A potent ASGPR-binding compound that degrades immunoglobulins and other proteins.

Abstract

Provided are extracellular protein degraders and compositions having a potent asialoglycoprotein receptor (ASGPR) binding ligand coupled to an extracellular protein targeting ligand that selectively degrade target extracellular proteins, such as immunoglobulins, in vivo to treat disorders mediated by extracellular proteins.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 63 / 331,592 filed on 15 April 2022, U.S. Provisional Patent Application No. 63 / 293,447 filed on 23 December 2021, U.S. Provisional Patent Application No. 63 / 228,067 filed on 31 July 2021, and U.S. Provisional Patent Application No. 63 / 183,450 filed on 3 May 2021. These applications in their entirety constitute part of this specification by reference for all purposes.

[0002] The present invention provides extracellular protein degraders and compositions having an asialoglycoprotein receptor (ASGPR)-binding ligand bound to an extracellular protein-targeting ligand, for selectively degrading target extracellular proteins, such as immunoglobulins or other extracellular proteins, in vivo to treat protein-mediated disorders.

[0003] [References] The text file is named "19121-007WO1_SequenceListing_ST25", was created on May 2, 2022, is 92.1KB in size, and its entire contents constitute part of this specification. [Background technology]

[0004] Historically, therapeutic strategies involving protein inhibition have utilized small molecule inhibitors that bind in the enzyme pocket or at allosteric sites. These non-enzymatic proteins are difficult to control, and some have been considered "drug-undetectable." However, many non-enzymatic proteins remain valuable targets for drug discovery due to their roles in signaling pathways. Immunoglobulins are important non-enzymatic drug targets due to their role in signaling throughout the body's immune response.

[0005] Asialoglycoprotein receptor (ASGPR) is expressed primarily in parenchymal hepatocytes. 2+ It is a receptor-dependent lectin. The main role of ASGPR is to assist in the regulation of serum glycoprotein levels by mediating the endocytosis of desialylated glycoproteins. The receptor binds ligands having terminal galactose or N-acetylgalactosamine. After binding to ASGPR, asialoglycoproteins are cleared by receptor-mediated endocytosis. The receptor and protein dissociate in the acidic endosomal compartment, and the protein is ultimately degraded by lysosomes. Publications describing various uses of the ASGPR mechanism include Patent Documents 1, 2, 3, 4, and 5, Non-Patent Documents 1 and 2, Patent Documents 6 and 7, which were transferred to Pfizer Inc. and Wave Life Sciences Ltd., Patent Document 8, Non-Patent Documents 3 and 4, which were transferred to Wave Sciences Ltd., Patent Documents 9, 10, 11, and 12, which were transferred to Yale University, Patent Document 13 and Non-Patent Document 5, which were transferred to the Board of Directors of Leland Stanford Junior University, and the paper from Bertozzi's group titled "LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation" (Non-Patent Document 6), published in Nature Chemical Biology.

[0006] While some progress has been made in the field of targeted degradation of extracellular proteins, there is still a need for further therapeutic compounds, methods of use, and methods of production to degrade extracellular proteins and treat the disorders mediated by these proteins. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 9,340,553 [Patent Document 2] U.S. Patent No. 9,617,293 [Patent Document 3] U.S. Patent No. 10,039,778 [Patent Document 4] U.S. Patent No. 10,376,531 [Patent Document 5] U.S. Patent No. 10,813,942 [Patent Document 6] International Publication No. 2018 / 223073 [Patent Document 7] International Publication No. 2018 / 223081 [Patent Document 8] International Publication No. 2018 / 223056 [Patent Document 9] International Publication No. 2019 / 199621 [Patent Document 10] International Publication No. 2019 / 199634 [Patent Document 11] International Publication No. 2021 / 072246 [Patent Document 12] International Publication No. 2021 / 072269 [Patent Document 13] International Publication No. 2020 / 132100 [Non-patent literature]

[0008] [Non-Patent Document 1] Sanhueza et al. (JACS, 2017, 139, 3528) [Non-Patent Document 2] Petrov et al. (Bioorganic and Medicinal Chemistry Letters, 2018, 28, 382) [Non-Patent Document 3] Schmidt et al. (Nucleic Acids Research, 2017, 45, 2294) [Non-Patent Document 4] Huang et al. (Bioconjugate Chem. 2017, 28, 283) [Non-Patent Document 5] Banik et al. (Nature, 2020, 584, 291) [Non-Patent Document 6] Ahn, et al. Nat. Chem. Biol. (2021) [Overview of the project]

[0009] Novel extracellular protein degraders and pharmaceutically acceptable salts thereof, as well as compositions thereof, for degrading target extracellular proteins, such as IgG, IgA, IgE, TNF-α, factor XIa, complement factor D, complement factor B, or other proteins described below, are also provided, as well as starting materials and intermediates for such extracellular protein degraders, and methods for using and preparing them. The extracellular protein degraders of the present invention comprise an ASGPR-binding ligand covalently attached to an extracellular protein targeting ligand by a linker. Examples of ASGPR-binding ligands used in the degraders described herein include derivatives of a 6-carbon pyranose moiety, specifically galactose and talose. These two sugars, shown below, are C 2 The only difference is the stereochemistry of the substituents. "Downward" C 2 The configuration corresponds to the stereochemistry of galactose, while the C has an "upward" configuration. 2 The substituents correspond to the stereochemistry of taloses. C of these two sugars 2 It was found that a specific substituent at a certain position improves the binding of the ligand ASGPR.

[0010] [ka]

[0011] In some embodiments of the present invention, the extracellular protein targeting ligand targets an immunoglobulin, such as IgG, IgA, or IgE.

[0012] The immunoglobulin-degrading compounds described herein degrade target immunoglobulins, such as IgG or IgA, by linking a ligand for a selected immunoglobulin to a strong ASGPR-binding substance via a specific linking group. In one embodiment of the present invention, the selected immunoglobulin degrades IgG.

[0013] In some embodiments, other extracellular proteins can be degraded, as will be further described below. For example, in non-limiting exemplary embodiments, selected extracellular proteins as generally described herein can be targeted, for example, using selected targeting ligands as shown in Figures 1 to 7, where applicable, or as otherwise known.

[0014] In some embodiments of the present invention, the extracellular protein degrader uses an ASGPR-binding ligand to extracellular protein-targeting ligand ratio of 3:1 or 2:1. By using a large number of ASGPR-binding ligands, the degrader can bind more firmly to ASGPR and thus have enhanced degradation efficiency.

