_HUMAN)). IFN-γ is an immunomodulatory cytokine. IFN-γ is associated with, but is not limited to, rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and numerous autoimmune disorders, including various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, and acne vulgaris.

[0615] The Protein Databank website provides not only the crystal structure of IFN-γ searchable by 1HIG (Ealick, SE, et al., Science 252, 1991, 698-702), but also the crystal structures of IFN-γ bound to various compounds searchable by 6E3K and 6E3L (Mendoza, JL, et al., Nature, 2019, 567 56-60). Furthermore, Randal et al. provide insights into the structure and activity of the monomeric interferon-γ:α chain receptor signaling complex (Randal, M., et al., Structure, 2001, 9(2), 155-163).

[0616] Representative IFN-γ targeting ligands are shown in Figure 1. Further IFN-γ targeting ligands can be found, for example, in J Med Chem 57: 4511-20 (2014) (which is incorporated herein by reference).

[0617] Vascular epithelial growth factor (VEGF) In some embodiments, the target protein is human vascular epithelial growth factor (VEGF) (UniProtKB - P15692(VEGFA_HUMAN)). VEGF is an active growth factor in angiogenesis, vascularization, and endothelial cell growth. VEGF induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis, and induces vascular permeability. VEGF is thought to be involved in tumor vascularization and angiogenesis.

[0618] The Protein Databank website allows you to search for VEGF crystal structures using 3QTK (Mandal, K., et al., Angew Chem Int Ed Engl., 2011, 50 8029-8033) and 4KZN (Shen et al.), as well as 5O4E (Lobner, E., et al., MAbs, 2017, 9 1088-1104), 4QAF (Giese, T., et al.), 5DN2 (Tsai, YCI, et al., FEBS, 2017, J 283 1921-1934), 4GLS (Mandal, K., et al., Proc Natl Acad Sci USA, 2012, 109 14779-14784), and 1KMX (Stauffer, ME et al., J Biomol NMR, Crystal structures of VEGF bound to various searchable compounds are also provided (2002, 23 57-61). Furthermore, Mueller, YA et al. provide insights into the crystal structure and functional mapping of the kinase domain receptor binding site of VEGF (Mueller, YA, et al., Proc Natl Acad Sci US A., 1997 Jul 8; 94(14): 7192-7197).

[0619] Representative VEGF-targeting ligands are shown in Figure 1. Further VEGF-targeting ligands, but not limited to (all cited references constitute part of this specification by reference), include the peptide VEPNCDIHVMWEWECFERL-NH2 (Biochemistry 1998, 37, 17754-177764). Further VEGF-targeting ligands are shown, for example, in J Med Chem 57: 3011-29 (2014), U.S. Patent No. 9884843, U.S. Patent No. 9446026, J Med Chem 53: 1686-99 (2010), J Med Chem 48: 8229-36 (2005), and J Nat Prod 76: 29-35 (2013) (each of which constitutes part of this specification by reference).

[0620] Transforming Growth Factor-β1 (TGF-β1) In some embodiments, the target protein is human transforming growth factor-β1 (TGF-β1) (UniProtKB - P01137(TGFB1_HUMAN)). TGF-β1 is a pluripotent protein that regulates the growth and differentiation of various cell types and is involved in a variety of processes, including normal development, immune function, microglial function, and responses to neurodegeneration. TGF-β1 can promote the differentiation of either T helper 17 cells (Th17) or regulatory T cell (Treg) lineages in a concentration-dependent manner. TGF-β1 expression in the tumor microenvironment is associated with poor prognosis and is involved in TGF-β1-mediated tumor suppression via T cell depletion. TGF-β1 expression has also been shown to be associated with hematological malignancies and fibrosis.

[0621] The Protein Databank website allows you to search for TGF-β1 crystal structures using 5E8S, 5E8T, and 5E8U (Tebben, AJ, et al., Acta Crystallogr D Struct Biol., 2016, 72 658-674), 2L5S (Zuniga, JE, et al, J Mol Biol., 2011, 412 601-618), and 2PJY (Groppe, J., et al., Mol Cell, 2008, 29 157-168), as well as 5QIK, 5QIL, and 5QIM (Zhang, Y., et al., ACS Med Chem Lett., 2018, 9 1117-1122), 6B8Y (Harikrishnan, LS, et al., Bioorg Med Chem., 2018, 26 1026-1034), 5E8W, 5E8X, 5E8Z, and 5E90 (Tebben, AJ, et al., Acta Crystallogr D Struct Biol., 2016, 72 658-674), 3TZM (Ogunjimi, AA et al., Cell Signal, 2012, 24 476-483), 2X7O (Roth, GJ, et al., J Med Chem., 2010, 53 7287), 3KCF (Guckian, K., et al., Bioorg Med Chem Lett., 2010, 20 326-329), 3FAA (Bonafoux, D., et al., Bioorg Med Chem Lett., 2009, 19 Crystal structures of TGF-β1 bound to various compounds searchable by 912-916), 1VJY (Gellibert, F, J., et al., J Med Chem., 2004 47 4494-4506), and 1PY5 (Sawyer, JS, et al., Bioorg Med Chem Lett., 2004, 14 3581-3584) are also provided.Furthermore, Hinck et al. have provided insights into the structural study of TGF-β and its receptors, offering further insights into the evolution of the TGF-β superfamily (Hinck, A., FEBS, 2012, 586(14), 1860-1870).

[0622] Representative TGF-β1 targeting ligands are shown in Figure 1. In some embodiments, the TGF-β1 targeting ligand is the peptide KRFK peptide (J. Biol. Chem. Vol. 274 (No.19) pp. 13586-13593 (1999)) (which is incorporated herein by reference). Further TGF-β1 targeting ligands are shown, for example, in Bioorg Med Chem Lett 21: 5642-5 (2011) (which is incorporated herein by reference).

[0623] Proprotein convertase subtilisin / kexin type 9 (PCSK-9) In some embodiments, the target protein is human proprotein convertase subtilisin / kexin type 9 (PCSK-9) (UniProtKB - Q8NBP7(PCSK9_HUMAN)). PCSK-9 plays a crucial role in regulating plasma cholesterol homeostasis. PCSK-9 binds to members of the low-density lipid receptor family, namely low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1 / APOER), and apolipoprotein receptor 2 (LRP8 / APOER2), promoting their degradation in the intracellular acidic compartment. PCSK-9 acts via a non-proteolytic mechanism to promote the degradation of hepatic LDLR via the clathrin LDLRAP1 / ARH-mediated pathway, preventing the reuse of LDLR from endosomes to the cell surface, or guiding it to lysosomes for degradation. PCSK-9 is associated with high blood cholesterol levels and the development of cardiovascular disease.

[0624] The Protein Databank website allows searching for the crystal structure of PCSK-9 using 2P4E (Cunningham, D., et al., Nat Struct Mol Biol., 2007, 14 413-419), as well as 3BPS (Kwon, HJ, et al., Proc Natl Acad Sci USA, 2008, 105 1820-1825), 6U26, 6U2N, 6U2P, 6U36, 6U38, and 6U3X (Petrilli, WL, et al., Cell Chem Biol., 2019, 27 32-40.e3), 5OCA (Gustafsen, C., et al., Nat Commun., 2017, 8 503-503), and 4NE9 (Schroeder, CI, et al., Chem Biol., Crystal structures of PCSK-9 bound to various compounds searchable by 2014, 21 284-294, 4OV6 (Mitchell, T., et al., J Pharmacol Exp Ther., 2014, 350 412-424), and 4NMX (Zhang, Y., et al., J Biol Chem., 2014, 289 942-955) are also provided. Furthermore, Piper et al. provide insights into the crystal structure of PCSK9 (Piper, DE, et al., Structure, 2007, 15(5), 545-52).

[0625] Representative PCSK-9 targeting ligands are shown in Figure 1. In some embodiments, the PCSK-9 targeting ligand is the peptide TVFTSWEEYLDWV (J. Bio. Chem. 2014 Jan; 289(2):942-955 (part of this specification by reference)). Further PCSK-9 targeting ligands are shown, for example, in U.S. Patent No. 9,227,956 and J Biol Chem 289:942-55 (2014) (each part of this specification by reference).

[0626] IL-21 In some embodiments, the target protein is human interleukin-21 (IL-21) (UniProtKB - Q9HBE4(IL21_HUMAN)). IL-21 is an immunomodulatory cytokine. IL-21 is associated with numerous autoimmune disorders, including Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

[0627] The Protein Databank website provides not only the crystal structure of IL-21, which can be searched using 2OQP (Bondensgaard, K., et al., J Biol Chem., 2007, 282 23326-23336) and 4NZD (Hamming et al.), but also the crystal structures of IL-21 bound to various compounds, which can be searched using 3TGX (Hamming, OJ, et al., J Biol Chem., 2012, 287(12), 9454-9460).

[0628] Representative IL-21 targeting ligands are shown in Figure 1. Further IL-21 targeting ligands can be found, for example, in U.S. Patent No. 9,701,663 (which is part of this specification by reference).

[0629] IL-22 In some embodiments, the target protein is human interleukin-22 (IL-22) (UniProtKB - Q9GZX6(IL22_HUMAN)). IL-22 is a member of the IL-10 family of cytokines produced by many different types of lymphocytes, including both innate and adaptive lymphocytes. IL-22 is associated with numerous autoimmune disorders, including, but not limited to, graft-versus-host disease (GVHD), psoriasis, rheumatoid arthritis, atopic dermatitis, and asthma.

[0630] The Protein Databank website provides not only the crystal structure of IL-22, which can be searched using 1M4R (Nagem, RAP, et al., Structure, 2002, 10 1051-1062), but also the crystal structures of IL-22 bound to various compounds, which can be searched using 3DGC (Jones, BC et al., Structure, 2008, 16 1333-1344).

[0631] Representative IL-22 targeting ligands are shown in Figure 1. Further IL-22 targeting ligands can be found, for example, in U.S. Patent No. 9,701,663 (which is incorporated herein by reference).

[0632] IL-10 In some embodiments, the target protein is human interleukin-10 (IL-10) (UniProtKB - P22301(IL10_HUMAN)). IL-10 is an inflammatory cytokine. IL-10 is thought to be involved in tumor survival and protection against cytotoxic chemotherapy drugs.

[0633] The Protein Databank website provides crystal structures of IL-10 searchable by 2ILK (Zdanov, A et al., Protein Sci., 1996, 5 1955-1962), 1ILK (Zdanov, A. et al., Structure, 1995, 3 591-601), 2H24 (Yoon, SI, et al., J Biol Chem., 2006, 281 35088-35096), and 3LQM (Yoon, SI, et al., Structure, 2010, 18 638-648). Furthermore, Zdanov, A. et al. provide insights into the crystal structure of IL-10 (Zdanov A., Current Pharmaceutical Design, 2004, 10, 3873-3884).

[0634] Representative IL-10 targeting ligands are shown in Figure 1. Further IL-10 targeting ligands can be found, for example, in ACS Chem Biol 11: 2015-11 (2016) (which is incorporated herein by reference).

[0635] IL-5 In some embodiments, the target protein is human interleukin-5 (IL-5) (UniProtKB - P05113(IL5_HUMAN)). IL-5 is a cytokine that regulates eosinophil maturation, recruitment, and survival. IL-5 is associated with numerous allergic disorders, including, but not limited to, asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, eosinophilic syndrome, and Churg-Strauss syndrome.

[0636] The Protein Databank website provides not only the crystal structure of IL-5, which can be searched using 1HUL (Milburn, MV, Nature, 1993, 363, 172-176) and 3VA2 (Kusano et al., Protein Sci., 2012, 21(6), 850-864), but also the crystal structures of IL-5 bound to various compounds, which can be searched using 1OBX and 1OBZ (Kang, BS, et al., Structure, 2003, 11, 845).

[0637] Representative IL-5 targeting ligands are shown in Figure 1. Further IL-5 targeting ligands can be found, for example, in Bioorg Med Chem 18: 4441-5 (2010), Bioorg Med Chem 18: 4625-9 (2011), Bioorg Med Chem 21: 2543-50 (2013), Eur J Med Chem 59: 31-8 (2013), Bioorg Med Chem 23: 2498-504 (2015), and Bioorg Med Chem 20: 5757-62 (2012) (each of which is incorporated herein by reference).

[0638] IL8 In some embodiments, the target protein is human interleukin-8 (IL-8) (UniProtKB - P10145(IL8_HUMAN)). IL-8 is a chemotactic that attracts neutrophils, basophils, and T cells, but not monocytes. IL-8 is also involved in neutrophil activation. IL-8 is released from several cell types in response to inflammatory stimuli. IL-8 is thought to be involved in promoting tumor progression, immune evasion, epithelial-mesenchymal transition, and the recruitment of myeloid suppressor cells. Studies have confirmed that high serum IL-8 levels correlate with poor prognosis in many malignancies. Preclinical studies have shown that blocking IL-8 may reduce mesenchymal characteristics in tumor cells and lead to lower resistance to treatment.

[0639] The Protein Databank website allows you to search for IL-8 crystal structures not only by 3IL8 (Baldwin, ET, et al., Proc Natl Acad Sci USA, 1991, 88, 502-506) and 1IL8 and 2IL8 (Clore, GM, et al., Biochemistry, 1990, 29, 1689-1696), but also by 1ILP and 1ILQ (Skelton, N, J., et al., Structure, 1999, 7, 157-168), 1ROD ​​(Sticht, H., et al., Eur J Biochem., 1996, 235, 26-35), 4XDX (Ostrov et al.), and 5WDZ (Beckamp, ​​S., J Biomol NMR, 2017, 69, Crystal structures of IL-8 bound to various compounds searchable by 111-121) are also provided.

[0640] Representative IL-8 targeting ligands are shown in Figure 1. Further IL-8 targeting ligands can be found, for example, in Bioorg Med Chem 19: 4026-30 (2009) (which is incorporated herein by reference).

[0641] Cholinesterase In some embodiments, the target protein is human cholinesterase (UniProtKB - P06276(CHLE_HUMAN)). Cholinesterase contributes to the inactivation of the neurotransmitter acetylcholine. Inhibiting cholinesterase results in an increase in acetylcholine levels in the synaptic cleft (the space between two nerve endings). The primary use of cholinesterase inhibitors is in the treatment of dementia in patients with Alzheimer's disease. People with Alzheimer's disease have reduced levels of acetylcholine in their brains. Cholinesterase inhibitors have been shown to be effective against symptoms of dementia, such as cognitive impairment.

[0642] The Protein Databank website allows you to search for cholinesterase crystal structures using 1P0I and 1P0Q (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147), as well as 1P0M and 1P0P (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147), 2J4C (Frasco, MF, et al., FEBS J., 2007, 274, 1849), 4BDT, 4BDS (Nachon, F., et al., Biochem J, 2013, 453, 393-399), 1GQR, and 1GQS (Bar-on, P., et al., Biochemistry, 2002, 41, 3555), 3DJY and 3DKK (Carletti, E., et al., J Am Chem Soc., 2008, 130, 16011-16020), 4AXB, 4B0O, 4B0P, and 4BBZ (Wandhammer, M., et al., Chem Biol Interact., 2013, 203, 19), 1DX6 (Greenblatt, HM, et al., FEBS Lett., 1999, 463 321), 1GPK and 1GPN (Dvir, H., et al., Biochemistry, 2002, 41, 10810), 6CQY (Bester, SM, et al., Chem Res Toxicol., 2018, 31, Crystal structures of cholinesterases bound to various compounds, searchable by 1405-1417), 1XLV and 1XLW (Nachon, F., et al., Biochemistry, 2005, 44, 1154-1162), 2Y1K (Carletti, E., et al., Chem Res Toxicol., 2011, 24, 797), as well as 2WIG, 2WIJ, 2WIK, 2WIL, and 2WSL (Carletti, E., et al., Biochem J., 2009, 421, 97-106), are also provided.Furthermore, Ahmad et al. have provided insights into the isolation, crystal structure, and cholinesterase inhibitory activity of isothalatididine hydrate from delphinium denudatum (Ahmad H., et al., Journal Pharmaceutical Biology, 2016, 55(1), 680-686).

[0643] Representative cholinesterase-targeting ligands are shown in Figure 1. Further targeting ligands can be found, for example, in ACS Med Chem Lett 4: 1178-82 (2013), J Med Chem 49: 3421-5 (2006), Eur J Med Chem 55: 23-31 (2012), J Med Chem 51: 3154-70 (2008), J Med Chem 46: 1-4 (2002), Eur J Med Chem 126: 652-668 (2017), Biochemistry 52: 7486-99 (2013), and Bioorg Med Chem 23: 1321-40 (2015) (each of which is incorporated herein by reference).