[0015] In other embodiments of the present invention, the extracellular protein degrader of the present invention has a 1:1 ratio of ASGPR-binding ligand to extracellular protein-targeting ligand. In some embodiments, the extracellular protein degrader has a high binding efficiency to ASGPR. 2 It contains heteroarylamine substituents at the 120 position. With these newly discovered substituents, the ligand has sufficient ASGPR binding efficiency to enable molecular degradation at a 1:1 ASGPR-binding ligand to extracellular protein-targeting ligand ratio.

[0016] Conventional biochemical approaches to treating diseases associated with extracellular proteins have been unsuccessful due to their lack of extracellular circulation, size, and / or active site. However, the extracellular protein degraders of the present invention can degrade target extracellular proteins by transporting them to hepatocytes. In some embodiments, these immunoglobulin degraders feature a selected ASGPR ligand characterized by high binding affinity to ASGPR (see Tables 4A and 4B as non-limiting examples). As a result of this high ASGPR binding affinity, the extracellular protein degraders of the present invention can often be administered at lower doses than previously disclosed immunoglobulin degraders, and may have fewer side effects, reduced side effects, enhanced efficacy, faster therapeutic effects, longer metabolic stability, and / or longer therapeutic efficacy.

[0017] In some embodiments of the present invention, selective degraders for immunoglobulin G (IgG) are provided. In certain embodiments, these immunoglobulin degraders have Fc-binding peptides such as Fc-III and Fc-BP2 or derivatives thereof. The Fc-binding peptides bind to the Fc portion of IgG, thereby promoting the selective recruitment of IgG to hepatocytes for degradation. For example, in certain embodiments, the immunoglobulin degrader is [ka] or a pharmaceutically acceptable salt thereof.

[0018] In other embodiments, these immunoglobulin degraders have small molecule or non-peptide IgG targeting ligands. Non-limiting examples of small molecule IgG targeting ligands include: [ka] These are some examples.

[0019] In some embodiments of the present invention, the IgG degrader of the present invention uses a 2:1 ratio of ASGPR-binding ligand to extracellular protein-targeting ligand.

[0020] In another embodiment of the present invention, the IgG degrader of the present invention has a 1:1 ratio of ASGPR-binding ligand to IgG-binding ligand. For example, in a particular embodiment, the immunoglobulin degrader is [ka] or a pharmaceutically acceptable salt thereof.

[0021] Selective targeting of IgG may be particularly beneficial when the present invention is used to treat diseases known to be primarily caused by IgG, such as thyroid eye disease, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, or type 1 autoimmune pancreatitis.

[0022] In certain embodiments, a treatment for IgG-mediated disorders is provided, comprising administering an effective amount of an IgG degrader or a pharmaceutically acceptable salt thereof to a patient. In certain embodiments, IgG disorders include antiphospholipid syndrome, Behçet's syndrome, Hashimoto's thyroiditis, MGUS, necrotizing xanthogranulomatous necrotizing rheumatoid arthritis, cancer, e.g., multiple myeloma or peripheral multiple myeloma, abnormal proteinemia, chronic urticaria, scleroderma, sclerosing myxedema, thrombocytopenia, e.g., heparin-induced thrombocytopenia, cryoglobulinemia, granulomatosis with polyangiitis, e.g., ANCA-associated vasculitis, idiopathic thrombocytopenic purpura, thrombocytopenia, and IgG4 -Selected from RD, paroxysmal nocturnal hemoglobinuria (PNH), warm autoimmune hemolytic anemia, rhabdomyolysis, lupus nephritis, acute disseminated meningitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Miller-Fischer syndrome, neuromyelitis optica spectrum disorder, opsoclonus-myoclonus syndrome, pediatric autoimmune streptococcal infection-associated neuropsychiatric disorders (PANDAS), peripheral neuropathy, transverse myelitis, fibrosis, IPF / fibrosis, and transplant rejection.

[0023] In another embodiment of the present invention, a selective degrader for immunoglobulin A (IgA) is provided. In a particular embodiment, the immunoglobulin degrader has an IgA-targeting ligand from an Opt-class peptide. Because Opt-class ligands are highly selective for IgA, they promote the selective recruitment of IgA to hepatocytes for degradation. For example, in a particular embodiment, the immunoglobulin degrader is [ka] or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments of the present invention, the IgA degrader uses a 2:1 ratio of ASGPR-binding ligand to IgA-binding ligand.

[0025] In another embodiment of the present invention, the IgA degrader of the present invention has a 1:1 ratio of ASGPR-binding ligand to IgA-binding ligand. For example, in a particular embodiment, the immunoglobulin degrader is [ka] That is the case.

[0026] Selective targeting of IgA may be particularly beneficial when the present invention is used to treat diseases known to be primarily caused by IgA, such as Henoch-Schönlein purpura, also known as IgA vasculitis. Additional disorders mediated by IgA include cryoglobulinemia, granulomatosis with polyangiitis, thrombocytopenia, peripheral neuropathy, MGUS, IgA nephropathy, and Henoch-Schönlein purpura.

[0027] The immunoglobulin degraders described herein can be used to treat immunoglobulin-mediated disorders, such as IgG or IgA, including, for example, autoimmune disorders, other immune deficiencies, abnormal cell proliferation such as tumors and cancers, hematology-related disorders, renal disorders, allergic conditions, or hepatic disorders. In certain embodiments of the present invention, a method is provided for treating an immunoglobulin-mediated disorder, comprising administering to a host in need of treatment an effective amount of the immunoglobulin degraders described herein, or pharmaceutically acceptable salts, prodrugs, N-oxides thereof, and / or optionally pharmaceutically acceptable compositions thereof in a pharmaceutically acceptable carrier.

[0028] Conventional biochemical approaches to treating immunoglobulin-related diseases have been unsuccessful due to their large size, extracellular circulation, and / or lack of active sites. However, the immunoglobulin degraders of the present invention can degrade targeted immunoglobulins. In some embodiments, these immunoglobulin degraders feature a newly discovered ASGPR ligand characterized by high binding affinity to ASGPR (see Table 4). As a result of this high ASGPR binding affinity, the immunoglobulin degraders of the present invention can be administered at lower doses and may have fewer side effects, enhanced efficacy, faster therapeutic effects, longer-lasting metabolic stability, and / or reduced side effects compared to previously disclosed immunoglobulin degraders.

[0029] In certain embodiments, extracellular proteolytic compounds degrade TNF-α. For example, in certain embodiments, the compounds of the present invention [ka] That is the case.

[0030] In a particular embodiment, the TNF-α-targeting ligand is [Chemical formula] selected from the following.

[0031] In certain embodiments, the extracellular proteolytic compound degrades Factor XIa. For example, in certain embodiments, the compounds of the present invention are [Chemical formula] as follows.

[0032] In certain embodiments, the Factor XIa targeting ligand is [Chemical formula] selected from the following.

[0033] In another embodiment, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII: [Chemical formula] (wherein R 1 and R 5 are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, 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)R3 , 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 , and -NR 8 R 9 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. R 10 Hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, C(O)R3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 25 These include heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, 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 the group consisting of, each is arbitrarily substituted with 1, 2, 3, or 4 substituents, R 65 , R 66 , and R 67 These are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocyclic, heterocycloalkyl, haloalkoxy, 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 selected from, each of which is optionally substituted with one, two, three, or four substituents, R 68 , R 69 , and R 70 are independently hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, 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, heteroaryl, aryl, and C0-C6 alkyl-OS(O)2R 3 Selected from, each optionally substituted with one, two, three, or four substituents, 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, 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] ASGPR-binding ligands 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.

[0034] In a particular embodiment, the ASGPR-binding ligand is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0035] In an alternative embodiment, the ASGPR-binding ligand is of the formula: [ka] It is a ligand for or a pharmaceutically acceptable salt thereof.

[0036] In certain embodiments, formula IX, formula X, or formula XI: [ka] (In the formula, ASPGR-binding ligands are [ka] (In the formula, R 1 or R 5 is a linker A A compound selected from (which is bonded to and replaced by, and all other variable parts are as defined herein), Linker A is a linker B Linker C , or linker D A bond or part that covalently connects the ASGPR-binding ligand to the ASGPR-binding ligand. Linker B is a linker A A bond or portion that covalently connects the extracellular protein-targeting ligand to the extracellular protein, Linker C Each linker A It is a chemical group that links to an extracellular protein-targeting ligand. Linker D Each linker A It is a chemical group that links to an extracellular protein-targeting ligand, and Extracellular protein-targeting ligands are provided as extracellular protein-degrading compounds (ligands that bind to extracellular proteins).

[0037] In certain embodiments, formula IX-A, formula XA, or formula XI-A: [ka] (In the formula, Immunoglobulin-targeting ligands are provided as immunoglobulin-degradable compounds of immunoglobulins (e.g., ligands that bind to immunoglobulins, such as IgG or IgA), or pharmaceutically acceptable salts thereof.

[0038] In a particular embodiment, the ASGPR-binding ligand is [ka] A compound selected from, or a pharmaceutically acceptable salt thereof.

[0039] In certain embodiments, the extracellular protein degrader of the present invention is provided as an isotopic-enriched extracellular protein degrader having at least one desired isotopic substitution of atoms in an amount exceeding the natural abundance of the isotope, for example, an immunoglobulin degrader. For example, one or more hydrogens in the extracellular protein degrader may be replaced with deuterium, and one or more carbon atoms may be replaced with 13 It can be replaced by C. In one embodiment, the isotopic substitution is located at one or more positions of the ASGPR ligand. In another embodiment, the isotopic substitution is located at one or more positions of the linker portion of the molecule. In yet another embodiment, the isotopic substitution is located at one or more positions of the extracellular protein targeting ligand portion of the molecule.

[0040] Therefore, the present invention includes at least the following features:

[0041] (i) Extracellular protein degraders as described herein, or pharmaceutically acceptable salts, prodrugs, N-oxides thereof, and / or pharmaceutical compositions thereof as described herein (ii) Extracellular protein degraders as described herein, used in the treatment of immunoglobulin-related medical disorders such as autoimmune disorders, other immunodeficiencies, hematological disorders, renal disorders, allergic conditions, or hepatic disorders. (iii) Isotope-enriched derivatives of extracellular protein degraders described herein, or pharmaceutically acceptable salts, prodrugs, N-oxides, and / or pharmaceutical compositions thereof (iv) A method for manufacturing a pharmaceutical product intended for therapeutic use to treat or prevent a disorder mediated by an extracellular protein, characterized in that an extracellular protein degrader described herein is used in the manufacturing process. (v) the extracellular protein degraders described herein or their salts in a purified or substantially pure form (e.g., at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%) (vi) Extracellular protein degraders described herein for treating the disorders described herein, (vii) Methods for producing extracellular protein degraders as described herein, (viii) Immunoglobulin degraders as described herein, or pharmaceutically acceptable salts, prodrugs, N-oxides thereof, and / or pharmaceutical compositions thereof as described herein. (ix) Immunoglobulin degraders as described herein, used in the treatment of immunoglobulin-related medical disorders such as autoimmune disorders, other immunodeficiencies, hematological disorders, renal disorders, allergic conditions, or hepatic disorders. (x) Isotope-enriched derivatives of immunoglobulin degraders described herein, or pharmaceutically acceptable salts, prodrugs, N-oxides, and / or pharmaceutical compositions thereof (xi) A method for manufacturing a pharmaceutical product intended for therapeutic use to treat or prevent an immunoglobulin-mediated disorder, characterized in that an immunoglobulin degrader described herein is used in the manufacturing process. (xii) The immunoglobulin degraders described herein or their salts in a purified or substantially pure form (e.g., at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%) (xiii) Immunoglobulin degraders described herein for treating the disorders described herein, (xiv) A method for producing an immunoglobulin degrader as described herein, and (xv) ASGPR-binding ligands as described herein.