[0644] CC motif chemokine ligand 2 (CCL2) Grygiel et al. have provided insights into the synthesis and crystalline structure of human CCL2 via natural chemical ligation (Grygiel, TL, et al., Biopolymers, 2010, 94(3), 350-9).

[0645] In some embodiments, the target protein is human CC motif chemokine ligand 2 (CCL2) (UniProtKB - P13500(CCL2_HUMAN)). CCL2 functions as a ligand for the CC chemokine receptor CCR2. CCL2 signals through binding to and activation of CCR2, inducing a potent chemotactic response and intracellular calcium ion recruitment. CCL2 exhibits chemotactic activity against monocytes and basophils, but not against neutrophils or eosinophils.

[0646] CCL2 is thought to be involved in the recruitment of monocytes to the arterial wall during the disease process of atherosclerosis.

[0647] Representative CCL2-targeting ligands are shown in Figure 1. Further CCL2-targeting ligands can be found, for example, in J Med Chem 56: 7706-14 (2013) (which is incorporated herein by reference).

[0648] Carboxypeptidase B2 In some embodiments, the target protein is human carboxypeptidase B2 (UniProtKB - Q96IY4(CBPB2_HUMAN)). Carboxypeptidase B2, also known as thrombin-activated fibrinolysis inhibitor (TAFIa), modulates the activity of biologically active peptides such as kinins or anaphylatoxins by cleaving their C-terminal arginine or lysine residues. Human carboxypeptidase B2 downregulates fibrinolysis by removing the C-terminal lysine residue from fibrin that has already been partially degraded by plasmin. Carboxypeptidase B2 is targeted because it is thought to be involved in the suppression of thrombosis.

[0649] The Protein Databank website allows you to search for the crystal structure of carboxypeptidase B2 (also known as thrombin-activated fibrinolysis inhibitor (TAFI)) using the following codes: 3D66 (Marx, PF, et al., Blood, 2008, 112, 2803-2809), 3DGV (Anand, K., et al., JBC, 2008, 283, 29416-29423), and 1KWM (Barbosa Pereira, PJ, et al., J Mol Biol., 2002, 321, 537-547). In addition, it also provides access to the following codes: 3D67 (Marx, PF, et al., Blood, 2008, 112, 2803-2809), 5HVF, 5HVG, 5HVH (Zhou, X., et al., J Thromb Haemost., Crystal structures of TAFI bound to various compounds searchable by 3LMS (Sanglas, L., et al., J Thromb Haemost., 2010, 8, 1056-1065) are also provided. Furthermore, Schreuder et al. provide insights into the interaction between TAFI and anabaenopeptin, a highly potent inhibitor of TAFI (Schreuder, H., et al., Sci Rep., 2016, 6, 32958).

[0650] Representative carboxypeptidase B2 targeting ligands are shown in Figure 1. Further carboxypeptidase B2-targeting ligands are, for example, Bioorg Med Chem Lett 20: 92-6 (2010), J Med Chem 50: 6095-103 (2007), Bioorg Med Chem Lett 14: 2141-5 (2004), J Med Chem 58: 4839-44 (2015), J Med Chem 55: 7696-705 (2012), J Med Chem 59: 9567-9573 (2016), Bioorg Med Chem Lett 17: 1349-54 (2007), U.S. Patent No. 9662310, U.S. Patent No. 8609710, U.S. Patent No. 9688645, J Med Chem 46: 5294-7 (2003) (each of which, by reference, constitutes part of this specification) can be found in these documents.

[0651] Neutrophil elastase In some embodiments, the target protein is human neutrophil elastase (UniProtKB - P08246(ELNE_HUMAN)). Neutrophil elastase modifies the function of natural killer cells, monocytes, and granulocytes. It inhibits C5a-dependent neutrophil enzyme release and chemotaxis.

[0652] Neutrophil elastase is thought to be involved in numerous disorders, including lung diseases, chronic obstructive pulmonary disease, pneumonia, dyspnea, acute lung injury (ALI), cystic fibrosis, and chronic kidney disease.

[0653] The Protein Databank website lists 3Q76 and 3Q77 (Hansen, G., et al., J.Mol.Biol., 2011, 409, 681-691), 5ABW (Von Nussbaum, et al., Bioorg Med Chem Lett., 2015, 25, 4370-4381), 1B0F (Cregge, RJ, et al., J Med Chem., 1998, 41, 2461-2480), 1H1B (Macdonald, SJF, et al., J Med Chem., 2002, 45, 3878), and 2Z7F (Koizumi, M., et al., J Synchrotron Radiat., 2008, 15 308-311), 5A09, 5A0A, 5A0B, and 5A0C (Von Nussbaum, F., et al., Chem Med Chem., 2015, 10, 1163-1173), 5A8X, 5A8Y, and 5A8Z (Von Nussbaum, F., et al., ChemMedChem., 2016, 11, 199-206), 1HNE (Navia, MA, et al., Proc Natl Acad Sci USA, 1989, 86, 7-11), 6F5M (Hochscherf, J., et al., Acta Crystallogr F Struct Biol Commun., 2018, 74, 480-489), as well as 4WVP (Lechtenberg, BC, et al., Crystal structures of human neutrophil elastases bound to various searchable compounds are provided by ACS Chem Biol., 2015, 10, 945-951).

[0654] Representative neutrophil elastase-targeting ligands are shown in Figure 1. Further neutrophil elastase-targeting ligands can be found in, for example, J Med Chem 53: 241-53 (2010), J Med Chem 38: 739-44 (1995), J Med Chem 37: 2623-6 (1994), J Med Chem 38: 4687-92 (1995), J Med Chem 45: 3878-90 (2002), Bioorg Med Chem Lett 5: 105-109 (1995), Bioorg Med Chem Lett 11: 243-6 (2001), J Med Chem 40: 1906-18 (1997), and Bioorg Med Chem Lett 25: 4370-81. (2015), as can be found in U.S. Patent No. 8,569,314, U.S. Patent No. 9,174,997, and U.S. Patent No. 9,290,457 (each of which is a part of this Specified Patent Publication by reference).

[0655] Factor Xa In some embodiments, the target protein is human factor Xa (UniProtKB - P00742(FA10_HUMAN)). Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium, and phospholipids during blood coagulation.

[0656] Factor X is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0657] On the website of the Protein Data Bank, 1G2L and 1G2M (Nar, H., et al., Structure, 2001, 9, 29-38), 2PR3 (Nan huis, C. A., et al., Chem Biol Drug Des., 2007, 69, 444-450), 2UWP (Young, R. J., et al., Bioorg Med Chem Lett., 2007, 17, 2927), 2VVC, 2VVV, 2VVU, 2VWL, 2VWM, 2VWN, and 2VWO (Zbinden, K. G., et al., Eur J Med Chem., 2009, 44, 2787), 4Y6D, 4Y71, 4Y7A, 4Y7B, 4zh8, 4ZHA (Convery, M.A. et al.), 4Y76, 4Y79, 2J94, and 2J95 (Chan, C., et al., J Med Chem., 2007, 50 1546-1557), 1FAX (Brandstetter, H., et al., J Biol Chem., 1996, 271, 29988-29992), 2JKH (Salonen, L. M., et al., Angew Chem Int Ed Engl., 2009, 48, 811), 2PHB (Kohrt, J. T., et al., Chem Biol Drug Des., 2007, 70, 100-112), 2W26 (Roehrig, S., et al., J Med Chem., 2005, 48, 5900), 2Y5F, 2Y5G, and 2Y5H (Salonen, L.M., et al., Chemistry, 2012, 18, 213), 3Q3K (Yoshikawa, K., et al., Bioorg Med Chem Lett., 2011, 21, 2133-2140), 2BMG (Matter, K., et al., J Med Chem., 2005, 48, 3290), 2BOH, 2BQ6, 2BQ7, and 2BQW (Nazare, M., et al., J Med Chem., 2005, 48, 4511), 2CJI (Watson, N.S., et al, Bioorg Med Chem Lett., 2006, 16, 3784), 2J2U, 2J34, 2J38, 2J41 (Senger, S., et al., Bioorg Med Chem Lett., 2006, 16, 5731), 3IIT (Yoshikawa, K., et al., Bioorg Med Chem., 2009, 17, 8221 - 8233), 1EZQ, 1F0R, and 1F0S (Maignan, S., et al., J Med Chem., 2000, 43, 3226 - 3232), 1FJS (Adler, M., et al., Biochemistry, 2000, 39, 12534 - 12542), 1KSN (Guertin, K. R., et al., Bioorg Med Chem Lett., 2002, 12, 1671 - 1674), 1NFU, 1NFW, 1NFX, and 1NFY (Maignan, S., et al., J Med Chem., 2003, 46, 685 - 690), 2XBV, 2XBW, 2XBX, 2XBY, 2XC0, 2XC4, and 2XC5 (Anselm, L., et al., Bioorg Med Chem Lett., 2010, 20, 5313), 4A7I (Nazare, M., et al., Angew Chem Int Ed Engl., 2012, 51, 905), 4BTI, 4BTT, and 4BTU (Meneyrol, L., et al., J Med Chem., 2013, 56, 9441), 3FFG, 3KQB, 3KQC, 3KQD, and 3KQE (Quan, M. L., et al., Bioorg Med Chem Lett., 2010, 20, 1373 - 1377), 2P93, 2P94, and 2P95 (Qiao, J. X., et al., Bioorg Med Chem Lett., 2007, 17, 4419 - 4427), 1V3X (Haginoya, N., et al., J Med Chem., 2004, 47, 5167 - 5182), 2P16 (Pinto, D.J.P., et al., J Med Chem, 2007, 50, 5339 - 5356), 2RA0 (Lee, Y.K., et al., J Med Chem., 2008, 51, 282 - 297), 3SW2 (Shi, Y., et al., Bioorg Med Chem Lett., 2011, 21, 7516 - 7521), 2VH6 (Young, R.J., et al., Bioorg Med Chem Lett., 2008, 18, 23), 2WYG and 2WYJ (Kleanthous, S., et al., Bioorg Med Chem Lett., 2010, 20, 618), 2Y7X (Watson, N.S., et al., Bioorg Med Chem Lett., 2011, 21, 1588), 2Y7Z, 2Y80, 2Y81, and 2Y82 (Young, R.J., et al., Bioorg Med Chem Lett., 2011, 21, 1582), 3KL6 (Fujimoto, T., et al., J Med Chem., 2010, 53, 3517 - 3531), 3LIW (Meuller, M.M., et al., Biol.Chem., 2003, 383, 1185), 5K0H (Schweinitz, A., et al., Med Chem., 2006, 2, 349 - 361), 1XKA and 1XKB (Kamata, K., et al., Proc Natl Acad Sci U S A, 1998, 95, 6630 - 6635), 2EI6 and 2EI7 (Nagata, T., et al., Bioorg Med Chem Lett., 2007, 17, 4683 - 4688), 2P3T (Ye, B., et al., J Med Chem., 2007, 50, 2967 - 2980), 1MQ5 and 1MQ6 (Adler, M., et al., Biochemistry, 2002, 41, 15514 - 15523), 3K9X and 3HPT (Shi, Y., et al., Bioorg Med Chem Lett., 2009, 19, 6882 - 6889), 3CEN (Corte, J.R., et al., Bioorg Med Chem Lett., 2008, 18, 2845-2849), 2W3I and 2W3K (Van Huis, CA, et al., Bioorg Med Chem., 2009, 17, 2501), 2H9E (Murakami, MT, et al., J Mol Biol., 2007, 366, 602-610), 1WU1 and 2D1J (Komoriya, S., et al., Bioorg Med Chem., 2005, 13, 3927-3954), 2G00 (Pinto, DJP, et al., Bioorg Med Chem Lett., 2006, 16, 5584-5589), 3M36 and 3M37 (Pruitt, JR et al., J Med Chem., 2003, Crystal structures of factor Xa bound to various compounds searchable by 46, 5298-5315), 3CS7 (Qiao, JX, et al., Bioorg Med Chem Lett., 2008, 18, 4118-4123), 1Z6E (Quan, ML, et al., J Med Chem., 2005, 48, 1729-1744), 2FZZ (Pinto, DJP, et al., Bioorg Med Chem Lett., 2006, 16, 4141-4147), and 3ENS (Shi, Y., et al., J Med Chem., 2008, 51, 7541-7551) are provided.

[0658] Representative factor Xa targeting ligands are shown in Figure 1. Further factor Xa targeting ligands are, for example, Bioorg Med Chem Lett 20: 5313-9 (2010), Bioorg Med Chem Lett 13: 679-83 (2003), J Med Chem 44: 566-78 (2001), J Med Chem 50: 2967-80 (2007), J Med Chem 38: 1511-22 (1995), Bioorg Med Chem Lett 18: 2845-9 (2008), J Med Chem 53: 6243-74 (2010), Bioorg Med Chem Lett 18: 2845-9 (2008), Bioorg Med Chem 16: 1562-95 (2008) (these may be found in these references, which by reference form part of this specification).

[0659] Factor XI In some embodiments, the target protein is human factor XI (UniProtKB - P03951(FA11_HUMAN)). Factor XI triggers an intermediate step in the intrinsic pathway of blood coagulation by activating factor IX.

[0660] Factor XI is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0661] On the website of the Protein Data Bank, 1ZSL, 1ZTJ, 1ZTK, and 1ZTL (Nagafuji, P., et al.), 1ZOM (Lin, J., et al., J Med Chem., 2006, 49, 7781-7791), 5EOK and 5EOD (Wong, S.S., et al., Blood, 2016, 127, 2915-2923), 1ZHM, 1ZHP, and 1ZHR (Jin, L., et al., Acta Crystallogr D Biol Crystallogr., 2005, 61, 1418-1425), 1ZMJ, 1ZLR, 1ZML, and 1ZMN (Lazarova, T.I., Bioorg Med Chem Lett., 2006, 16, 5022-5027), 1ZRK, 1ZSJ, and 1ZSK (Guo, Z., et al), 4CRA, 4CRB, 4CRC, 4CRD, 4CRE, 4CRF, and 4CRG (Fjellstrom, O., et al., PLoS One, 2015, 10, 13705), 3SOR and 3SOS (Fradera, X., et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2012, 68, 404-408), 1ZPB, 1ZPC, 2FDA (Deng, H., et. al., Bioorg Med Chem Lett., 2006, 16, 3049-3054), 5WB6 (Wang, C., et al., Bioorg Med Chem Lett.,2017, 27, 4056-4060), 4NA7 and 4NA8 (Quan, M.L., et al., J Med Chem., 2014, 57, 955-969), 4WXI (Corte, J.R., et al., Bioorg Med Chem Lett., 2015, 25, 925-930), 5QTV, 5QTW, 5QTX, and 5QTY (Fang, T., et al., Bioorg Med Chem Lett., 2020, 126949-126949), 6C0S (Hu, Z., et al., Bioorg Med Chem Lett., 28, 987-992), 5QQP and 5QQO (Clark, CG, et al., Bioorg Med Chem Lett., 2019, 29, 126604-126604), 5Q0D, 5Q0E, 5Q0F, 5Q0G, and 5Q0H (Corte, JR, et al., Bioorg Med Chem Lett., 2017, 27, 3833-3839), 5QCK, 5QCL, 5QCM, and 5QCN (Pinto, DJP, et al., J Med Chem., 2017, 60, 9703-9723), 5TKS and 5TKU (Corte, JR, et al., J Med Chem., 2017, 60, 1060-1075), 1XXD and 1XX9 (Jin, L., et al., J Biol Chem., 2005, 280, 4704-4712), 5QTT and 5QTU (Corte, JR, et al., J Med Chem., 2019, 63, 784-803), 4TY6, 4TY7 (Hangeland, JJ, et al., J Med Chem., 2014, 57, 9915-9932), 4X6M, 4X6N, 4X6O, and 4X6P (Pinto, DJP, et al., Bioorg Med Chem Lett., 2015, 25, 1635-1642), and 5EXM (Corte, JR, et al., Bioorg Med Chem., Crystal structures of factor XI bound to various searchable compounds are provided (2016, 24, 2257-2272). Furthermore, Al-Horani et al. provide insights into a review of patent literature on factor Xia inhibitors (Al-Horani et al., Expert Opin Ther Pat. 2016; 26(3), 323-345).

[0662] Representative factor XI targeting ligands are shown in Figure 1. Further factor XI targeting ligands can be found, for example, in U.S. Patent No. 9,783,530, U.S. Patent No. 1,014,3681, U.S. Patent No. 1,021,4512, ACS Med Chem Lett 6: 590-5 (2015), J Med Chem 60: 9703-9723 (2017), J Med Chem 60: 9703-9723 (2017), U.S. Patent No. 9,453,018 (2016), J Med Chem 60: 1060-1075 (2017), and J Med Chem 57: 955-69 (2014) (each of which is incorporated herein by reference).

[0663] Factor XII In some embodiments, the target protein is human factor XII (UniProtKB - P00748(FA12_HUMAN)). Factor XII is a serum glycoprotein involved in the initiation of blood coagulation, fibrinolysis, and the production of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII into α-XIIa, after which trypsin cleaves it into β-XIIa. α-XIIa activates factor XI into factor XIa.

[0664] Factor XII is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0665] The Protein Databank website provides crystal structures of factor XII bound to various compounds, searchable by 4XDE and 4XE4 (Pathak, M., et al., J Thromb Haemost., 2015, 13(4), 580-591), 6GT6 and 6QF7 (Pathak, M., et al., Acta Crystallogr D Struct Biol., 2019, 75, 578-591), and 6B74 and 6B77 (Dementiev, AA, et al., Blood Adv., 2018, 2, 549-558). Furthermore, Pathak et al. provide insights into the crystal structure of factor XII (Pathak, M., et al., J Thromb Haemost., 2015, 13(4), 580-591).

[0666] Representative factor XII targeting ligands are shown in Figure 1. Further factor XII targeting ligands can be found, for example, in J Med Chem 60: 1151-1158 (2017), J Med Chem 48: 2906-15 (2005), J Med Chem 50: 5727-34 (2007), J Med Chem 50: 1876-85 (2007), and Chembiochem 18: 387-395 (2017) (each of which is incorporated herein by reference).

[0667] Factor XIII In some embodiments, the target protein is human factor XIII (UniProtKB - P00488(F13A_HUMAN)). Factor XIII is activated by thrombin and calcium ions and catalyzes the formation of γ-glutamyl-ε-lysine crosslinks between fibrin chains, thus becoming a transglutaminase that stabilizes fibrin clots. Alternatively, an α2-plasmin inhibitor or fibronectin may be crosslinked to the α-chain of fibrin.

[0668] Factor XIII is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0669] The Protein Databank website provides not only the crystal structure of factor XIII, searchable by 1FIE (Yee, VC, et al., Thromb Res., 1995, 78, 389-397) and 1F13 (Weiss, MS, et al., FEBS Lett., 1998, 423, 291-296), but also the crystal structures of factor XIII bound to various compounds, searchable by 1DE7 (Sadasivan, C., et al., J Biol Chem., 2000, 275, 36942-36948), as well as 5MHL, 5MHM, 5MHN, and 5MHO (Stieler, M., et al.). Furthermore, Gupta et al. have provided insights into the mechanisms of activation and regulation of coagulation factor XIII from a structural / functional perspective (Gupta, S., et al., Sci Rep., 2016; 6, 30105), and Komaromi et al. have provided insights into novel structural and functional aspects of factor XIII (Komaromi, Z., et al., J Thromb Haemost 2011, 9, 9-20).

[0670] Representative factor XIII targeting ligands are shown in Figure 1. Further factor XIII targeting ligands can be found, for example, in Eur J Med Chem 98: 49-53 (2015), J Med Chem 55: 1021-46 (2012), and J Med Chem 48: 2266-9 (2005) (each of which is incorporated herein by reference).

[0671] Prothrombin In some embodiments, the target protein is human prothrombin (UniProtKB - P00734(THRB_HUMAN)). Thrombin cleaves the posterior bonds of Arg and Lys to convert fibrinogen to fibrin, activates factors V, VII, VIII, and XIII, and forms a complex with thrombomodulin to activate protein C. It functions in blood homeostasis, inflammation, and wound healing.

[0672] Thrombin is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0673] The Protein Databank website allows you to search for prothrombin crystal structures not only by 3NXP (Chen, Z. et al., Proc Natl Acad Sci USA, 2010, 107, 19278-19283), but also by 2HPP and 2HPQ (Arni, RK, et al., Biochemistry, 1993, 32, 4727-4737), 6BJR, 6C2W (Chinnaraj, M., et al., Sci Rep., 2018, 8, 2945-2945), 5EDK, 5EDM (Pozzi, N., et al., J Biol Chem., 2016, 291, 6071-6082), and 3K65 (Adams, TE, et al., Biochimie, 2016, 122). Crystal structures of prothrombin bound to various compounds, searchable by 235-242), as well as 6BJR and 6C2W (Chinnaraj, M. et al., Sci Rep., 2018, 8, 2945-2945), are also provided. Furthermore, Pozzi et al. have provided insights into the mechanism and conformational flexibility of the prothrombin crystal structure (Pozzi, N. et al., J Biol Chem., 2013, 288(31), 22734-22744), and Zhiwei et al. have provided insights into the crystal structure of prothrombin-1 (Zhiwei, C. et al., PNAS, 2010, 107(45), 19278-19283).

[0674] Since prothrombin is converted to thrombin, on the Protein Data Bank website, 1XMN (Carter, W.J. et al., J.Biol.Chem., 2005, 280, 2745-2749), 4CH2 and 4CH8 (Lechtenberg, B.C. et al., J Mol Biol., 2014, 426, 881), 3PO1 (Karle, M. et al., Bioorg Med Chem Lett., 2012, 22, 4839-4843), 3DA9 (Nilsson, M. et al., J Med Chem., 2009, 52, 2708-2715), 2H9T and 3BF6 (Lima, L.M.T.R. et al., Biochim Biophys Acta., 2009, 1794, 873-881), 3BEF and 3BEI (Gandhi, P.S. et al., Proc Natl Acad Sci U S A, 2008, 105, 1832-1837), 3BV9 (Nieman, M.T. et al., J Thromb Haemost., 2008, 6, 837-845), 2HWL (Pineda, A.O. et al., Biophys Chem., 2007, 125, 556-559), 2AFQ (Johnson, D.J.D. et al., Biochem J., 2005, 392, 21-28), 1SHH (Pineda, A.O. et al., J Biol Chem., 2004, 279, 31842-31853), 1JWT (Levesque, S. et al., Bioorg Med Chem Lett., 2001, 11, 3161-3164), 1G37 (Bachand, B. et al., Bioorg Med Chem Lett., 2001, 11, 287-290), 1EOJ and 1EOL (Slon-Usakiewicz, J.J. et al., Biochemistry, 2000, 39, 2384-2391), 1AWH (Weir, M.P. et al., Biochemistry, 1998, 37, 6645-6657), 1DIT (Krishnan, R. et al.Crystal structures of thrombin bound to compounds searchable by Protein Sci., 1996, 5, 422-433, 1HAO and 1HAP (Padmanabhan, K. et al., Acta Crystallogr D Biol Crystallogr., 1996, 52, 272-282), and 1HBT (Rehse, PH et al., Biochemistry, 1995, 34, 11537-11544) are provided.

[0675] Representative prothrombin-targeting ligands are shown in Figure 1. Further prothrombin-targeting ligands can be found, for example, in J Med Chem 46: 3612-22 (2003), Bioorg Med Chem Lett 12: 1017-22 (2002), J Med Chem 40: 830-2 (1997), Bioorg Med Chem Lett 15: 2771-5 (2005), J Med Chem 42: 3109-15 (1999), J Med Chem 47: 2995-3008 (2004), Bioorg Med Chem 16: 1562-95 (2008), and J Med Chem 42: 3109-15 (1999) (each of which is incorporated herein by reference).

[0676] Coagulation factor VII In some embodiments, the target protein is human coagulation factor VII (UniProtKB - P08709(FA7_HUMAN)). Factor VII initiates the extrinsic pathway of blood coagulation. Factor VII is a serine protease that circulates in the blood in the form of zymogen. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, and factor IXa, or converted to thrombin by mild proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa also converts factor IX to factor IXa in the presence of tissue factor and calcium.

[0677] Factor VII is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0678] On the website of the Protein Data Bank, 2F9B (Rai, R., et al., Bioorg Med Chem Lett., 2006, 16, 2270-2273), 5U6J (Wurtz, N.R., et al., Bioorg Med Chem Lett., 2017, 27, 2650-2654), 5L2Y, 5L2Z, and 5L30 (Ladziata,.U., et al., Bioorg Med Chem Lett., 2016, 26, 5051-5057), 5I46 (Glunz, P. W., et al., J Med Chem., 2016, 59, 4007-4018), 4YLQ, 4Z6A, and 4ZMA (Sorensen, A.B., et al., J Biol Chem., 2016, 291, 4671-4683), 4YT6 and 4YT7 (Glunz, P.W., et al., Bioorg Med Chem Lett, 2015, 25, 2169-2173), 4NA9 (Quan, M.L., et al., J Med Chem., 2014, 57, 955-969), 4NG9 (hang, X., et al., ACS Med Chem Lett., 2014, 5, 188-192), 4JZD, 4JZE, and 4JZF (Bolton, S. A., et al., Bioorg Med Chem Lett., 2013, 23, 5239-5243), 4JYU and 4JYV (Glunz, P.W., et al., Bioorg Med Chem Lett., 2013, 23, 5244-5248), 4ISH (Priestley, E.S., et al., Bioorg Med Chem Lett., 2013, 23, 2432-2435), 4ISI (Zhang, X., et al., Bioorg Med Chem Lett., 2013, 23, 1604-1607), 2ZZU (Shiraishi, T., et al., Chem Pharm Bull(Tokyo), 2010, 58, 38-44), 1WV7 and 1WUN (Kadono, S., et al., Biochem Biophys Res Commun., 2005, 327, 589-596), 2ZWL, 2ZP0 (Kadono, S., et al.), 2EC9 (Krishan, R., et al., Acta Crystallogr D Biol Crystallogr., 2007, 63, 689-697), 2PUQ (Larsen, K. S., et al., Biochem J., 2007, 405, 429-438), 2FLR (Riggs, J. R., et al., Bioorg Med Chem Lett., 2006, 16, 3197-3200), 2C4F (Kohrt, J.T., et al., Bioorg Med Chem Lett., 2006, 16, 1060), 2AEI (Kohrt, J.T. et al., Bioorg Med Chem Lett., 2005, 15, 4752-4756), 1WTG (Kadono, S., et al., Biochem Biophys Res Commun., 2005, 326, 859-865), 1WSS (Kadono, S., et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2005, 61, 169-173), 1W7X and 1W8B (Zbinden, K.G., et al., Bioorg Med Chem Lett., 2005, 15, 5344), 1WQV (Kadono, S., et al., Biochem Biophys Res Commun., 2004, 324, 1227-1233), 1Z6J (Schweitzer, B. A., et al., Bioorg Med Chem Lett., 2005, 15, 3006-3011), 1YGC (Olivero, A. G., et al., J Biol Chem., 2005, 280, 9160-9169), 6R2W (Sorensen, A.B., et al., J Biol ChemCrystal structures of factor VII bound to various compounds searchable by Mayweg, AV, et al., 5PA8, 5PA9, 5PAA, 5PAB, 5PAC, 5PAE, 5PAF, 5PAG, 5PAI, 5PAJ, 5PAK, 5PAM, 5PAN, 5PAO, 5PAQ, 5PAR, 5PAS, 5PAT, 5PAU, 5PABV, 5PAW, 5PAX, 5PAY, 5PB0, 5PB1, 5PB2, 5PB3, 5PB4, 5PB5, and 5PB6 (Mayweg, AV, et al.), as well as 5L0S (Li, Z., et al., Nat Commun., 2017, 8, 185-185) are provided. Furthermore, Kemball-Cook et al. provide insights into the crystal structure of factor VIIa with inhibited active site (Kemball-Cook, G., et al., J Struct Biol., 1999, 127(3), 213-23).

[0679] Representative factor VII targeting ligands are shown in Figure 1. Further factor VII targeting ligands can be found, for example, in U.S. Patent No. 9,174,974, Bioorg Med Chem Lett 26: 5051-5057 (2016), Bioorg Med Chem Lett 11: 2253-6 (2001), Bioorg Med Chem Lett 15: 3006-11 (2005), and Bioorg Med Chem Lett 12: 2883-6 (2002) (each of which is incorporated herein by reference).

[0680] coagulation factor IX In some embodiments, the target protein is human coagulation factor IX (UniProtKB - P00740(FA9_HUMAN)). Factor IX is Ca 2+ It is a vitamin K-dependent plasma protein involved in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of ions, phospholipids, and factor VIIIa.

[0681] Factor IX is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0682] The Protein Databank website lists 6MV4 (Vadivel, K., et al., J Thromb Haemost., 2019, 17, 574-584), 4ZAE (Zhang, T., et al., Bioorg Med Chem Lett., 2015, 25, 4945-4949), 4YZU and 4Z0K (Parker, DL, et al., Bioorg Med Chem Lett., 2015, 25, 2321-2325), 5TNO and 5TNT (Sakurada, I., et al., Bioorg Med Chem Lett., 2017, 27, 2622-2628), 5JB8, 5JB9, 5JBA, 5JBB, and 5JBC (Kristensen, LH, et al., Biochem J., 2016, 473, 2395-2411), 3LC3(Wang, S., et al., J Med Chem., 2010, 53, 1465-1472), 3LC5(Wang, S., et al., J Med Chem., 2010, 53, 1473-1482), 3KCG(Johnson, DJD, et al., Proc Natl Acad Sci USA, 2010, 107, 645-650), 1NL0(Huang, M., et al., J Biol Chem., 2004, 279, 14338-14346), 1RFN(Hopfner, KP, et al., Structure, 1999, 7, 989-996), and 6RFK (Sendall, TJ, Crystal structures of factor IX bound to various compounds are provided by et al. (et al.).

[0683] Representative factor IX targeting ligands are shown in Figure 1. Further factor IX targeting ligands can be found, for example, in U.S. Patent No. 9,409,908, Bioorg Med Chem Lett 25: 5437-43 (2015), and U.S. Patent No. 1,018,9819 (each of which is incorporated herein by reference).

[0684] Fibroblast growth factor 1 (FGF1) In some embodiments, the target protein is human fibroblast growth factor 1 (FGF1) (UniProtKB - P05230(FGF1_HUMAN)). FGF1 plays a crucial role in regulating cell survival, cell division, angiogenesis, cell differentiation, and cell migration. FGF1 functions as a ligand for FGFR1 and integrins, binding to FGFR1 in the presence of heparin and inducing dimerization and activation of FGFR1 via sequential autophosphorylation at tyrosine residues that function as docking sites for interacting proteins, leading to the activation of several signaling cascades. FGF1 induces phosphorylation and activation of FGFR1, FRS2, MAPK3 / ERK1, MAPK1 / ERK2, and AKT1. FGF1 can induce angiogenesis. FGF1 is thought to be involved in carcinogenesis, cancer cell proliferation, resistance to anticancer therapies, and angiogenesis.

[0685] The Protein Databank website allows you to search for the crystal structure of FGF1 using 2AFG (Blaber, M., et al., Biochemistry, 1996, 35, 2086-2094) and 1BAR (Zhu, X. et al., Science, 1991, 251, 90-93), as well as 1AFC (Zhu, X., et al., Structure, 1993, 1, 27-34), 1AXM and 2AXM (DiGabriele, AD, et al., Nature, 1998, 393, 812-817), 1EVT (Plotnikov, AN, et al., Cell, 2000, 101, 413-424), and 1E0O (Pellegrini, L., et al., Nature, 2000, 407). Crystal structures of FGF1 bound to various compounds searchable by 1029) and 2ERM (Canales, A., et al., FEBS J, 2006, 273, 4716-4727) are also provided.

[0686] Representative FGF1-targeting ligands are shown in Figure 1. Further FGF1-targeting ligands can be found, for example, in Bioorg Med Chem Lett 18: 344-9 (2008), Chembiochem 6: 1882-90 (2005), J Med Chem 55: 3804-13 (2012), J Med Chem 47: 1683-93 (2004), and J Med Chem 53: 1686-99 (2010) (each of which is incorporated herein by reference).

[0687] Fibroblast growth factor 2 (FGF2) In some embodiments, the target protein is human fibroblast growth factor 2 (FGF2) (UniProtKB - P09038(FGF2_HUMAN)). FGF2 functions as a ligand for FGFR1, FGFR2, FGFR3, and FGFR4. FGF2 also functions as an integrin ligand required for FGF2 signaling and plays a crucial role in regulating cell survival, cell division, cell differentiation, and cell migration. FGF2 also induces angiogenesis. FGF2 is thought to be involved in carcinogenesis, cancer cell proliferation, resistance to anticancer therapies, and angiogenesis.

[0688] The Protein Databank website provides crystal structures of FGF2 bound to various compounds, searchable by 4OEE, 4OEF, and 4OEG (Li, YC, et al., ACS Chem Biol., 2014, 9, 1712-1717), 1EV2 (Plotnikov, AN, et al., Cell, 2000, 101, 413-424), and 5X1O (Tsao, YH).

[0689] Representative FGF2-targeting ligands are shown in Figure 1. Further FGF2-targeting ligands can be found, for example, in U.S. Patent No. 8,933,099, Bioorg Med Chem Lett 12: 3287-90 (2002), Chem Biol Drug Des 86: 1323-9 (2015), and Bioorg Med Chem Lett 25: 1552-5 (2015) (each of which is incorporated herein by reference).