[0042] The extracellular protein target ligand ("EPTL") is covalently bound to the linker in the ASGPR-binding extracellular protein degrader compound via an anchoring linkage (a chemical bond between the EPTL and either linker B, linker C, or linker D). This linkage can be located anywhere on the ligand that does not unacceptably interfere with the EPTL's ability to bind to the target extracellular protein. The anchoring linkage is shown in the non-limiting example of the extracellular protein target ligand in the diagram. [ka] It is represented as follows. [Brief explanation of the drawing]

[0043] [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-converting enzyme 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 1HHHH-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 lipases (LPLs). [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-1 (PAI-1), endothelial plasminogen activator inhibitors, 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 activator, tissue type (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 activator (UPA, uPA). [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 graphs of cellular uptake of compound 28 at various concentrations. The y-axis represents the mean fluorescence intensity (MFI), and the x-axis represents the concentration of compound 28 measured in micromolars. The experimental procedure is described in Example 3. [Figure 9] This figure shows graphs of ternary complex formation of compound 28, IgG, and ASGPR at various concentrations of compound 28. The y-axis represents the ratio in the ternary complex, and the x-axis represents the concentration of compound 28 measured in micromolars. The experimental procedure is described in Example 4. [Figure 10] This figure shows a Western blot illustrating the degradation of IgG-AF488 by compound 28. The experimental procedure is described in Example 5. [Figure 11] This figure shows a colocalization image illustrating the incorporation of DNP-IgG in the presence of compound 28. The experimental procedure is described in Example 4. [Figure 12] This figure shows graphs of ternary complex formation of compound 4, IgG, and ASGPR, as well as IgG uptake by cells, at various concentrations of compound 4. The y-axis represents the concentration of ternary complex formation (in relation to ternary complex formation) or the ratio of IgG+ to total cells (in relation to uptake), indicated by the overall mean fluorescence intensity (MFI), and the x-axis represents the concentration of compound 4 measured in micromolars. The experimental procedure is described in Example 3. [Figure 13]This figure shows a graph of ternary complex formation of compound 4 or the inactive compound, IgG, and ASGPR at various concentrations of compound 4 or the inactive compound. The y-axis represents the concentration of ternary complex formation, indicated by the overall mean fluorescence intensity (MFI), and the x-axis represents the concentration of compound 4 or the inactive compound measured in micromolars. The experimental procedure is described in Example 3. [Figure 14] This figure shows a graph of cellular uptake of IgG at various concentrations of compound 4 or the inactive compound. The y-axis represents the ratio of IgG+ to total cells, and the x-axis represents the concentration of compound 4 or the inactive compound, measured in micromolars. The experimental procedure is described in Example 3. [Figure 15] This figure shows a bar graph of surface IgG concentrations resulting from the formation of a ternary complex of compound 4, IgG, and ASGPR in wild-type cells and ASGPR knockout cells, in the presence or absence of compound 4. The y-axis represents the surface IgG concentration, indicated by the overall mean fluorescence intensity (MFI), and the x-axis represents the presence or absence of compound 4. The experimental procedure is described in Example 3. [Figure 16] This figure shows a bar graph of cellular uptake of IgG over time in either wild-type cells or ASGPR knockout cells in the presence of compound 4. The y-axis represents the concentration of IgG, indicated by the overall mean fluorescence intensity (MFI), and the x-axis represents the time measured in minutes and hours. The experimental procedure is described in Example 3. [Figure 17] This figure shows a Western blot illustrating the concentration of IgG degradation products over time in the presence of compound 21. The experimental procedure is described in Example 6. [Figure 18] This figure shows a Western blot illustrating the concentration of full-length IgG over time in the presence of compound 21. The experimental procedure is described in Example 7. [Figure 19] This figure shows Western blots taken from rat liver cell lysates, illustrating the concentration of IgG over time in the presence of compound 4. The experimental procedure is described in Example 8. [Figure 20]This figure shows a colocalization image illustrating the incorporation of DNP-IgG in the presence of compound 4. The experimental procedure is described in Example 9. [Figure 21] This figure shows a line graph illustrating the ASGPR binding of compound 4 as measured by the SPR described in Example 1. The y-axis represents the response measured in units, and the x-axis represents the time measured in seconds. [Figure 22] This figure shows a line graph indicating the IgG binding of compound 4 as measured by SPR as described in Example 2. The y-axis represents the response measured in units, and the x-axis represents the time measured in seconds. [Figure 23] This figure shows a line graph indicating the TNFa binding of compound 36 as measured by SPR as described in Example 2. The y-axis represents the response measured in units, and the x-axis represents the time measured in seconds. [Figure 24] This figure shows a Western blot illustrating the time-dependent degradation of TNF by 0.5 μM compound 36. The experimental procedure is described in Example 11. [Figure 25] This figure shows a Western blot illustrating ASGPR-mediated TNF uptake in the presence of compound 36. The experimental procedure is described in Example 12. [Figure 26] This figure shows a non-limiting example of the formula of the present invention. [Modes for carrying out the invention]

[0044] Novel extracellular protein degraders that degrade target extracellular proteins, such as IgG, and their pharmaceutically acceptable salts, as well as compositions thereof, are provided, along with starting materials and intermediates for such extracellular protein degraders, and methods for their use and preparation. These extracellular protein degraders are highly potent conjugates of both ASGPR and their respective extracellular protein targets. Some of the extracellular protein degraders of the present invention utilize highly binding ASGPR-binding ligands. This enhanced binding affinity to ASGPR results in extracellular protein degraders with various advantages compared to previously known extracellular protein degraders. For example, when the extracellular protein degraders of the present invention are compared to other extracellular protein degraders, they can be administered at lower doses, less frequently, with fewer side effects, and / or with increased potency. In some embodiments, an extracellular protein degrader containing one of the highly binding ASGPR ligands described herein may be sufficiently active in the form of a monodentate compound (i.e., a 1:1 extracellular protein ligand versus ASGPR ligand in the therapeutic molecule).

[0045] In certain embodiments, extracellular proteolytic compounds degrade immunoglobulins. The immunoglobulin degraders described herein degrade selected immunoglobulins by covalently binding the ligand of the selected immunoglobulin to a strong ASGPR-binding substance via a selected linking group. Immunoglobulins that can be targeted by the present invention include, but are not limited to, IgA, IgG, IgD, IgE, and IgM, as well as their mutants. In certain embodiments of the present invention, the selected immunoglobulin degrader degrades IgG.

[0046] I. Terminology of Compounds Extracellular protein degraders are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0047] All extracellular protein degraders described herein, unless otherwise indicated or excluded by context, independently include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, as if each were specifically described.

[0048] 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.

[0049] The present invention includes an extracellular protein degrader having an isotopic substitution of at least one desired atom in an amount exceeding the natural abundance of the isotope, i.e., an enriched amount.

[0050] Examples of isotopes that can be incorporated into the extracellular protein degrader 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, an isotope-labeled extracellular protein degrader is used in metabolic studies (e.g., 14 (using C), reaction dynamics studies (for example) 2 H or 3 It 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. The isotope-labeled extracellular protein degraders and their prodrugs of the present invention can generally be prepared by using readily available isotope-labeling reagents instead of non-isotope-labeling reagents, by following the procedures disclosed in the scheme or the examples and preparations below.