[0690] Fibronectin-1 In some embodiments, the target protein is human fibronectin 1 (FN1) (UniProtKB - P02751(FINC_HUMAN)). Fibronectin (FN) polymerization is required for collagen matrix deposition and is a major inducer of increased cardiac fibroblast (MF) abundance after traumatic cardiac injury. Inhibiting FN polymerization may reduce MF and fibrosis and improve cardiac function after ischemia / reperfusion (I / R) injury.

[0691] The Protein Databank website provides crystal structures of fibronectin-1 bound to various compounds, searchable by 3M7P (Graille, M., et al., Structure, 2010, 18, 710-718), 3MQL (Erat, MC, et al., J Biol Chem., 2010, 285, 33764-33770), and 3EJH (Erat, MC, et al., Proc Natl Acad Sci USA, 2009, 106, 4195-4200).

[0692] Representative FN-targeting ligands are shown in Figure 1. Further FN-targeting ligands can be found, for example, in Bioorg Med Chem Lett 18: 2499-504 (2008) (which is incorporated herein by reference).

[0693] Kallikrein-1 (KLK1) In some embodiments, the target protein is human kallikrein-1 (UniProtKB - P06870(KLK1_HUMAN)). Glandular kallikrein cleaves the Met-Lys and Arg-Ser bonds in kininogen, releasing Lys-bradykinin. Kallikrein is thought to be involved in adverse reactions in hereditary angioedema (HAE).

[0694] The Protein Databank website provides not only the crystal structure of KLK1, searchable by 1SPJ (Laxmikanthan, G., et al., Proteins, 2005, 58, 802-814), but also the crystal structures of KLK1 bound to various compounds, searchable by 5F8Z, 5F8T, 5F8X (Xu, M., et al.), and 6A8O (Xu, M., et al., FEBS Lett., 2018, 592, 2658-2667). Furthermore, Katz et al. have provided insights into the crystal structure of kallikrein (Katz, BA, et al., Protein Sci., 1998, 7(4), 875-85).

[0695] Representative kallikrein-targeting ligands are shown in Figure 1. Further kallikrein-targeting ligands can be found, for example, in U.S. Patent No. 9,783,530, J Med Chem 38: 2521-3 (1995), U.S. Patent No. 9,234,000, U.S. Patent No. 1,022,1161, U.S. Patent No. 9,687,479, U.S. Patent No. 9,670,157, U.S. Patent No. 9,834,513, J Med Chem 38: 1511-22 (1995), and U.S. Patent No. 1,021,4512 (each of which is incorporated herein by reference).

[0696] Plasma kallikrein In some embodiments, the target protein is human plasma kallikrein (UniProtKB - P03952(KLKB1_HUMAN)). Plasma kallikrein cleaves Lys-Arg and Arg-Ser bonds. After binding to a negatively charged surface, plasma kallikrein activates factor XII in the reverse reaction. Plasma kallikrein may also play a role in the renin-angiotensin system by releasing bradykinin from HMW kininogen and converting prorenin to renin. Plasma kallikrein is thought to be involved in the development of retinal dysfunction, diabetic macular edema, and hereditary angioedema (HAE).

[0697] The Protein Databank website provides crystal structures of plasma kallikreine bound to various compounds, searchable by 5TJX (Li, Z., et al., ACS Med Chem Lett., 2017, 8, 185-190), 6O1G and 6O1S (Patridge, JR, et al., J Struct Biol., 2019, 206, 170-182), 4OGX and 4OGY (Kenniston, JA, et al., J Biol Chem., 2014, 289, 23596-23608), as well as 5F8T, 5F8X, and 5F8Z (Xu, M., et al.).

[0698] Representative plasma kallikrein-targeting ligands are shown in Figure 1. Further plasma kallikrein-targeting ligands can be found, for example, in J Med Chem 61: 2823-2836 (2018), J Med Chem 55: 1171-80 (2012), U.S. Patent No. 8,598,206, U.S. Patent No. 9,738,655, Bioorg Med Chem Lett 16: 2034-6 (2006), U.S. Patent No. 9,409,908, U.S. Patent No. 1,014,4746, and U.S. Patent No. 9,290,485 (each of which is incorporated herein by reference).

[0699] Lipoprotein lipase In some embodiments, the target protein is human lipoprotein lipase (UniProtKB - P06858(LIPL_HUMAN)). Lipoprotein lipase is a major enzyme in triglyceride metabolism. It catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low-density lipoproteins (VLDL), thereby playing a crucial role in lipid clearance from the bloodstream, lipid utilization, and storage. Lipoprotein lipase mediates the peripheral migration of high-triglyceride lipoprotein particles within capillaries. Lipoprotein lipase is associated with the development of cardiovascular disease and obesity.

[0700] The Protein Databank website provides crystal structures of lipoprotein lipases bound to various compounds, searchable by 6E7K (Birrane, G., et al., Proc Natl Acad Sci USA, 2018 116 1723-1732).

[0701] Representative lipoprotein lipase-targeting ligands are shown in Figure 1. Further lipoprotein lipase-targeting ligands can be found, for example, in J Med Chem 47: 400-10 (2004) (which is incorporated herein by reference).

[0702] Matrix metallopeptidase 1 (MMP-1) In some embodiments, the target protein is human matrix metallopeptidase 1 (MMP-1) (UniProtKB - P03956(MMP1_HUMAN)). MMP-1 cleaves type I, type II, and type III collagen at a single site in the helical domain. MMP-1 also cleaves type VII and type X collagen. MMP-1 is associated with cardiovascular disease.

[0703] The Protein Databank website provides not only the crystal structure of MMP-1, which can be searched using 3SHI (Bertini, I., et al., FEBS Lett., 2012, 586, 557-567), but also the crystal structures of MMP-1 bound to various compounds, which can be searched using 4AUO (Manka, SW, et al., Proc Natl Acad Sci USA, 2012, 109, 12461), 3MA2 (Grossman, M., et al., Biochemistry, 2010, 49, 6184-6192), and 2J0T (Iyer, S., et al., J.Biol.Chem., 2007, 282, 364). Furthermore, Iyer et al. have provided insights into the crystal structure of the active form of MMP-1 (Iyer, S., et al., J Mol Biol., 2006, 362(1), 78-88), and Lovejoy et al. have provided insights into the crystal structure of MMP1 and its selectivity as a collagenase inhibitor (Lovejoy, B., et al., Nat Struct Mol Biol., 1999, 6, 217-221).

[0704] Representative MMP-1 targeting ligands are shown in Figure 1. Additional MMP-1 targeting ligands are available, for example Bioorg Med Chem Lett 5: 1415-1420 (1995), Bioorg Med Chem Lett 16: 2632-6 (2006), Bioorg Med Chem Lett 8: 837-42 (1999), Eur J Med Chem 60: 89-100 (2013), J Med Chem 54: 4350-64 (2011), Bioorg Med Chem Lett 8: 3251-6 (1999), J Med Chem 42: 4547-62 (1999), J Med Chem 61: 2166-2210 (2018), J Med Chem 41: 1209-17 This can be found in (1998) (which, by reference, forms part of this specification).

[0705] Macrophage migration inhibitory factor (MIF) In some embodiments, the target protein is human macrophage migration inhibitory factor (MIF) (UniProtKB - P14174(MIF_HUMAN)). MIF is a pro-inflammatory cytokine involved in the innate immune response to bacterial pathogens. MIF expression at inflammatory sites suggests its role as a mediator that modulates macrophage function in host defense. MIF counteracts the anti-inflammatory activity of glucocorticoids.

[0706] MIF is particularly associated with tumor progression, systemic inflammation, atherosclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

[0707] The mammalian catalyst is 1MIF(Sun, HW. et al., Proc Natl Acad Sci USA, 1996, 93, 94). 5191-5196) and the MIF fragmentation requirements were 6PEG(Cirillo, PF et al.) and 5XEJ(Fukushima, 2005). K) and 6FVE and 6FVH(Sokolov, AV, et al., Biochemistry(Moscow), 2018, 83, 701-707); 2018, 13, 1092-1097), 6B1C, 6B1K, 6B2C(Dawson, TK, et al., ACS Med Chem Lett., 2017, 8, 1287-1291), 4Z15, 4Z1T, and indeed 4Z1U(Singh, 2018). AK, et al., J Cell Mol Med., 2017, 21, 142-153), 5HVS and 5HVT(Cisneros, JA, et al., J Am Chem Soc., 2016, 138, 8630-8638), 4PKK(Pantouris, G., et al.). al.), 5J7P and 5J7Q(Cisneros, JA, et al., Bioorg Med Chem Lett., 2016, 26, 2764-2767); 1282-1294), 4PLU, 4TRF, 4P0H, and 4P01 (Pantouris, G., et al., Chem Biol., 2015, 22, 1197-1205), 4WR8 and 4WRB (Dziedzic, P., et al., J Am Chem Soc., 2015, 137 2996-3003), 4K9G(Ioannou, K., etal., Int J Oncol., 2014, 45, 1457-1468), 4OSF, 3WNR, 3WNS, and 3WNT (Spencer, ES, et al., Eur J Med Chem., 2015, 93, 501-510), 4OYQ (Spencer, ES et al.), 3SMB and 3SMC (Crichlow, GV et al., Biochemistry, 2012, 51, 7506-7514), 3U18 (Bai, F., et al., J Biol Chem., 2012, 287, 30653-30663), 4F2K (Tyndall, JDA, et al., Acta Crystallogr Sect F Struct Biol Cryst Commun., 2012, 68, 999-1002), 3IJG and 3IJJ (Cho, Y., et al., Proc Natl Acad Sci USA, 2010, 107, 11313-11318), 3L5P, 3L5R, 3L5S, 3L5T, 3L5U, and 3L5V (McLean, LR et al., Bioorg Med Chem Lett., 2010, 20, 1821-1824), 3JSF, 3JSG, and 3JTU (McLean, LR, et al., Bioorg Med Chem Lett., 2009, 19, 6717), 3HOF (Crawley, L., et al.), 3CE4 and 3DJI (Crichlow GV, et al., Biochemistry, 2009, 48, 132-139), 3B9S (Winner, M. et al., Cancer Res., 2008, 68, Crystal structures of MIF bound to various compounds searchable by 7253-7257), 2OOH, 2OOW, and 2OOZ (Crichlow, GV et al., J Biol Chem., 2007, 282, 23089-23095), 1GCZ and 1GD0 (Orita, M. et al., J Med Chem., 2001, 44, 540-547), as well as 1CA7, 1CGQ, and 1P1G (Lubetsky, JB et al., Biochemistry, 1999, 38, 7346-7354) are also provided. Furthermore, Sun et al. provide insights into the crystal structure of MIF (Proc Natl Acad Sci US A., 1996, 28;93(11), 5191-6).

[0708] Representative MIF-targeting ligands are shown in Figure 1. Further MIF-targeting ligands can be found, for example, in ACS Med Chem Lett 8: 124-127 (2017), J Med Chem 44: 540-7 (2001), J Med Chem 52: 416-24 (2009), and J Med Chem 50: 1993-7 (2007) (which are incorporated herein by reference).

[0709] Transforming Growth Factor-β2 (TGF-β2) In some embodiments, the target protein is human transforming growth factor-β2 (TGF-β2) (UniProtKB - P61812(TGFB2_HUMAN)). TGF-β2 is a pluripotent protein that regulates various processes, including angiogenesis and cardiac development. When activated after LAP release, TGF-β2 functions by binding to TGF-β receptors (TGFBR1 and TGFBR2), thereby transmitting signals. TGF-β2 expression in the tumor microenvironment is associated with poor prognosis and is involved in TGF-β2-mediated tumor suppression via T cell depletion. TGF-β2 expression has also been shown to be associated with hematological malignancies and fibrosis.

[0710] The Protein Databank website allows you to search for the crystal structure of TGF-β2 using 6I9J (Del Amo-Maestro L. et al., Sci Rep. 2019, 9, 8660-8660), as well as 1M9Z (Boesen, CC, et al. Structure, 2002, 10, 913-919), 5QIN (Zhang, Y. et al., ACS Med Chem Lett., 2018, 9, 1117-1122), 5E8V, 5E8Y, 5E91, and 5E92 (Tebben, AJ et al., Acta Crystallogr D Struct Biol., 2016, 72, 658-674), 4P7U (Wangkanont, K. et al., Protein Expr Purif., 2015, 115, Crystal structures of TGF-β2 bound to various compounds searchable by 19-25), 4XJJ (Wangkanont et al.), and 1KTZ (Hart, PJ, et al., Nat Struct Biol., 2002, 9, 203-208) are also provided.

[0711] Representative TGF-β2 targeting ligands are shown in Figure 1.

[0712] Thrombospongin-1 (TSP-1) In some embodiments, the target protein is human thrombospondin-1 (TSP-1) (UniProtKB - P61812(TGFB2_HUMAN)). TSP1 functions as an angiogenesis inhibitor by stimulating apoptosis in endothelial cells, inhibiting endothelial cell migration and proliferation, and regulating the bioavailability and activity of vascular endothelial growth factor. TSP1 influences tumor cell behavior, including tumor immune responses, adhesion, invasion, migration, apoptosis, and proliferation.

[0713] TSP-1 expression is thought to be associated with the promotion of certain cancers such as breast cancer, prostate cancer, melanoma, SCLC, osteosarcoma, cutaneous squamous cell carcinoma, oral squamous cell carcinoma, papillary thyroid carcinoma, thyroid cancer, and medulloblastoma, as well as fibrous disorders such as diabetes mellitus and hepatic fibrosis, and multiple myeloma.

[0714] The Protein Databank website allows you to search for the crystal structure of TSP-1 using 1LSL (Tan, K. et al., J Cell Biol., 2002, 159, 373-382), 2ES3 (Tan, K., et al., J Biol Chem., 2008, 283, 3932-3941), 1Z78 and 2ERF (Tan, K., et al., Structure, 2006, 14, 33-42), and 3R6B (Klenotic, PA, et al., Protein Expr Purif., 2011, 80, 253-259), as well as 2OUH and 2OUJ (Tan, K., et al., J Biol Chem., 2008, 283, 3932-3941), and 1ZA4 (Tan, K., et al.). Crystal structures of TSP-1 bound to various searchable compounds are also provided (al., Structure, 2006, 14, 33-42).

[0715] Representative TSP-1 targeting ligands are shown in Figure 1.

[0716] CD40 ligand (CD40L) In some embodiments, the target protein is human CD40 ligand (CD40L) (UniProtKB - P29965(CD40L_HUMAN)). CD40L is a cytokine that functions as a ligand for CD40 / TNFRSF5. CD40L co-stimulates T cell proliferation and cytokine production. Its crosslinking in T cells generates a co-stimulatory signal that enhances IL4 and IL10 production in combination with TCR / CD3 ligation and CD28 co-stimulation. CD40L induces activation of NF-κB, as well as the kinases MAPK8 and PAK2, in T cells. CD40L also induces tyrosine phosphorylation of isoform 3 of CD28. CD40L mediates B cell proliferation in the absence of co-stimulation and mediates IgE production in the presence of IL4, and is involved in immunoglobulin class switching.

[0717] The Protein Databank website provides not only the crystal structure of CD40L, which can be searched using 1ALY (Karpusas, M., et al., Structure, 1995, 3, 1031-1039), but also the crystal structures of CD40L bound to various compounds, which can be searched using 3QD6 (An, HJ, et al., J Biol Chem., 2011, 286, 11226-11235) and 6BRB (Karnell, JL, et al., Sci Transl Med., 2019, 11(489), 6584).

[0718] CD40L expression is associated with HIV-related neurocognitive disorders and cardiovascular complications. Representative CD40L-targeting ligands are shown in Figure 1.

[0719] Urokinase-type plasminogen activator (UPA) In some embodiments, the target protein is human urokinase-type plasminogen activator (UPA) (UniProtKB - P00749(UROK_HUMAN)). Urokinase-type plasminogen activator (uPA) is a serine protease present in the blood and the extracellular matrix of many tissues. The main physiological substrate of this enzyme is plasminogen, which is the inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, is involved in thrombolysis or extracellular matrix degradation. This cascade is thought to be involved in vascular disease and cancer progression. Elevated expression levels of urokinase and several other components of the plasminogen activator system have been found to correlate with tumor malignancy.

[0720] 5ZA7, 5ZAJ, 5ZA8, 50 ZA9, 5ZAE, 5ZAF, 5ZAG, 5ZAH, and 5ZC5(Buckley, BJ et al., J Med Chem., 2018, 61, 8299-8320), 5LHP, 5LHQ, 5LHR, and 35LHS(Kromann-Hansen, T. et al., Sci Rep., 2017, 7, 3385-3385), 2VNT(Fish, 2017). PV et al., J Med Chem., 2007, 50, 2341). 303-324), 1SQA, 1SQO, and 1SQT (Wendt, MD, et al., Bioorg Med Chem Lett., 2004, 14, 3063-3068); 93-98), 3OX7, 3OY5, and 3OY6 (Jiang, LG et al., J Mol Biol., 2011, 412, 235-250). S. et al., Nat Chem., 2014, 6, 1009-1016), 3IG6(West, CW et al., Bioorg Med Chem Lett., 2009, 19, 5712-5715), 4X0W and 4X1P(Jiang, L. et al., Int J Biochem Cell). Biol., 2015, 62, 88-92) and 4X1N, 4X1Q, 4X1R, and 4X1S(Zhao, B. et al., PLoS One, 2014, 9, e115872-e115872), 5WXO and 5WXP(Jiang, 2015). L. et al., Biochim Biophys Acta., 2018, 1862, 2017-2023) 4MNV, 4MNW, 4MNX, and 4MNY(Chen, S., et al., Angew Chem Int Ed Engl., 2014, 53, 1602 - 1606), 4GLY (Chen, S., et al., J Am Chem Soc., 2013, 135, 6562 - 6569), 4JK5 and 4JK5 (Chen, S., et al., Chembiochem., 2013, 14, 1316 - 1322), 3QN7 (Angelini, A. et al., ACS Chem Biol., 2012, 7, 817 - 821), 2NWN (Zhao, G. et al., J Struct Biol., 2007, 160, 1 - 10), 6NMB (Wu, G. et al., Blood Adv., 2019, 3, 729 - 733), 1W0Z, 1W10, 1W11, 1W12, 1W13, and 1W14 (Zeslawska, E. et al., J Mol Biol., 2003, 328, 109), 4DVA (Jiang, L et al., Biochem J., 2013, 449, 161 - 166), 6A8G, 6A8N (Wang, D. et al., J Med Chem., 2019, 62, 2172 - 2183), 2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, and 2VIW (Frederickson, M. et al., J Med Chem., 2008, 51, 183), 1EJN (Speri, S., et al., Proc Natl Acad Sci U S A, 2000, 97, 5113 - 5118), 3PB1 (Lin, Z. et al., J Biol Chem., 2011, 286, 7027 - 7032), 3U73 (Xu, X. et al., J Mol Biol., 2012, 416, 629 - 641), 1C5W, 1C5X, 1C5Y, and IC5Z (Katz, B.A., et al., Chem Biol., 2000, 7, 299 - 312), 5XG4 (Xue, G. et al., Food Funct., 2017, 8, 2437 - 2443), 5WXF (Jiang, L. et al., Biochim Biophys Acta., 2018, 1862, 2017-2023), 5WXS, 4ZKS, 5WXQ, 5WXT, 5YC6, 5YC7, 5Z1C (Jiang, L. et al.), 4H42 (Yu, HY et al.), 6AG3 and 6AG9 (Buckley, B. et al. al.), 3KGP, 3KHV, 3KID, 3M61, 3MHW, and 3MWI (Jiang, LG et al.), 4ZKN, 4ZKO, and 4ZKR (Jiang, L. et al.), 2O8T, 2O8U, 2O8W (Zhao, G. et al. Crystal structures of UPA bound to various compounds searchable by 4FU7, 4FU8, 4FU9, 4FUB, 4FUC, 4FUD, 4FUE, 4FUF, 4FUG, 4FUH, 4FUI, and 4FUJ (Kang, YN et al.) are provided.

[0721] Representative UPA-targeting ligands are shown in Figure 1. Further UPA targeting ligands are, for example, J Med Chem 38: 1511-22 (1995), Bioorg Med Chem Lett 11: 2253-6 (2001), Bioorg Med Chem Lett 14: 3063-8 (2004), J Med Chem 52: 3159-65 (2009), CSAR 1: (2012), Bioorg Med Chem 22: 3187-203 (2014), J Med Chem 50: 2341-51 (2007), J Mol Biol 329: 93-120 (2003), Bioorg Med Chem Lett2:1399-1404 (1992), J Med Chem 35: 4297-305 As shown in (1992), J Med Chem 35: 4150-9 (1992), J Med Chem 49: 5785-93 (2006), Bioorg Med Chem 23: 3696-704 (2015), Bioorg Med Chem Lett 10: 983-7 (2000), J Med Chem 49: 5785-93 (2006) (each of which constitutes part of this specification by reference).

[0722] Plasminogen activator, tissue type (TPA) In some embodiments, the target protein is human plasminogen activator, tissue type (TPA) (UniProtKB - P00750(TPA_HUMAN)). TPA converts abundant but inactive zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By regulating plasmin-mediated proteolysis, TPA plays a crucial role in tissue remodeling and degradation, cell migration, and many other physiological and pathological events. TPA plays a direct role in promoting neuronal migration. PLA has been shown to be activated in various cancers, including oral malignancies.

[0723] The Protein Databank website provides not only the crystal structure of TPA searchable by 1VR1 (Dekker, RJ et al., J Mol Biol., 1999, 293, 613-627), but also the crystal structures of TPA bound to various compounds searchable by 1RTF (Lamba, D. et al., J Mol Biol., 1996, 258, 117-135), 1A5H (Renatus, M. et al., J Biol Chem., 1997, 272, 21713-21719), and 1BDA (Renatus, M. et al., EMBO J., 1997, 16, 4797-4805).

[0724] Representative TPA-targeting ligands are shown in Figure 1. Further TPA-targeting ligands are shown, for example, in Bioorg Med Chem Lett 15: 4411-6 (2005), Bioorg Med Chem Lett 13: 2781-4 (2003), Bioorg Med Chem Lett 6: 2913-2918 (1996), J Med Chem 44: 2753-71 (2001), J Med Chem 41: 5445-56 (1999), Bioorg Med Chem Lett 12: 3183-6 (2002), U.S. Patent No. 10118930, and J Biol Chem 285: 7892-902 (2010) (each of which is incorporated herein by reference).

[0725] Plasminogen (PLG) In some embodiments, the target protein is human plasminogen (PLG) (UniProtKB - P00747(PLMN_HUMAN)). PLG dissolves fibrin in blood clots and functions as a proteolytic factor in various other processes, including embryogenesis, tissue remodeling, tumor invasion, and inflammation. PLG activates urokinase-type plasminogen activators, collagenases, and several complement zymogens, such as C1 and C5. Its role in tissue remodeling and tumor invasion can be regulated by CSPG4.

[0726] The Protein Databank website provides crystal structures of PLG that can be searched using 1DDJ (Wang, X. et al., J.Mol.Biol., 2000, 295, 903-914), as well as 4DUR and 4DUU (Law, RHP, et al., Cell Rep., 2012, 1, 185-190).

[0727] Representative PLG-targeting ligands are shown in Figure 1. Further PLG-targeting ligands are, for example, J Med Chem 35: 4297-305 (1992), J Med Chem 38: 1511-22 (1995), J Med Chem 56: 820-31 (2013), U.S. Patent No. 8598206, U.S. Patent No. 8921319, J Med Chem 55: 1171-80 (2012), Bioorg Med Chem Lett 12: 3183-6 (2002), Bioorg Med Chem 23: 3696-704 (2015), Bioorg Med Chem Lett 13: 723-8 (2003), Bioorg Med Chem Lett 7: 331-336. These are shown in (1997) (each of which, by reference, constitutes part of this specification).

[0728] Plasminogen activator inhibitor-1 (PAI-1) In some embodiments, the target protein is human plasminogen activator inhibitor 1 (PAI-1) (UniProtKB - P05121(PAI1_HUMAN)). PAI-1 is a serine protease inhibitor and a primary inhibitor of tissue plasminogen activator (PLAT) and urokinase plasminogen activator (PLAU). As a PLAT inhibitor, PAI-1 is required for the downregulation of fibrinolysis and plays a role in controlling the breakdown of blood clots. As a PLAU inhibitor, PAI-1 is involved in the regulation of cell adhesion and diffusion and functions as a regulator of cell migration, independently of its role as a protease inhibitor. Overexpression of PAI-1 promotes angiogenesis, metastasis, and poor prognosis in tumors, including oral cancer and breast cancer, but is not limited to these.

[0729] The Protein Databank website allows you to search for the crystal structure of PAI-1 using 3Q02 and 3Q03 (Jensen, JK et al., J Biol Chem., 2011, 286, 29709-29717), 1B3K (Sharp, AM et al., Structure, 1999, 7, 111-118), 1C5G (Tucker, HM et al., Nat Struct Biol., 1995, 2, 442-445), 1DVM (Stout, TJ et al., Biochemistry, 2000, 39, 8460-8469), and 3UT3 (Lin, ZH et al.), as well as 4AQH (Fjellstrom, O. et al., J Biol Chem., 2013, 288, 873), 3R4L (Jankun, J. et al., Int J Mol Med., 2012, 29 61-64), 1A7C (Xue, Y., et al., Structure, 1998, 6, 627-636), 1OC0 (Zhou, A. et al., Nat Struct Biol., 2003, 10, 541), 6I8S (Vousden, KA et al., Sci Rep., 2019, 9, 1605-1605), 4G8O and 4G8R (Li, SH et al., Proc Natl Acad Sci USA, 2013, 110, E4941-E4949), 6GWQ, 6GWN, and 6GWP (Sillen, M. et al. al., J Thromb Crystal structures of PAI-1 bound to various compounds searchable by Haemost (2019) and 4IC0 (Hong, ZB et al.) are also provided.

[0730] Representative PAI-1 targeting ligands are shown in Figure 1. Further PAI-1 targeting ligands are shown, for example, in J Biol Chem 285: 7892-902 (2010), U.S. Patent No. 9,120,744, Bioorg Med Chem Lett 13: 3361-5 (2003), Bioorg Med Chem Lett 12: 1063-6 (2002), Bioorg Med Chem Lett 13: 1705-8 (2003), Bioorg Med Chem Lett 11: 2589-92 (2001), and U.S. Patent No. 9,718,760 (each of which is incorporated herein by reference).

[0731] Placental growth factor (PIGF) In some embodiments, the target protein is human placental growth factor (PGF) (UniProtKB - P49763(PLGF_HUMAN)). PGF is effective in angiogenesis and endothelial cell growth, and is a growth factor that stimulates their proliferation and migration. PGF binds to the receptor FLT1 / VEGFR-1. The isoform PIGF-2 binds to NRP1 / neuropillin-1 and NRP2 / neuropillin-2 in a heparin-dependent manner. PGF is also thought to promote the growth of cell tumors and is associated with age-related macular degeneration (AMD) and choroidal angiogenesis (CNV).

[0732] The Protein Databank website provides not only the crystal structure of PIGF searchable by 1FZV (Iyer, S. et al., J Biol Chem., 2001, 276, 12153-12161), but also the crystal structures of PIGF bound to various compounds searchable by 1RV6 (Christinger, HW, J Biol Chem., 2004, 279, 10382-10388). Furthermore, De Falco provides insights into the discovery and biological activity of placental growth factor (De Falco, Exp Mol Med., 2012, 44, 1-9).

[0733] Representative PGF-targeting ligands are shown in Figure 1. Further PGF-targeting ligands are shown, for example, in J Med Chem 54: 1256-65 (2011) and J Nat Prod 76: 29-35 (2013) (each of which is incorporated herein by reference).

[0734] Phospholipase A2, Group IB (PA21B) In some embodiments, the target protein is human phospholipase A2, group IB (PA21B) (UniProtKB - P04054(PA21B_HUMAN)). PA21B preferentially cleaves phospholipids at the sn-2 position, releasing free fatty acids and lysophospholipids. PA21B is associated with numerous diseases, including cardiovascular disease, atherosclerosis, immune disorders, and cancer.

[0735] The Protein Databank website provides crystal structures of PA21B, which can be searched using 3FVJ and 3FVI (Pan, YH et al., Biochim.Biophys.Acta., 2010, 1804, 1443-1448).

[0736] Representative PA21B-targeting ligands are shown in Figure 1. Further PA21B-targeting ligands are shown, for example, in J Med Chem 39: 3636-58 (1996), Chembiochem 4: 181-5 (2003), J Med Chem 39: 5159-75 (1997), and J Med Chem 51: 4708-14 (2008) (each of which is incorporated herein by reference).

[0737] Phospholipase A2, Group IIA (PA2GA) In some embodiments, the target protein is human phospholipase A2, group IIA (PA2GA) (UniProtKB - P04054(PA21B_HUMAN)). PA2GA catalyzes the calcium-dependent hydrolysis of the 2-acyl group in 3-sn-phosphoglycerides. PA2GA is thought to be involved in regulating phospholipid metabolism in biological membranes, including eicosanoid biosynthesis. Independent of its catalytic activity, PA2GA also functions as an integrin ligand. PA2GA induces cell proliferation in an integrin-dependent manner. PA2GA is associated with numerous diseases, including cardiovascular disease, atherosclerosis, immunodeficiency, and cancer.

[0738] The Protein Databank website provides crystal structures of PA2GA bound to various compounds, searchable by 2ARM and 1SV3 (Singh, N. et al., Proteins, 2006, 64, 89-100), 5G3M and 5G3N (Giordanetto, F., et al. ACS Med Chem Lett., 2016, 7, 884), 1KQU (Jansford, KA, et al., Chembiochem., 2003, 4, 181-185), and 1ZYX (Singh, N. et al.). Furthermore, Singh et al. have provided insights into the crystal structure of the complex of group IIA phospholipase A2 with anisic acid and atropine, two natural anti-inflammatory agents exhibiting similar binding modes (Singh, N. et al., Proteins, 2006, 64(1):89-100), and Kitadokoro et al. have provided insights into the crystal structure of the human secreted phospholipase A2-IIA complex with the potent indolidine inhibitor 120-1032 (Kitadokoro, K. et al., J Biochem., 1998, 123(4), 619-23).

[0739] Representative PA2GA-targeting ligands are shown in Figure 1. Further PA2GA-targeting ligands are shown, for example, in J Med Chem 48: 893-6 (2005) and J Med Chem 39: 5159-75 (1997) (each of which is incorporated herein by reference).

[0740] B factor In some embodiments, the target protein is human complement factor B (UniProtKB - P00751(CFAB_HUMAN)). Complement factor B, part of an alternative pathway in the complement system, is cleaved by factor D into two fragments: Ba and Bb. Then, Bb, a serine protease, combines with complement factor 3b to produce C3 convertase or C5 convertase. Factor B is also thought to be involved in the proliferation and differentiation of pre-activated B lymphocytes, the rapid diffusion of peripheral blood monocytes, stimulation of lymphocyte blast formation, and erythrocyte lysis. Ba inhibits the proliferation of pre-activated B lymphocytes.

[0741] The Protein Databank website provides not only the crystal structure of complement factor B, searchable by 2OK5 (Milder, FJ, et al., Nat Struct Mol Bio 2007, 14, 224-228), but also the crystal structures of complement factor B bound to various compounds, searchable by 6QSW, 6QSX, and 6RAV (Schubart, A., et al., Proc Natl Acad Sci 2019, 116, 7926-7931), 6T8U, 6T8W, and 6T8V (Mainolfi, N., et al, J Med Chem 2020, 63, 5697-5722), and 7JTN (Xu, X., et al., J Immunol 2021, 206, doi:10.4049 / jimmunol.2001260).

[0742] Representative complement factor B targeting ligands are shown in Figure 5. Further complement factor B targeting ligands are shown, for example, in U.S. Patent Nos. 9,682,968, 9,475,806, 9,452,990, Proc Natl Acad Sci 116: 7926-7931 (2019), J Med Chem 52: 6042-6052 (2009), and J Med Chem 63: 5697-5722 (2020) (each of which is incorporated herein by reference).

[0743] In a particular embodiment, the extracellular targeting ligand is [ka] (Each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents independently selected from the original).

[0744] In certain embodiments, the factor B targeting ligand is selected from the ligands described in Mainolfi, N. et. al. Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-Methoxy-7-Methyl-1H-Indol-4-Yl)Methyl)Piperidin-2-Yl)Benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases. J. Med. Chem. 2020, 63 (11), 5697-5722, International Publication No. 2020 / 016749, International Publication No. 2018 / 005552, International Publication No. 2013 / 192345, or International Publication No. 2015 / 009616.

[0745] In a particular embodiment, the factor B-targeting ligand-linker is [ka] Selected from.

[0746] In certain embodiments, the compound of the present invention is the following compound: [ka] TIFF0007849881000481.tif192170, TIFF0007849881000482.tif80170, or their two-seat or three-seat forms are selected.