[0051] 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 maxThese improvements are achieved by substituting hydrogen with deuterium at one or more positions on the molecule. For example, deuterium can be bonded 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).

[0052] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial isotope 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 interest. In certain embodiments, deuterium is enriched to 80%, 85%, 90%, 95%, or 99% at a 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 a detectable drug in humans.

[0053] The extracellular protein degrader of the present invention can form solvates with a solvent (including water). Therefore, in one embodiment, the present invention includes a solvated form of the active extracellular protein degrader. The term "solvate" refers to a molecular complex of the extracellular protein degrader (including its salts) of the present invention 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 comprising the extracellular protein degrader of the present invention and water. Pharmaceutically acceptable solvates according to the present invention may include those in which the crystallization solvent isotope-substituted, e.g., D2O, d6-acetone, d6-DMSO. Solvates may be in liquid or solid form.

[0054] "Dosage form" refers to the unit of administration of the active ingredient. 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, and implants.

[0055] A "pharmaceutical composition" is a composition comprising at least one activator and at least one other substance, such as a carrier. The present invention includes the pharmaceutical composition of the extracellular protein degrader described.

[0056] A "pharmaceutical combination" is a combination of at least two active ingredients that can be administered together in a single dosage form or in separate dosage forms.

[0057] "Pharmacologically acceptable salts" are derivatives of the extracellular protein degraders of the disclosure, modified by the parent extracellular protein degrader to produce its inorganic and organic salts, pharmaceutically acceptable acid-added salts, or base-added salts. Salts of the extracellular protein degraders can be synthesized from parent extracellular protein degraders containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these extracellular protein degraders 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 extracellular protein degraders 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 extracellular protein degraders further include solvates of the extracellular protein degraders and salts of the extracellular protein degraders.

[0058] 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 parental extracellular protein degraders 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, and HOOC-(CH2) 1~4 Examples include salts prepared from organic acids such as -COOH, or using 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).

[0059] In application to the pharmaceutical compositions / combinations of the present invention, the term "carrier" refers to a diluent, excipient, or vehicle that results in an active extracellular protein degrader.

[0060] "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.

[0061] "Patient," "host," or "subject" is a human or non-human animal that requires treatment or prevention of any of the disorders specifically described herein. Typically, the host, patient, or subject is human. "Patient," "host," or "subject" can also refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc.

[0062] The "therapeutic effective amount" of the extracellular protein degrader, pharmaceutical composition, or combination of the present invention means the amount that, when administered to a host, produces therapeutic effects such as improvement of symptoms or reduction or mitigation of the disease itself.

[0063] In one embodiment, the substitution of a hydrogen atom with a deuterium atom is present within any variable group. For example, if any variable group is methyl, ethyl, or methoxy, or contains them, for example, through 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 may 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.

[0064] The term "immunoglobulin" typically refers to a large Y-shaped protein (e.g., an antibody) that identifies and neutralizes foreign compounds or objects, such as pathogens or diseased tissues. Non-limiting examples of immunoglobulin proteins include IgA, IgD, IgE, IgG, and IgM. Immunoglobulins used herein may also include binding fragments known to those skilled in the art.

[0065] 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.

[0066] 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.

[0067] "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.

[0068] 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.

[0069] 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.

[0070] "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.

[0071] 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 a specified number of carbon atoms covalently bonded by a sulfur crosslink (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

[0072] "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.

[0073] "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.

[0074] 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 that are fused 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.

[0075] An unrestricted example of a biring complex algebra is: [ka] These are some examples.

[0076] 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.

[0077] 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.

[0078] "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 2 or less. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is 1 or less.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.

[0079] "Heteroarylalkyl" refers to an alkyl group as described herein that is substituted with a heteroaryl group as described herein.

[0080] "Arylalkyl" refers to an alkyl group as described herein that is substituted with an aryl group as described herein.

[0081] "Hypercycloalkyl" refers to an alkyl group as described herein that is substituted with a heterocyclo group as described herein.

[0082] 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 heteroatom is nitrogen only. In one embodiment, the heteroatom is oxygen only. In one embodiment, the heteroatom is sulfur only. 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.

[0083] 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 -OR, if permitted by 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 formed. For example, [ka] As long as a stable compound is produced, alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 F, Cl, Br, I, -NR 6 R 7, 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.

[0084] An unrestricted example of an arbitrarily substituted CH2 group is: [ka] These are some examples.

[0085] An unrestricted example of an arbitrarily substituted -S- group is: [ka] These are some examples.

[0086] "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.

[0087] In one embodiment, the "alkyl" has one carbon atom.

[0088] In one embodiment, the "alkyl" has two carbon atoms.

[0089] In one embodiment, the "alkyl" has three carbon atoms.

[0090] In one embodiment, the "alkyl" has four carbon atoms.

[0091] In one embodiment, the "alkyl" has five carbon atoms.

[0092] In one embodiment, the "alkyl" has six carbon atoms.

[0093] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0094] Further non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0095] Further non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0096] Further non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0097] Further non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0098] In alternative embodiments, the "alkyl" group is optionally substituted.

[0099] In alternative embodiments, the "alkenyl" group is optionally substituted.

[0100] In alternative embodiments, the "alkynyl" group is optionally substituted.

[0101] "Haloalkyl" embodiment In one embodiment, "haloalkyl" is C1-C 10These include 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.

[0102] In one embodiment, the "haloalkyl" has one carbon atom.

[0103] In one embodiment, the "haloalkyl" has one carbon and one halogen.

[0104] In one embodiment, the "haloalkyl" has one carbon and two halogens.

[0105] In one embodiment, the "haloalkyl" has one carbon and three halogens.

[0106] In one embodiment, the "haloalkyl" has two carbon atoms.

[0107] In one embodiment, the "haloalkyl" has three carbon atoms.

[0108] In one embodiment, the "haloalkyl" has four carbon atoms.

[0109] In one embodiment, the "haloalkyl" has five carbon atoms.

[0110] In one embodiment, the "haloalkyl" has six carbon atoms.

[0111] As a non-limiting example of "haloalkyl", [ka] These are some examples.

[0112] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0113] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0114] As a further non-limiting example of "haloalkyl", [ka] These are some examples.

[0115] "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.

[0116] As a further non-restrictive example of a 5-membered "heteroaryl" group, [ka] These are some examples.

[0117] 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).

[0118] As a non-limiting example of a six-membered "heteroaryl" group containing one or two nitrogen atoms, [ka] These are some examples.