[0747] D factor In some embodiments, the target protein is human complement factor D (UniProtKB - P00746(CFAD_HUMAN)). Factor D cleaves factor B when factor B forms a complex with factor C3b, activating the C3bbb complex, and then becomes a C3 convertase for an alternative pathway. Its function is consistent with the function of C1s in the classical pathway.

[0748] The Protein Databank website lists 6FTZ, 6FUT, 6FUH, 6FUG, 6FUJ, and 6FUI (Vulpetti, A., et al., ACS Med Chem Lett 2018, 9, 490-495), 5TCA and 5TCC (Yang, CY, et al., ACS Med Chem Lett 2016, 7, 1092-1096), 5MT4 (Vulpetti, A., et al., J Med Chem 2017, 60, 1946-1958), 1DFP (Cole, LB, et al., Acta Crystallogr D Biol Crystallogr 1997, 53, 143-150), and 1DIC (Cole, LB, et al., Acta Crystallogr D Biol Crystallogr 1998, 54). Crystal structures of complement factor D bound to various compounds, searchable by 711-717), 6QMR, and 6QMT (Karki, RG, et al., J Med Chem 2019, 62, 4656-4668), are provided.

[0749] Representative complement factor D targeting ligands are shown in Figure 6. Further complement factor D targeting ligands can be found, for example, in J Med Chem 60: 5717-5735 (2017) and Nat Chem Biol 12: 1105-1110. (2016), U.S. Patent No. 9598446, U.S. Patent No. 9643986, U.S. Patent No. 9663543, U.S. Patent No. 9695205, U.S. Patent No. 9732103, U.S. Patent No. 9732104, U.S. Patent No. 9758537, U.S. Patent No. 9796741, U.S. Patent No. 9828396, U.S. Patent No. 10000516, U.S. Patent No. 10005802, U.S. Patent No. 10011612, U.S. Patent No. 10081645, U.S. Patent No. 10087203, U.S. Patent No. 10092584, U.S. Patent No. 10100072, U.S. Patent No. 10106563, U.S. Patent No. 101 As shown in U.S. Patent Nos. 38225, 10189869, 10253053, 10287301, 10301336, 10370394, 10385097, 10428094, 10428095, 10464956, 10550140, 10660876, 10662175, 10689409, 10807952, 10822352, 9464081, and Haematologica 102: 466-475 (2017) (each of which is incorporated herein by reference).

[0750] In a particular embodiment, the extracellular targeting ligand is [ka] (In the formula, R 21a , R 21b , R 21c , R 21d , R 21e , R 21f , and R 21gIndependently, in each case, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Haloalkyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, -SR 3 , -C(O)OR 3 -C(O)NR 6 NR 7 , -OR 3 Selected from the group consisting of , and complex rings, R 201 , R 202 , R 202 ', and R 203 These are independently hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C2-C6 alkynyl, C2-C6 alkanoyl, C1-C6 thioalkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, and -C0-C4 alkylNR 9 R 10 , -C(O)OR 9 -OC(O)R 9 , -NR 9 C(O)R 10 -C(O)NR 9 R 10 -OC(O)NR 9 R 10 -O (heteroaryl), -NR 9 C(O)OR 10 , selected from C1-C2 haloalkyl, -C0-C4 alkyl (C3-C7 cycloalkyl) and -O-C0-C4 alkyl (C3-C7 cycloalkyl), and C1-C2 haloalkoxy, where R 209 and R 210 Independently, in each case, are selected from hydrogen, C1-C6 alkyl, and (C3-C7 cycloalkyl)C0-C4 alkyl, or R 202 and R 202’may together form a 3- to 6-membered spiro ring optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, -COOH, C1-C4 alkyl (especially including methyl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C2-C4 alkanoyl, hydroxymethyl C1-C4 alkyl, (mono-C1-C4 alkylamino and di-C1-C4 alkylamino)C0-C4 alkyl, -C0-C4 alkyl(C3-C7 cycloalkyl), -O-C0-C4 alkyl(C3-C7 cycloalkyl), C1-C2 haloalkyl, and C1-C2 haloalkoxy, or, R 201 and R 202 may together form a 3-membered carbocyclic ring optionally substituted with one, two, or three substituents selected from R 21 or, R 201 and R 202 may together form a 4- to 6-membered carbocyclic ring, or a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, optionally substituted with one, two, or three substituents selected from R 21 or, R 202 and R 203 may together form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring optionally substituted with one, two, or three substituents selected from R 21 or, L 100 is

Chemical formula

[0751] In a particular embodiment, the extracellular targeting ligand is [ka] (Each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents independently selected from the original).

[0752] In certain embodiments, the D factor targeting ligand is selected from ligands described in U.S. Patent No. 9,796,74, U.S. Patent No. 10,011,612, International Publication No. 2018 / 160889, International Publication No. 2019 / 195720, International Publication No. 2019 / 057946, Karki, RG et al. Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway. J. Med. Chem. 2019, 62 (9), 4656-4668, or Belanger, DB et al., International Publication No. 2015 / 009977.

[0753] In a particular embodiment, the complement factor D targeting ligand-linker is [ka] Selected from TIFF0007849881000487.tif230170, TIFF0007849881000488.tif211170, and TIFF0007849881000489.tif61170.

[0754] In certain embodiments, the compound of the present invention is the following compound: [ka] TIFF0007849881000491.tif200170TIFF0007849881000492.tif205170TIFF0007849881000493.tif221170TIFF0007849881000494.tif210170TIFF0007849881000495.tif224170TIFF0007849881000496.tif120170 or selected from their two-seat or three-seat forms.

[0755] H factor In some embodiments, the target protein is human complement factor H (UniProtKB - P08603(CFAH_HUMAN)). Complement factor H is a glycoprotein that plays an essential role in maintaining a balanced immune response by regulating complement activation. It acts as a complement solubility inhibitor, binding to automarkers such as glycan structures to prevent complement activation and amplification on the cell surface. Complement factor H accelerates the breakdown of the complement alternative pathway (AP) C3 convertase C3bBb, thus preventing the local formation of more C3b, which plays a central role in the complement amplification loop. As a cofactor of serine protease factor I, CFH also regulates the proteolysis of already deposited C3b. Furthermore, CFH mediates several cellular responses through interactions with specific receptors. For example, CFH interacts with the CR3 / ITGAM receptor, thereby mediating the adhesion of human neutrophils to various pathogens. These pathogens are subsequently phagocytosed and destroyed.

[0756] The Protein Databank website allows you to search not only for the crystal structures of highly similar complement H factor mutants, which can be searched using 3KXV and 3KZJ (Bhattacharjee, A., et al., Mol Immunol 2010, 47, 1686-1691), but also for 2UWN (Prosser, BE, et al., J Exp Med 2007, 204, 2277), 5WTB (Zhang, Y., et al., Biochem J 2017, 474, 1619-1631), 5O32 and 5O35 (Xue, X., et al., Nat Struct Mol Biol 2017, 24, 643-651), and 4ONT (Blaum, BS, et al., Nat Chem Biol 2015, 11, Crystal structures of wild-type complement H factor bound to various compounds searchable by 77-82) and 4ZH1 (Blaum, BS, et al., Glycobiology 2016, 26, 532-539) are provided.

[0757] Representative complement factor H targeting ligands are shown in Figure 7. Further complement factor H targeting ligands are shown, for example, in J Immunol 182: 6394-6400 (2009), PLoS Pathogens 4: e1000250 (2008), PLoS Pathogens 6: e1001027 (2010), U.S. Patent No. 10865238, U.S. Patent No. 8962795, U.S. Patent Application Publication No. 2016 / 0317573, and U.S. Patent Application Publication No. 2019 / 0315842 (each of which is incorporated herein by reference).

[0758] Complement component 5 (C5) In some embodiments, the target protein is human complement component 5 (C5) (UniProtKB - P01031(CO5_HUMAN)). When C5 is activated by C5 convertase, late complement components C5-C9 spontaneously assemble to form membrane-invasive complexes. C5b has a transient binding site for C6. The C5b-C6 complex is the base upon which soluble complexes assemble.

[0759] The Protein Databank website provides not only the crystal structure of complement component 5, searchable by 3CU7 (Fredslund, F., Nat Immunol 2008, 9, 753-760), but also the crystal structures of complement component 5 bound to various compounds, searchable by 5I5K (Schatz-Jakobsen, JA, et al, J Immunol 2016, 197, 337-344), 3PVM and 3PRX (Laursen, NS, et al., EMBO J 2011, 30, 606-616), and 3KLS (Laursen, NS, et al., Proc Natl Acad Sci 2010, 107, 3681-3686).

[0760] Representative complement component 5-targeting ligands are shown in Figure 8. Further complement component 5-targeting ligands are shown, for example, in J Immunol 197: 337-344 (2016), Ther Adv Hematol 10: 1-11 (2019), BioDrugs 34: 149-158 (2020), Blood 135: 884-885 (2020), U.S. Patent Application Publication 2017 / 0342139, and U.S. Patent Application Publication 2020 / 0095307 (each of which is incorporated herein by reference).

[0761] In a particular embodiment, the extracellular targeting ligand is [ka] (Each is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents independently selected from the original).

[0762] In certain embodiments, the complement C5 targeting ligand is selected from ligands described in Jendza, K. et al. A Small-Molecule Inhibitor of C5 Complement Protein. Nat Chem Biol 2019, 15 (7), 666-668, or Zhang, M.; Yang, X.-Y.; Tang, W.; Groeneveld, TWL; He, P.-L.; Zhu, F.-H.; Li, J.; Lu, W.; Blom, AM; Zuo, J.-P.; Nan, F.-J. Discovery and Structural Modification of 1-Phenyl-3-(1-Phenylethyl)Urea Derivatives as Inhibitors of Complement. ACS Med. Chem. Lett. 2012, 3 (4), 317-321.

[0763] In a particular embodiment, the C5-targeting ligand is [ka] Selected from.

[0764] Complement C1s In certain embodiments, the extracellular targeting ligand is a C1s targeting ligand.

[0765] In certain embodiments, the complement C1s-targeting ligand is selected from ligands described in International Publication No. 2020 / 198062 or U.S. Patent No. 6,683,055.

[0766] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, a choice can be made between these two-seat or three-seat configurations.

[0767] MASP In a particular embodiment, the extracellular targeting ligand is a MASP targeting ligand.

[0768] In certain embodiments, the MASP-targeting ligand is selected from ligands described in Heja, D. et al. Monospecific Inhibitors Show That Both Mannan-Binding Lectin-Associated Serine Protease-1 (MASP-1) and -2 Are Essential for Lectin Pathway Activation and Reveal Structural Plasticity of MASP-2. Journal of Biological Chemistry 2012, 287 (24), 20290-20300, Dobo, J.; Kocsis, A.; Gal, P. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Front. Immunol. 2018, 9, 1851, or International Publication No. 2014 / 144542.

[0769] In certain embodiments, the MSAP-1 targeting ligand is an SGMI-1 peptide linked via the N-terminus or C-terminus.

[0770] In certain embodiments, the MSAP-1 targeting ligand is an SGMI-2 peptide linked via the N-terminus or C-terminus.

[0771] In certain embodiments, the MSAP-1 targeting ligand is a TFMI-3 peptide linked via the N-terminus or C-terminus.

[0772] Factor XIa In certain embodiments, the extracellular targeting ligand is a factor XIa targeting ligand.

[0773] In a particular embodiment, the factor XIa targeting ligand is selected from the ligands described in Lorthiois, E. et al. Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach. J. Med. Chem. 2020, 63 (15), 8088-8113.

[0774] In a particular embodiment, the factor XIa targeting ligand is selected from the ligands described in Quan, ML et al. Factor XIa Inhibitors as New Anticoagulants. J. Med. Chem. 2018, 61 (17), 7425-7447.

[0775] In a particular embodiment, the factor XIa targeting ligand is selected from the ligands described in Yang, W. et al. Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species. J. Med. Chem. 2020, 63 (13), 7226-7242.

[0776] In a particular embodiment, the factor XIa-targeting ligand-linker is [ka] That is the case.

[0777] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, a choice can be made between these two-seat or three-seat configurations.

[0778] In a particular embodiment, a factor Xia-targeting ligand is selected, which is positioned at any suitable location where the anchor bond may or may not have functionalization.

[0779] [ka]

[0780] Further complement extracellular targeting ligands In certain embodiments, the extracellular targeting ligand is selected from OMS721, Amy 101, APL2, ACH-4471, LNP023, eculizumab, and avacopan. In other embodiments, the extracellular targeting ligand is selected from C1-INH, lucin, TP10, CAB-2, eculizumab, pexelizumab, ofatumumab, compstatin, PMX-53, and rhMBL. In other embodiments, the extracellular targeting ligand is selected from BCX1470, TP-20, mirococept, TNX-234, TNX-558, TA106, neutrazumab, anti-properzine, HuMax-CD38, ARC1905, and JPE-1375.

[0781] TNF-α In certain embodiments, the extracellular targeting ligand is a TNF-α targeting ligand.

[0782] In certain embodiments, the TNF-α-targeting ligand is selected from the ligands described in Dietrich, JD et al. Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design. J. Med. Chem. 2021, 64 (1), 417-429.

[0783] In a particular embodiment, the TNF-α-targeting ligand-linker is [ka] Selected from.

[0784] In certain embodiments, the compound of the present invention is the following compound: [ka] TIFF0007849881000505.tif115170 or a selection of their two-seat or three-seat versions.

[0785] Specific extracellular targeting ligands In certain embodiments, the extracellular protein targeting ligand is OPT-3. OPT-3 has the following structure. OPT-3 can be bound to the linker at any available position using standard linking chemistry.

[0786] [ka]

[0787] In a particular embodiment, OPT-3 is attached to the linker via a primary amine of histidine, as shown below.

[0788] [ka]

[0789] OPT-NH2 has the structure shown below.

[0790] [ka]

[0791] In a particular embodiment, OPT-3 is attached to the linker via an alkyne-azidocrick reaction. The OPT-alkyne has the following structure:

[0792] [ka]

[0793] In certain embodiments, the extracellular protein targeting ligand is OPT-2. OPT-2 has the following structure:

[0794] [ka]

[0795] In a particular embodiment, OPT-2 is attached to the linker via a primary amine of histidine, as shown below.

[0796] [ka]

[0797] In certain embodiments, the extracellular protein targeting ligand is OPT-1. OPT-1 has the following structure:

[0798] [ka]

[0799] In a particular embodiment, OPT-1 is attached to the linker via a primary amine of histidine, as shown below.

[0800] [ka]

[0801] IV. Pharmaceutical compositions and dosage forms relating to the extracellularly degradable compounds of the present invention The compounds of the present invention disclosed herein, or their pharmaceutically acceptable salts, solvates, or prodrugs, may be administered as solvent-free chemicals, but more typically, they may be administered as pharmaceutical compositions containing an effective amount for a host requiring such treatment, typically a human, to treat disorders mediated by target extracellular proteins, either those described herein or otherwise well known for their effect on the target extracellular proteins.

[0802] The ASGPR-binding extracellular protein degrader of the present invention can be administered in any manner in which the degrader typically binds to an extracellular protein in the bloodstream, is transported to ASGPR-containing hepatocytes in the liver, and is taken up and degraded within the cells. Therefore, examples of methods for delivering the degrader of the present invention include, but are not limited to, oral, intravenous, sublingual, subcutaneous, parenteral, buccal, rectal, intra-aortic, intracranial, subdermal, transdermal, controlled drug delivery, intramuscular, or nasal, or by other means, in a dosage unit formulation comprising one or more conventionally pharmaceutically acceptable carriers as appropriate. In certain embodiments, the degrader is provided in liquid dosage form, solid dosage form, gel, particle form, etc.

[0803] In certain embodiments, the compounds of the present invention are administered subcutaneously. Typically, the compounds are formulated in liquid dosage forms for subcutaneous injection, such as buffer solutions. Non-limiting examples of solutions for subcutaneous injection include phosphate buffer solutions and saline buffer solutions. In certain embodiments, the solution is buffered with multiple salts.

[0804] In certain embodiments, the compounds of the present invention are administered intravenously. Typically, the compounds are formulated in liquid dosage forms for intravenous injection, such as buffer solutions. Non-limiting examples of solutions for intravenous injection include phosphate buffer solutions and saline buffer solutions. In certain embodiments, the solution is buffered with multiple salts.

[0805] Accordingly, the present disclosure provides a pharmaceutical composition comprising an effective amount of a degradable compound or a pharmaceutically acceptable salt thereof, along with at least one pharmaceutically acceptable carrier for any suitable application thereof. The pharmaceutical composition may comprise the compound or salt as the sole active agent, or, in alternative embodiments, the compound and at least one additional active agent.