[0119] In one embodiment, the "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0120] Non-restrictive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[0121] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0122] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0123] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0124] In one embodiment, the "heteroaryl" is a 10-membered bicyclic aromatic group comprising one or two atoms selected from nitrogen, oxygen, and sulfur.

[0125] Non-exclusive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0126] As a further non-restrictive example of a bicyclic "heteroaryl" group, [ka] These are some examples.

[0127] "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.

[0128] 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.

[0129] In one embodiment, "heterocyclic ring" refers to a ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[0130] In one embodiment, "heterocyclic ring" refers to a ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[0131] In one embodiment, “heterocyclic” refers to a ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[0132] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[0133] Further non-restrictive examples of "heterocyclic rings" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[0134] Further non-restrictive examples of "heterocyclic compounds" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0135] Further non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0136] 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.

[0137] for example, [ka] This is a "heterocyclic" group.

[0138] however, [ka] This is an "aryl" group.

[0139] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0140] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0141] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0142] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0143] As an unrestricted example of a "complex algebra", [ka] This can also be mentioned.

[0144] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0145] As a further non-restrictive example of "complex algebras", [ka] These are some examples.

[0146] Ariel In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0147] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0148] 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.

[0149] for example, [ka] This is an "aryl" group.

[0150] however, [ka] This is a "heterocyclic" group.

[0151] "Arylalkyl" Embodiment Non-exclusive examples of "arylalkyl" include: [ka] These are some examples.

[0152] In one embodiment, "arylalkyl" is, [ka] That is the case.

[0153] In one embodiment, "arylalkyl" refers to a two-carbon alkyl group substituted with an aryl group.

[0154] Non-exclusive examples of "arylalkyl" include: [ka] These are some examples.

[0155] II. Extracellular protein degradation 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.

[0156] Extracellular protein degraders described herein, or pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable compositions thereof, can be used to treat injuries mediated by target extracellular proteins that bind to extracellular protein targeting ligands. The degraders described herein can target and lysosomal degrade specific extracellular proteins that mediate pathological injuries. Target extracellular proteins can modulate injuries 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 extracellular protein is a protein that is not drug-worthy in the classical sense, in that it can be inhibited or otherwise bound and does not have a binding pocket or active site that cannot be readily allosterically controlled. In another embodiment, the target extracellular protein is a drug-worthy protein in the classical sense, but for therapeutic purposes, protein degradation is preferred over inhibition. The target extracellular protein is recruited together with an extracellular protein targeting ligand, which is a ligand for the target extracellular protein. Typically, the extracellular protein targeting ligand binds to the target extracellular protein non-covalently. In alternative embodiments, the target extracellular protein is covalently bound to the extracellular protein targeting ligand in a manner that may be irreversible or reversible.

[0157] Accordingly, in some embodiments, methods are provided for treating a host with a disorder mediated by a target extracellular protein, comprising administering to the host, typically a human, an effective amount of a degrader targeting the target extracellular protein, optionally in a pharmaceutically acceptable composition.

[0158] The target extracellular protein can be any amino acid sequence to which a degrader containing an extracellular protein-targeting ligand can bind, and through its degradation, a beneficial therapeutic effect is achieved. In one embodiment, the target extracellular protein is a non-endogenous peptide, such as one derived from a pathogen or toxin. In another embodiment, the target extracellular 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 extracellular 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.

[0159] An extracellular protein targeting ligand is a ligand that covalently or noncovalently binds to a target extracellular protein selected to be lysosomal degraded. In certain embodiments, the extracellular protein targeting ligand is a small molecule or moiety (e.g., a peptide, nucleotide, antibody fragment, aptamer, biomolecule, or other chemical structure) that binds to the target extracellular protein, where the target extracellular protein is a mediator of disease in the host, as described in detail below. Exemplary extracellular protein targeting ligands are shown in the figure.

[0160] Anchor connection Extracellular protein-targeting 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 interfere with the EPTL's ability to bind to the target extracellular protein. Anchoring bonds are shown in Figure 1 as an example of an extracellular protein-targeting ligand. [ka] It is represented as follows.

[0161] Many of the exemplary target extracellular proteins for 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 site 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 target extracellular proteins, and from this information a reasonable anchoring site can be determined.

[0162] 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 a target 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 target extracellular protein. In this case, the ASGPR ligand binds at a site that does not excessively negatively affect binding to the target extracellular protein via linker and anchor junctions.

[0163] Any substituent In certain embodiments, the extracellular protein targeting ligands described herein, for example as shown in one of the figures, include alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), and -OR 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] The compound is optionally substituted with one, two, three, or four substituents independently selected from the compound, where the substituents are chosen such that a stable compound is formed.

[0164] In certain embodiments, the target extracellular proteins include IgA, IgG, IgE, TNF-α, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-β1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, kallikrein 1, LPL, MMP1, MIF, GIF, L-dopachrome isomerase or phenylpyruvate tautomerase, and neutrophil elastase. The following are selected from: prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpine E1, phospholipase A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), transforming growth factor β2 (TGF-β2, TGFB2), thrombospondin 1, urokinase, urokinase-type plasminogen activator, complement factor B, complement factor D, targeted complement factor H, and complement component 5.

[0165] In certain embodiments, if the target extracellular protein has a receptor, the target extracellular protein can be used to degrade the receptor.

[0166] In certain embodiments, the extracellular protein targeting ligand is IgA, IgG, IgE, TNF-α, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-β1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L, Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, kallikrein 1, LPL, MMP1, MIF, GIF, L-dopachrome isomerase or phenylpyruvate tautomerase, neutrophil elastomerase Selected from Tase, prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpine E1, phospholipase A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), transforming growth factor β2 (TGF-β2, TGFB2), thrombospondin 1, urokinase, urokinase-type plasminogen activator, complement factor B, complement factor D, targeted complement factor H, and complement component 5.

[0167] amino acid In certain embodiments, the extracellular protein targeting ligand comprises one or more amino acids. The present invention aims to achieve desired targeting ligand properties using natural amino acids, non-natural amino acids, or any combination thereof.

[0168] The term "natural amino acids" refers to amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0169] In certain embodiments, a natural amino acid is replaced with a corresponding non-natural amino acid, for example, phenylalanine is replaced with 4-chlorophenylalanine. Non-limiting examples of non-natural amino acids include 4-chlorophenylalanine, 3-fluorophenylalanine, 4-trifluoromethylphenylalanine, 3,4-dichlorophenylalanine, 4-phenylphenylalanine, N-methylalanine, N-methylglutamic acid, N-methylphenylalanine, and homoserine.