[0806] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a described compound that, within the bounds of sound medical judgment, is suitable for administration to a host such as a human without excessive toxicity, irritation, or allergic reactions, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. Therefore, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts of the compounds disclosed herein. These salts can be prepared during the final isolation and purification of the compound, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid and isolating the resulting salt. Basic compounds can form a wide range of salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by conventional methods by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by conventional methods by contacting the salt form with a base and isolating the free base. The free base forms may differ from their respective salt forms in certain physical properties, such as solubility in polar solvents. Pharmaceutically acceptable base addition salts can be formed from metals or amines, such as alkali and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Base addition salts of acidic compounds are prepared by conventional methods by contacting the free acid form with a sufficient amount of the desired base to produce a salt. The free acid form can be regenerated by conventional methods by contacting the salt form with an acid and isolating the free acid. The free acid forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents.

[0807] Salts can be prepared from inorganic acids such as sulfate ions, pyrosulfate ions, bisulfate ions, sulfite ions, bisulfite ions, nitrate ions, phosphate ions, monohydrogen phosphate ions, dihydrogen phosphate ions, metaphosphate ions, pyrophosphate ions, chloride ions, bromide ions, iodide ions, nitrate ions, phosphate ions, sulfate ions, hydrobromide ions, hydroiodide ions, and phosphorus-containing acid ions. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, and isethionate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Typical salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkalis and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine, and may also include non-toxic ammonium, quaternary ammonium, and amine cations. Salts of amino acids such as arginates, glucons, and galacturons are also considered. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19 (which is incorporated herein by reference).

[0808] Any dosage form can be used to achieve the desired result. In certain embodiments, the pharmaceutical composition exists in dosage forms containing about 0.1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the active compound and optionally about 0.1 mg to about 1500 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of additional active substances in a unit dosage form. Examples include dosage forms containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or a salt thereof.

[0809] In certain embodiments, the dose is in the range of about 0.01 mg to 100 mg per kg of patient body weight, for example, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about The dosages are approximately 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg.

[0810] In some embodiments, the compounds used as disclosed or described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds used as disclosed or described herein are administered at least once a day for a period of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer.

[0811] In certain embodiments, the compound of the present invention is administered once, twice, three times, or four times a day.

[0812] Pharmaceutical compositions may be formulated in any pharmaceutically useful form, such as pills, capsules, tablets, injections or infusions, syrups, inhalations, suppositories, buccal or sublingual preparations, parenteral preparations, or in medical devices. Some dosage forms, such as tablets and capsules, may be repackaged into appropriate unit doses of a suitable size containing an appropriate amount of the active ingredient, for example, an amount effective to achieve the desired purpose.

[0813] Examples of carriers include additives and diluents, which must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert, or it may have its own pharmaceutically beneficial properties. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of the material administered per unit dose of the compound. When supplied in liquid form, it may be a solution or suspension.

[0814] Typical carriers include phosphate-buffered saline, water, solvents (sometimes multiple), diluents, pH adjusters, preservatives, antioxidants, suspending agents, wetting agents, viscosity agents, tonic agents, stabilizers, and combinations thereof. In some embodiments, the carrier is an aqueous carrier. Examples of aqueous carriers, but not limited to, include aqueous solutions or aqueous suspensions, such as saline, plasma, bone marrow aspirate, buffers, such as Hanks buffer solution (HBSS), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringer's buffer, ProVisc®, diluted ProVisc®, ProVisc® diluted in PBS, Krebs buffer, Dulbecco's PBS, standard PBS, sodium hyaluronate solution (HA, 5 mg / mL in PBS), citrate buffer, pseudo-body fluids, plasma platelet concentrates and tissue culture media, or aqueous solutions or aqueous suspensions containing organic solvents. Acceptable solutions include, for example, water, Ringer's solution, and isotonic sodium chloride solution. The formulation may also be a sterile solution, sterile suspension, or sterile emulsion in a non-toxic diluent or solvent such as 1,3-butanediol.

[0815] If desired, a thickener may be added to the pharmaceutical composition to increase its viscosity. Examples of useful thickeners, but not limited to, include hyaluronic acid, sodium hyaluronate, carbomer, polyacrylic acid, cellulose derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextin, polysaccharides, polyacrylamide, polyvinyl alcohol (including partially hydrolyzed polyvinyl acetate), polyvinyl acetate, derivatives thereof, and mixtures thereof.

[0816] The administered solution, suspension, or emulsion may be buffered in an effective amount necessary to maintain a pH suitable for the selected administration. Suitable buffers are well known to those skilled in the art. Some examples of useful buffers are acetate buffer, borate buffer, carbonate buffer, citrate buffer, and phosphate buffer. Solutions, suspensions, or emulsions administered topically, for example ocularly, may also contain one or more tonic agents to adjust the isotonic range of the formulation. Suitable tonic agents are well known in the art. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes.

[0817] Examples of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be of two or more types; for example, vegetable oil can be used as a lubricant in some formulations and as a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc, and vegetable oils. Any active ingredient that does not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical composition.

[0818] Pharmaceutical compositions / combination pharmaceuticals can be formulated for oral administration. These pharmaceutical compositions may contain any amount of the active compound to achieve the desired result, e.g., between 0.1% (wt.%) and 99% (wt.%) of the compound, typically at least about 5% (wt.%) of the compound. Some embodiments contain about 25% to about 50% (wt.), or about 5% to about 75% (wt). Enteric-coated oral tablets can also be used to increase the bioavailability of the compound for the oral administration route.

[0819] Formulations suitable for rectal administration are typically provided as suppositories of a unit dose. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then excipienting the resulting mixture.

[0820] VII. Therapy of Diseases with Disclosed ASGPR-Binding Extracellular Protein Degraders The target proteins of the present invention may include, but are not limited to, immunoglobulins, cytokines, chemokines, growth factors, coagulation factors, extracellular matrix proteins, and proteins, esterases, lipases, peptidases, and convertases involved in the formation and / or degradation of the extracellular matrix. These proteins mediate a wide range of diseases that can be treated with an effective amount of the disclosed ASGPR-binding extracellular protein degrader described herein.

[0821] Immunoglobulins 1) Abnormal expression of immunoglobulin A (IgA) mediates a wide range of autoimmune and immune-mediated disorders, including, in particular, IgA nephropathy (also known as Buerger's disease), celiac disease, Crohn's disease, Henoch-Schöne purpura (HSP) (also known as IgA vasculitis), linear IgA bullous dermatosis, IgA pemphigus, herpetiform dermatitis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic cirrhosis, acquired immunodeficiency syndrome, IgA type multiple myeloma, alpha-chain disease, IgA monoclonal gammaglobulinemia, monoclonal gammaglobulinemia of unknown significance (MGUS), and linear IgA bullous dermatosis.

[0822] 2) Immunoglobulin G (IgG) mediates a wide range of autoimmune diseases, infectious diseases, and metabolic diseases, including systemic fibroinflammatory diseases. Furthermore, IgG4 overexpression is generally associated with multi-organ IgG4-related disorders, including, in particular, type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, mat-like fibrosis, Mikulicz's disease, Küttner tumor, inflammatory pseudotumor (in various parts of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond's disease), aortitis and periaortitis, proximal bile duct stenosis, idiopathic hypocomplementary tubulointerstitial nephritis, multifocal fibrosclerosis, meningitis, pancreatic enlargement, mass-like lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren's syndrome, psoriatic arthritis, and systemic lupus erythematosus (SLE), sclerosing cholangitis, and IgG monoclonal gammaglobulinemia and monoclonal gammaglobulinemia of unknown significance (MGUS).

[0823] 3) Immunoglobulin E (IgE) - IgE is a potent mediator of allergic diseases, including, but not limited to, atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergies, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, and eosinophilic gastrointestinal diseases, bullous pemphigoid, chemotherapy-induced hypersensitivity reactions, seasonal allergic rhinitis, interstitial cystitis, eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic embolic pulmonary disease, gastroenteritis, hyper-IgE syndrome (Job's syndrome), IgE monoclonal gammaglobulinemia, and monoclonal gammaglobulinemia of unknown significance (MGUS).

[0824] Cytokines / chemokines 1) TNF-α mediates a number of disorders, including, but not limited to, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupus erythematosus, diabetes mellitus, and the induction of cachexia.

[0825] 2) IL-2 mediates host-versus-graft rejection in transplantation, as well as autoimmune disorders, including, but not limited to, multiple sclerosis, idiopathic arthritis, iritis, anterior uveitis, IL-2-induced hypotension, psoriasis, and other autoimmune disorders.

[0826] 3) IL-1 mediates, but is not limited to, numerous autoinflammatory and autoimmune disorders, including Blau syndrome, cryopyrin-associated periodic syndromes, familial Mediterranean fever, Magid syndrome, mevalonate kinase deficiency syndrome, suppurative arthritis-pyoderma gangrenosum-acne syndrome, tumor necrosis factor receptor-associated periodic syndromes, Behçet's disease, Sjögren's syndrome, gout and chondrocalcinosis, periodic fever, aphthous stomatitis, pharyngitis, and cervical lymphadenitis (or PFAPA) syndrome, rheumatoid arthritis, type 2 diabetes mellitus, acute pericarditis, chronic interstitial lung disease (ILD), and Still's disease.

[0827] 4) IFN-γ mediates a wide range of autoimmune disorders, including, but not limited to, rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, and acne vulgaris.

[0828] 5) IL-21 mediates numerous autoimmune disorders, including Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

[0829] 6) IL-22 mediates numerous autoimmune disorders, including, but not limited to, graft-versus-host disease (GVHD), psoriasis, rheumatoid arthritis, atopic dermatitis, and asthma.

[0830] 7) IL-10 is thought to be involved in tumor survival and protection against cytotoxic chemotherapy drugs.

[0831] 8) IL-5 is thought to be associated with a number of allergic disorders, including, but not limited to, asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, eosinophilic syndrome, and Churg-Strauss syndrome.

[0832] 9) IL-6 is thought to be associated with numerous inflammatory diseases and cancers, including, but not limited to, Castleman disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large cell lung cancer, ovarian cancer, rheumatoid arthritis, and asthma.

[0833] 10) IL-8 is thought to be involved in tumor progression, immune evasion, epithelial-mesenchymal transition, and promotion of myeloid suppressor cell recruitment. Studies have confirmed that high serum IL-8 levels are correlated with poor prognosis in many malignancies. Preclinical studies have shown that blocking IL-8 reduces mesenchymal characteristics in tumor cells and may lead to lower resistance to treatment.

[0834] 11) CC motif chemokine ligand 2 (CCL2) is thought to be involved in the recruitment of monocytes to the arterial wall during the disease process of atherosclerosis.

[0835] 12) Macrophage migration inhibitory factors (MIFs) are mediators of tumor progression, systemic inflammation, atherosclerosis, rheumatoid arthritis, and systemic lupus erythematosus, among other things.

[0836] growth factors 1) Fibroblast growth factor 1 (FGF1) can induce angiogenesis. FGF1 is thought to be involved in carcinogenesis, cancer cell proliferation, resistance to anticancer therapy, and angiogenesis.

[0837] 2) Fibroblast growth factor 2 (FGF2) is thought to be involved in carcinogenesis, cancer cell proliferation, resistance to anticancer therapy, and angiogenesis.

[0838] 3) Vascular epithelial growth factor (VEGF-A) is thought to be involved in tumor vascularization and angiogenesis.

[0839] 4) Transforming growth factor-β1 (TGF-β1) expression in the tumor microenvironment is associated with poor prognosis and is involved in TGF-β1-mediated tumor suppression via T cell depletion. TGF-β1 expression is also known to be related to hematological malignancies and fibrosis.

[0840] 5) Transforming growth factor-β2 (TGF-β2) expression in the tumor microenvironment is associated with poor prognosis and is involved in TGF-β2-mediated tumor suppression via T cell depletion. TGF-β2 expression is also thought to be related to hematological malignancies and fibrosis.

[0841] 6) Placental growth factor (PGF) is also thought to promote the growth of cell tumors and is associated with age-related macular degeneration (AMD) and choroidal neovascularization (CNV).

[0842] Esterase 1) Cholinesterase is thought to be related to cognitive impairments such as dementia and Alzheimer's disease.

[0843] clotting factors 1) Carboxypeptidase B2 is thought to be involved in the suppression of thrombosis and is therefore targeted.

[0844] 2) Coagulation factor Xa is a mediator in the development of deep vein thrombosis and acute pulmonary embolism, as well as in the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0845] 3) Coagulation factor XI is a mediator in the development of deep vein thrombosis and acute pulmonary embolism, as well as in the risk of stroke and embolism in individuals with non-valvular atrial fibrillation.

[0846] 4) Coagulation factor XII is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[0847] 5) Coagulation factor XIII is associated with the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[0848] 6) Prothrombin is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0849] 7) Coagulation factor VII is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0850] 8) Coagulation factor IX is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0851] Extracellular matrix proteins 1) Neutrophil elastase - Neutrophil elastase is associated with numerous disorders, including lung diseases, chronic obstructive pulmonary disease, pneumonia, dyspnea, and acute lung injury (ALI), as well as cystic fibrosis and chronic kidney disease.

[0852] 2) Inhibiting fibronectin-1-FN polymerization may reduce myofibroblast activity and fibrosis, and may improve cardiac function after ischemia / reperfusion (I / R) injury.

[0853] 3) Thrombospondin-1 (TSP-1) is thought to be involved in the promotion of certain cancers such as breast cancer, prostate cancer, melanoma, SCLC, osteosarcoma, cutaneous squamous cell carcinoma, oral squamous cell carcinoma, papillary thyroid carcinoma, thyroid cancer, and medulloblastoma, as well as in numerous diseases including diabetes mellitus, hepatic fibrosis and other fibrotic disorders, and multiple myeloma.

[0854] 4) Urokinase-type plasminogen activator (UPA) - UPA is thought to be associated with vascular disease and cancer progression. Elevated expression levels of urokinase and several other components of the plasminogen activator have been found to correlate with tumor malignancy.

[0855] 5) Plasminogen activator, histological type (TPA) - PLA has been shown to be activated in various cancers, including oral malignancies.

[0856] 6) Plasminogen (PLG) - PLG is thought to be involved in tumor invasion and inflammation.

[0857] 7) Plasminogen activator inhibitor-1 (PAI-1) - PAI-1 is associated with angiogenesis, metastasis, and poor prognosis in tumors, including oral cancer and breast cancer, though not limited to these.

[0858] Peptidase 1) Kallikrein-1 - Kallikrein is thought to be associated with adverse reactions in hereditary angioedema (HAE).

[0859] 2) Plasma kallikrein - Plasma kallikrein is thought to be associated with the development of retinal dysfunction, diabetic macular edema, and hereditary angioedema (HAE).

[0860] 3) Matrix metallopeptidase-1 (MMP-1) is thought to be involved in the development of cardiovascular disease, fibrosis, and the growth of certain cancers, such as bladder cancer.

[0861] 4) Phospholipase A2, group IIA (PA2GA) - PA2GA is thought to be associated with numerous diseases, including cardiovascular disease, atherosclerosis, immune disorders, and cancer.

[0862] Lipase 1) Lipoprotein lipase - Lipoprotein lipase is thought to be involved in the development of cardiovascular disease and obesity.

[0863] 2) Phospholipase A2, group IB (PA21B) - PA21B is thought to be associated with numerous diseases, including cardiovascular disease, atherosclerosis, immune disorders, and cancer.

[0864] converting enzyme 1) Proprotein convertase subtilisin / kexin type 9 (PCSK-9) - PCSK-9 is associated with high blood cholesterol levels and the development of cardiovascular disease.

[0865] Certain extracellular protein targets are not limited to, but include: SAA (serum amyloid A), amyloid light chain, antibodies against Klebsiella dipeptidase protein, Ig antibodies against anionic phospholipids and β2 glycoprotein I, IL-13, MIF, (misfolded) transthyretin, thyroid peroxidase, thyroglobulin, and IgG autoantibodies against TSH receptor, TNF-α, protein arginine deiminase (PAD, PAD4), antibodies against citrullinated protein antibodies (ACPA), anti-DNA antibodies, IL-17, lysyl oxidase 2 (LOXL2), IL-18, Blys, B cell activator (BAFF), CD40 (soluble), CXCL12, soluble PSMA, and matrix metalloproteinase I. X (MMP-9), hormone-sensitive lipase, lipoprotein-associated phospholipase A2, factor Xa, DPP4, thrombin, PCSK9, ApoB-100, complement component C3b, PKK (prekallikrein), factor XI, PF4, anti-vWF antibody, anti-cardiolipin antibody and lupus anticoagulant, FGF23 (fibroblast growth factor 23), plasminogen activator inhibitor type 1 (PAI-1), extracellular myeloperoxidase (MPO), myostatin, Beta2-m, suPAR (soluble urokinase plasminogen activator receptor), anti-ganglioside IgG, amyloid β, tau, CJD-related prion, anti-ganglioside IgG, HTT, anti-ganglioside IgG, synuclein, elastase, PABA (Bacillus anthracis (Bacillus) Examples include anthracis protective antigens, edema factors, botulinum toxin, C. difficile toxin B, hemolysin, tetanus toxin, IL-2, growth hormone, and ACTH.