[0170] Examples of adding non-natural amino acids include: [ka] TIFF0007867715000056.tif130170 is one example.

[0171] In certain embodiments, the extracellular protein targeting ligand is a sequence of amino acids. In certain embodiments, the amino acid sequence is linked to the linker moiety of the molecule by binding to a terminal amine. In certain embodiments, the amino acid sequence is linked to the linker moiety of the molecule by binding to a terminal carboxylic acid (e.g., an ester or amide). In certain embodiments, the peptide comprises an amine side chain, a hydroxyl side chain, or a carboxylic acid side chain, and the linker may be bound to one of these side chains.

[0172] For example, if the amino acid sequence is MLKKIE of SEQ ID NO: 1, a non-limiting example of the possible positions where the peptide can be attached to the linker is: [ka] These are some examples.

[0173] An amino acid sequence can be attached to a linker using the chemical reactions described herein and as otherwise known in the art. For example, if the desired linking group is an amide, an amine, carboxylic acid, ester, or other amide precursor can be given to the linker, and the targeted ligand can be attached by an amide coupling reaction such as a HATU coupling reaction or an HBTU coupling reaction.

[0174] Non-limiting examples of extracellular protein targeting ligands, which are amino acid sequences, include aptamers, antibodies, and peptides. In certain embodiments, the leftmost amino acid listed in the sequence listing is the C-terminus. In other embodiments, the rightmost amino acid listed in the sequence listing is the C-terminus.

[0175] In certain embodiments, the amino acid sequence refers to a sequence that does not have a specific chirality. In other embodiments, the amino acid sequence is all D-amino acids, all L-amino acids, or a mixture of D-amino acids and L-amino acids.

[0176] Where a peptide is indicated by the amino acid sequence in a structure depicted herein, unless otherwise excluded by context, the left side of the peptide is typically the N-terminus and the right side is typically the C-terminus. For example, the proline in PIESESLK is attached to the linker via the N-terminal nitrogen in the following structure.

[0177] [ka]

[0178] To clarify, NH, which is part of the amide, is part of the proline, and CO, which is part of the linker.

[0179] When the lysine in PIESESLK is attached to the linker via the C-terminal carbonyl, the structure is as follows:

[0180] [ka]

[0181] To clarify, the NH group bound to lysine is part of the linker, and lysine is bound to the NH group by a carbonyl group which is part of the C-terminus.

[0182] TNF-Alpha (TNF-α) In some embodiments, the target extracellular 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.

[0183] 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.

[0184] 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).

[0185] In certain embodiments, the TNF-α-targeting ligand is [ka] Selected from.

[0186] In certain embodiments, the TNF-α-targeting ligand is [ka] Selected from.

[0187] Non-limiting examples of TNFa-degrading compounds include: [ka] Examples include TIFF0007867715000063.tif190170, TIFF0007867715000064.tif170170, TIFF0007867715000065.tif193170, and TIFF0007867715000066.tif143170.

[0188] IL-1 In some embodiments, the target extracellular 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.

[0189] 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).

[0190] 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).

[0191] In a particular embodiment, the IL-1 targeting ligand is [ka] Selected from.

[0192] IL-2 In some embodiments, the target extracellular 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.

[0193] 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).

[0194] 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).

[0195] In a particular embodiment, the IL-2 targeted ligand is [ka] Selected from.

[0196] IL-6 In some embodiments, the target extracellular 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.

[0197] 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.

[0198] 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).

[0199] IFN-γ In some embodiments, the target extracellular 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.

[0200] 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).

[0201] 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).

[0202] Vascular epithelial growth factor (VEGF) In some embodiments, the target extracellular 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.

[0203] 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).

[0204] 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).

[0205] Transforming Growth Factor-β1 (TGF-β1) In some embodiments, the target extracellular 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 various processes such as normal development, immune function, microglial function, and response 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.

[0206] 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).

[0207] 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).

[0208] Proprotein-converting enzyme subtilisin / kexin type 9 (PCSK-9) In some embodiments, the target extracellular protein is human proprotein-converting enzyme 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.

[0209] 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).

[0210] 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).

[0211] In certain embodiments, the PCSK-9 ligand is any PCSK-9 ligand described in International Publication No. 2021 / 156792, which is incorporated herein by reference.

[0212] In a particular embodiment, the formula is: [ka] (In the formula, ASGPR ligand is an ASGPR ligand as described herein, PCSK-9 targeted ligands are provided as compounds of any PCSK-9 ligand described in International Publication No. 2021 / 156792, or pharmaceutically acceptable salts thereof.

[0213] Non-limiting examples of PCSK-9 targeting ligands that can be used in any of the formulas of the present invention include: [ka] TIFF0007867715000071.tif195170TIFF0007867715000072.tif195170TIFF0007867715000073.tif209170TIFF0007867715000074.tif36170 (in the formula, L A1 is a combination, NR 8 Examples include, or O.

[0214] In a particular embodiment, the PCSK9-targeting ligand is of the formula: [ka] (In the formula, R B1 H is, R B2 (C1~C6) alkoxy, -L B1 - or -C(=O)OH-substituted (C1~C6) alkyl, R B3is H or (C1-C6) alkyl, R B6 is H, (C1~C6) alkyl, or L B1 And, R B7 is H, (C1~C6) alkyl, or L B1 And, or R B6 and R B7 These, together with the carbon atoms to which they are attached, form (C3-C7) cycloalkyl groups. R B9 H or one or more R B27 These are (C1-C6) alkyl groups that are arbitrarily substituted, R B9’ is H or (C1-C6) alkyl, R B10 is OR B13 Replaced by one or more R B14 (C6~C 10 ) is an aryl, R 11 is (C1~C6) alkyl or L B1 And, R B12 These are halogens, (C1-C6) alkyl groups, (C1-C6) alkoxy groups, (C1-C6) haloalkyl groups, (C1-C6) haloalkoxy groups, -OH groups, or CN groups. R B13 R B16 Replaced by (C6~C 10 ) is an aryl, Each R B14 Independently, in each case, these are halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN. R B16 is one or more R B26 A 5- to 7-membered heteroaryl compound containing 1 to 3 heteroatoms selected from N, O, and S which are arbitrarily substituted, Each R B26 Independently, in each case, one or more R B29These are (C1-C6) alkyl groups that are arbitrarily substituted, Each R B27 These are independent, in each case, (C6~C 10 ) is an aryl, Each R B29 These are, independently, in each case, -NR B31 R B32 Alternatively, a 4- to 7-membered heterocycline containing 1 to 3 heteroatoms selected from N, O, and S, Each R B31 These are independently selected from H and (C1-C6) alkyl groups. Each R B32 These are independently selected from H and (C1-C6) alkyl groups. L B1 is, -(CH2) p NH- * And here, L B1 of * is Linker (L A The point to be attached to ) and R B11 , R B6 , or R B7 At least one of them is -L B1 -and, It is a compound where n is 1.