[0866] VIII. Exemplary methods for treating extracellular protein-mediated diseases The present invention can be used to treat any disorder mediated by selected target disease-mediated extracellular proteins. Non-limiting examples of indications include autoimmunity, other immunodeficiencies, complement-mediated disorders, abnormal cell proliferation, cancer, tumors, hematological disorders, renal disorders, and hepatic disorders.

[0867] In certain embodiments, the degraders or salts or compositions described herein are used in the treatment of autoimmune disorders. In some embodiments, the extracellular protein is Ig, such as IgA or IgG. Degradation of IgG can treat, for example, thyroid eye disease, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and warm autoimmune hemolytic anemia.

[0868] Non-exclusive examples of autoimmune diseases include lupus, allograft rejection, autoimmune thyroid diseases (e.g., Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, focal colitis, granulomatous colitis, distal ileitis, focal ileitis, and terminal ileitis), diabetes mellitus, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis, and scleroderma.

[0869] In one embodiment, the degraders or salts or compositions described herein are used in the treatment of lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, chilblain lupus erythematosus, or lupus erythematosus-lichen planus overlap syndrome. Lupus erythematosus is a general category of disease that includes both systemic and cutaneous disorders. The systemic form of this disease may have systemic symptoms as well as cutaneous symptoms. However, there are also forms of the disease that are cutaneous only and do not have systemic lesions. For example, SLE is an inflammatory disorder of unknown etiology that occurs mainly in women and is characterized by joint symptoms, butterfly rash, recurrent pleurisy, pericarditis, systemic lymphadenopathy, splenomegaly, and CNS lesions and progressive renal failure. The serum of the majority of patients (over 98%) contains antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific to SLE. Conventional treatments for this disease have involved the administration of corticosteroids or immunosuppressants.

[0870] There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a chronic disorder that primarily affects the skin and impairs appearance, characterized by well-defined macules and plaques showing erythema, keratinization, scaling, telangiectasia, and atrophy. This condition is often triggered by sun exposure, and the initial lesions are erythematous, circular, desquamating papules 5-10 mm in diameter, showing keratinization. DLE lesions are most commonly found on the cheeks, nose, scalp, and ears, but can also be systemic, extending to the upper trunk, extensor surfaces of the limbs, and oral mucosa. If left untreated, the central lesions atrophy and leave scars. Unlike SLE, antibodies against double-stranded DNA (e.g., DNA binding assays) are almost without exception absent in DLE.

[0871] Multiple sclerosis (MS) is an autoimmune demyelinating disorder thought to be T lymphocyte-dependent. MS generally presents with a relapsing-remitting or chronically progressive course. The etiology of MS is unknown, but viral infection, genetic predisposition, environmental factors, and autoimmunity all appear to contribute to this disorder. Lesions in MS patients primarily consist of T lymphocyte-mediated microglial and infiltrating macrophage infiltrations. CD4 + T lymphocytes are the dominant cell type present in these lesions. A characteristic feature of MS lesions is the presence of plaques, which are demyelinated areas with very clear boundaries from normal white matter, as seen on MRI scans. Histological findings of MS plaques vary depending on the stage of the disease. In active lesions, the blood-brain barrier is damaged, causing serum proteins to leak into the extracellular space. Inflammatory cells can be seen in the perivascular cuff and throughout the white matter. CD4 + T cells, particularly Th1 cells, accumulate around the posterior capillary venules at the plaque edges and are also scattered throughout the white matter. In active lesions, adhesion molecules, as well as markers of lymphocyte and monocyte activation, such as IL2-R and CD26, are observed to be upregulated. Demyelination in active lesions does not involve the destruction of oligodendrocytes. In contrast, in the chronic phase of the disease, lesions are characterized by the loss of oligodendrocytes and, consequently, the presence of myelin oligodendrocyte glycoprotein (MOG) antibodies in the blood.

[0872] Diabetes mellitus may refer to either type 1 or type 2 diabetes mellitus. In some embodiments, the degrader or salt or composition described herein is administered in a dose effective for the treatment of a patient with type 1 diabetes mellitus. In one embodiment, the degrader or salt or composition described herein is administered in a dose effective for the treatment of a patient with type 2 diabetes mellitus.

[0873] Type 1 diabetes is an autoimmune disease. Autoimmune diseases occur when the body's immune system, which fights infection, becomes hostile to a part of the body. In this case, the pancreas produces little to no insulin.

[0874] Examples include the degrader or salt or composition described herein for autoimmune oophoritis, endometriosis, autoimmune orchitis, and ord's thyroiditis. Thyroiditis, autoimmune enteropathy, celiac disease, Hashimoto's encephalopathy, antiphospholipid syndrome (APLS) (Hughes' syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canal-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis (Darcum's disease), adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Schulman syndrome), Felty syndrome, IgG4-related disease, mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis (Hentch-Rosenberg syndrome), Parry-Romberg syndrome, Personage-Turner syndrome, relapsing polychondritis (Maienburg-Alter-Eulinger syndrome), retroperitoneal fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia (Isaac's disease) Diseases)), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus-related disorder, chikungunya virus-related disorder, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatic vasculitis, alopecia areata, autoimmune progesterone dermatitis, herpetiform dermatitis, erythema nodosum, bullous pemphigoid of pregnancy, suppurative Hidradenitis, lichen sclerosing, linear IgA disease (LAD), focal scleroderma, myositis, acute pityriasis lichenoides, post-dressler syndrome, autoimmune retinopathy, Cogan syndrome, Graves' ophthalmopathy, woody conjunctivitis, Mohren's ulcer, opsoclonus-myoclonus syndrome, optic neuritis, retinocochleocerebral vascular diseaseVasculopathy (Suzack syndrome), sympathetic ophthalmia, Tolosa-Hunt syndrome, interstitial lung disease, antisynthesis syndrome, Addison's disease, APS type I, APS type II, APS type III, disseminated sclerosis (multiple sclerosis, pattern II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-associated arthritis, reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus It is useful in the treatment or prevention of disorders selected from lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartate receptor encephalitis, Barlow concentric sclerosis (Schilder's disease), Vickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorders (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham syndrome, transverse myelitis, lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, or ischemia-reperfusion injury of the eye.

[0875] In certain embodiments, an effective amount of the degrader or salt or composition thereof described herein is used to treat a medical disorder mediated by a targeted extracellular protein. For example, when the targeted extracellular protein is a complement protein, such as complement factor B, factor D, factor H, C1s, C3, or C5, the medical disorder to be treated may be an inflammatory or immunopathological condition, a disorder mediated by a complement cascade (including a dysfunctional cascade), or an alternative complement pathway-related disorder, a cellular disorder or abnormality that adversely affects the ability of cells to participate in or respond to normal complement activity, or an unwanted complement-mediated response to medical treatment such as surgery or other medical procedures, or administration of pharmaceuticals or biopharmaceuticals, blood transfusions, or administration of other allogeneic tissues or fluids.

[0876] In some embodiments, the disorders treated by the degraders or salts or compositions described herein are selected from fatty liver and conditions resulting from fatty liver, such as non-alcoholic steatohepatitis (NASH), hepatitis, cirrhosis, and hepatic failure.

[0877] In another embodiment, the degraders or salts or compositions described herein are used to modulate the immune response before or during surgical or other medical procedures. A non-limiting example is use in relation to acute or chronic graft-versus-host disease, a common complication resulting from allogeneic tissue transplantation, which can also occur as a result of blood transfusions.

[0878] In certain embodiments, the present invention provides a method for treating or preventing dermatomyositis by administering an effective amount of the degrader or a salt or composition thereof described herein to a subject in need of treatment or prevention of dermatomyositis.

[0879] In certain embodiments, the present invention provides a method for treating or preventing amyotrophic lateral sclerosis (ALS) by administering an effective amount of the degrader or a salt or composition thereof described herein to a subject in need of treatment or prevention of ALS.

[0880] In certain embodiments, the present invention provides a method for treating or preventing abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis by administering an effective amount of the degrader described herein or its salt or composition to a subject requiring treatment or prevention of hemodialysis for abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis.

[0881] In certain embodiments, a method is provided for treating or preventing a cytokine response or inflammatory response in a host in response to the administration of a pharmaceutical or biological agent (e....

Claims

1. formula: 【Chemistry 1】 【change】 【change】 (In the formula, R １ It is selected from the group consisting of hydrogen, alkyl, alkenyl, and haloalkyl, R ２ -NR ６ - Selected from the group consisting of heteroaryls, alkyl, haloalkyl, -OR ６ , F, Cl, and -NR ６ It is optionally substituted with one or two substituents independently selected from the group consisting of R7, R ３ In each case, independently, is hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, alkenyl, aryl, heteroaryl, heterocycle, -OR ８ and -NR ８ R ９ selected from the group consisting of, R ６ and R ７ These are independently, in each case, hydrogen, alkyl, arylalkyl, alkenyl, aryl, haloalkyl, heteroaryl, heterocyclic, and C(O)R ３ Selected from the group consisting of, R ８ and R ９ Independently, in each case, is selected from the group consisting of hydrogen, alkyl, arylalkyl, alkenyl, aryl, heteroaryl, and heterocycle. Linker Ａ It is a combination, Linker Ｂ teeth, 【Chemistry 2】 And, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ These are independently, in each case, bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR ６ -, -NR ６ C(O)-, -O-, -S-, -NR ６ -, -C(R ２１ R ２１ )-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, -[-(CH ２ ) ２ -O-] ｎ -, and -[O-(CH ２ ) ２ ] ｎ - Selected from the group consisting of, R ２１ It is optionally substituted with one or two substituents independently selected from the above, n is independently selected from 0, 1, 2, 3, 4, or 5 in each case. R ２１ Independently, in each case, hydrogen, alkyl, alkenyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR ６ R ７ , -NR ８ SO ２ R ３ , -NR ８ S(O)R ３ Selected from the group consisting of haloalkyl, aryl, heteroaryl, and heterocyclic compounds, Linker Ｃ teeth, 【Transformation 3】 Selected from, R ２２ These are alkyl, -C(O)N-, -NC(O)-, -N-, -C(R ２１ Selected from the group consisting of )-, -P(O)-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, respectively, R ２１ It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. Linker Ｄ teeth, 【Chemistry 4】 Selected from, R ３２ These are, independently, alkyl and N in each case. ＋ X － Selected from the group consisting of -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, each of the following is R ２１ It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. X － It is an anionic group, An extracellular protein-targeting ligand is a chemical portion that binds to a disease-modifying extracellular protein that is being targeted. Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R ６ The compound according to claim 1, wherein is hydrogen.

3. R １ The compound according to claim 1 or 2, wherein is hydrogen.

4. Heteroaryl compounds substituted with one or two substituents are 【Transformation 5】 A compound according to any one of claims 1 to 3, selected from the group consisting of the following.

5. Heteroaryls include alkyl, haloalkyl, and -OR. ６ , F, Cl, and -NR ６ R ７ The compound according to any one of claims 1 to 3, which is a pyrazine that is optionally substituted with one or two substituents independently selected from the group consisting of the following.

6. The compound according to claim 5, wherein the pyrazine is substituted with trifluoromethyl.

7. Heteroaryls include alkyl, haloalkyl, and -OR. ６ , F, Cl, and -NR ６ R ７ The compound according to any one of claims 1 to 3, which is a pyrimidine optionally substituted with one or two substituents independently selected from the group consisting of the following.

8. Heteroaryls include alkyl, haloalkyl, and -OR. ６ , F, Cl, and -NR ６ R ７ The compound according to any one of claims 1 to 3, which is a pyridine that is optionally substituted with one or two substituents independently selected from the group consisting of the following.

9. The compound according to claim 4, wherein the one or two substituents are independently selected from the group consisting of haloalkyls and halogens.

10. The compound according to claim 9, wherein the haloalkyl is trifluoromethyl.

11. formula: 【Transformation 6】 A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Linker Ｂ The compound according to claim 11, selected from the group consisting of the following. 【Transformation 7】

13. Linker Ｂ The compound according to claim 11, selected from the group consisting of the following. 【Transformation 8】

14. formula: 【Chemistry 9】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. Linker C is a compound according to claim 14, selected from the following. 【Chemistry 10】

16. Linker C is a compound according to claim 14, selected from the following. 【Chemistry 11】

17. formula: 【Chemistry 12】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. Linker D is a compound according to claim 17, selected from the following. 【Chemistry 13】 (In the formula, R ３２ These are, independently, alkyl and N in each case. ＋ X － Selected from the group consisting of -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, each of the following is R ２１ It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. X － (This is an anionic group.)

19. The extracellular protein-targeting ligand is a compound according to any one of claims 1 to 18, which targets an immunoglobulin.

20. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets IgA.

21. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets IgG.

22. The compound according to claim 21, wherein the extracellular protein targeting ligand that targets IgG is Fc-III.

23. The compound according to claim 21, wherein the extracellular protein targeting ligand that targets IgG is Fc-III-4C.

24. The compound according to claim 21, wherein the extracellular protein targeting ligand that targets IgG is Fc-BP-2.

25. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets IgE.

26. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets TNF-α.

27. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets IL-1b, IL-2, or IL-6.

28. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets IFN-γ or VEGF.

29. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets TGF-β1.

30. The extracellular protein targeting ligand is a compound according to any one of claims 1 to 18, which targets PCSK-9.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by a targeted disease-modifying extracellular protein.

33. The extracellular protein is IgG, and the disorders include type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, mat-like fibrosis, Mikulicz's disease, Küttner tumor, inflammatory pseudotumor, mediastinal fibrosis, retroperitoneal fibrosis (Ormond's disease), aortitis, periaortitis, proximal bile duct stenosis, idiopathic hypocomplementary tubulointerstitial nephritis, multifocal fibrosclerosis, meningitis, pancreatic enlargement, mass-like lesions, pericarditis, and rheumatoid arthritis (RA). The pharmaceutical composition according to claim 32, selected from inflammatory bowel disease, multiple sclerosis, myasthenia gravis, thyroid eye disease, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, ankylosing spondylitis, primary Sjögren's syndrome, psoriatic arthritis, and systemic lupus erythematosus (SLE), sclerosing cholangitis, and IgG monoclonal gammaglobulinemia, monoclonal gammaglobulinemia of unspecified significance (MGUS).

34. The pharmaceutical composition according to claim 32, wherein the extracellular protein is IgA, and the disorder is selected from IgA nephropathy (Buerger's disease), celiac disease, Crohn's disease, Henoch-Schöne purpura (HSP), linear IgA bullous dermatosis, IgA pemphigus, herpetiform dermatitis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic cirrhosis, acquired immunodeficiency syndrome, IgA type multiple myeloma, alpha chain disease, IgA monoclonal gammaglobulinemia, monoclonal gammaglobulinemia of unknown significance (MGUS), and linear IgA bullous dermatosis.

35. The pharmaceutical composition according to claim 32, wherein the extracellular protein is IgE, and the disorder is selected from atopic asthma, allergic rhinitis, atopic dermatitis, IgE-mediated food allergy, IgE-mediated animal allergy, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, and eosinophilic gastrointestinal diseases, bullous pemphigoid, chemotherapy-induced hypersensitivity reactions, seasonal allergic rhinitis, interstitial cystitis, eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic embolic pulmonary disease, gastroenteritis, hyper-IgE syndrome (Job syndrome), IgE monoclonal gammaglobulinemia, and monoclonal gammaglobulinemia of unknown significance (MGUS).

36. The pharmaceutical composition according to claim 32, wherein the disorder is dementia or Alzheimer's disease.

37. The pharmaceutical composition according to claim 32, wherein the extracellular protein is TNF-α, and the disorder is selected from rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupus erythematosus, diabetes mellitus, and the induction of cachexia.

38. The pharmaceutical composition according to claim 32, wherein the extracellular protein is IL-2, and the disorder is selected from, but is not limited to, host-versus-graft rejection in transplantation, and autoimmune disorders including, multiple sclerosis, idiopathic arthritis, iritis, anterior uveitis, IL-2-induced hypotension, and psoriasis.

39. The pharmaceutical composition according to claim 32, wherein the extracellular protein is IL-6, and the disorder is selected from Castleman disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large cell lung cancer, ovarian cancer, rheumatoid arthritis, and asthma.

40. The pharmaceutical composition according to claim 32, wherein the extracellular protein is IFN-γ, and the disorder is selected from rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, and acne vulgaris.

41. The pharmaceutical composition according to claim 32, wherein the disorder is cancer.

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