[0215] In a particular embodiment, the PCSK9-targeting ligand is of the formula: [ka] (In the formula, R C1 is -OR C10 and one or more R C11 Replaced by (C6~C 10 ) is an aryl, R C2 H, (C1~C6) alkyl, -L C1 , or (C3~C9) carbocyric, where alkyl is one R C18 It is substituted with and carbocyclyl has one or more R C19 It has been replaced with, R C3is H or (C1~C6) alkyl, R C4 is H or (C1-C6) alkyl, or R C3 and R C4 These, together with the attached atoms, form a 5- to 7-membered heterocyclyl ring containing 1 to 3 heteroatoms selected from N, O, and S. R C5 is H or (C1-C6) alkyl, R C6 is (C1~C6) alkyl or -L C1 Here, the alkyl group is optionally substituted with one or more substituents independently selected from -OH or (C1-C6) alkoxy groups. R C8 is H, (C1~C6) alkyl, or -L C1 And, R C9 It is a halogen, R C10 is one R C22 Replaced by (C6~C 10 ) is an aryl, Each R C11 Independently, in each case, are halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN. R C18 (C6~C 10 ) is an aryl, Each R C19 Independently, in each case, are halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN. R C22 is one or more R C23 A 5-membered or 6-membered heteroaryl compound containing 1 to 3 heteroatoms selected from N, O, and S substituted with, Each R C23 These are, independently, in each case, -NR C24 R C25Alternatively, an alkyl group (C1-C6) optionally substituted with a 4- to 7-membered heterocycline containing 1 to 3 heteroatoms selected from N, O, and S, R C24 These are H, (C1~C6) alkyl, R C25 These are H, (C1~C6) alkyl, L C1 is, -(CH2) p NH- * And here, L C1 of * is Linker (L A The point to be attached to ) and R C2 , R C6 , or R C8 At least one of them is -L C1 And, The compound is (where p is 1, 2, 3, 4, 5, or 6).

[0216] In certain embodiments, PCSK-9 targeting ligands that can be used in any of the formulas of the present invention include: [ka] These are some examples.

[0217] In certain embodiments, PCSK-9 targeting ligands that can be used in any of the formulas of the present invention include: [ka] These are some examples.

[0218] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007867715000080.tif201170 and TIFF0007867715000081.tif68170.

[0219] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF0007867715000083.tif180170 and TIFF0007867715000084.tif92170.

[0220] In certain embodiments, the PCSK9-targeting ligand is [ka] Selected from.

[0221] Non-limiting examples of PCSK-9 degradable compounds include: [ka] These are some examples.

[0222] FHR3 Human complement factor H-related protein 3 (FHR-3) belongs to the complement factor H (FH) family. The FH family, which includes complement factor H-related protein (FHR1), complement factor H-related protein 2 (FHR2), complement factor H-related protein 3 (FHR3), complement factor H-related protein 4 (FHR4A and FHR4B), including isoforms 4A and 4B, and complement factor H-related protein 5 (FHR5), is thought to have arisen from non-allelic homologous recombination and interlocus gene conversion.

[0223] Unlike factor H, FHR3 lacks the complement regulatory domain essential for complement inactivation and competes with factor H, leading to complement hyperactivation. Therefore, the present invention provides compounds used to treat disorders caused by excessive complement activation by regulating the concentration of complement factor H protein, particularly FHR3, to eliminate competitors of factor H and thereby restore factor H-mediated regulation.

[0224] Because factor H plays a central role in complement regulation, many clinical associations arise from abnormal FH activity. Loss-of-function mutations in factor H increase susceptibility to renal disease, atypical hemolytic uremic syndrome (aHUS), and dense deposit disease (ODD), while polymorphic mutations in complement factor H are strongly associated with important human diseases, including age-related macular degeneration (AMO) and meningococcal sepsis (Clin Exp lmmunol 151(2):210-230; lmmunobiology 217(11):1034-1046).

[0225] In certain embodiments, the present invention provides use in the treatment of diseases or disorders mediated by FHR3.

[0226] In certain embodiments, FHR3-mediated diseases or disorders include complement-related disorders, complement dysregulation disorders, autoimmune diseases, renal diseases, retinal degenerative diseases, rheumatic diseases, associated degenerative diseases, autoimmune kidney diseases, dense deposit disease (ODD), and systemic autoimmune diseases.

[0227] In certain embodiments, non-limiting examples of diseases or disorders mediated by FHR3 include nephropathy, age-related macular degeneration, atypical hemolytic uremic syndrome (aHUS), autoimmune hemolytic uremic syndrome, hepatocellular carcinoma (HCC), C3 nephropathy, paroxysmal nocturnal hemoglobinuria, polymyalgia rheumatica, rheumatoid arthritis, meningococcal sepsis, and systemic lupus erythematosus (SLE).

[0228] In certain embodiments, the present invention provides compounds that remove or reduce the level of complement factor H-related protein 3 (FHR3) from plasma using receptor-mediated endocytosis.

[0229] In a particular embodiment, the FHR3-targeting ligand is [ka] Selected from TIFF0007867715000088.tif185170 and TIFF0007867715000089.tif88170.

[0230] In a particular embodiment, the FHR3 compound is [ka] Selected from TIFF0007867715000091.tif185170 and TIFF0007867715000092.tif182170.

[0231] Tau protein In some embodiments, the target extracellular protein is tau protein. Accumulation of tau in the brain causes aggregates associated with Alzheimer's disease and other tauopathies.

[0232] Non-limiting examples of tau protein targeting ligands include: [ka] These are some examples.

[0233] IL-21 In some embodiments, the target extracellular 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.

[0234] 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).

[0235] 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).

[0236] IL-22 In some embodiments, the target extracellular 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 immune 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.

[0237] 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).

[0238] 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).

[0239] IL-10 In some embodiments, the target extracellular 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.

[0240] 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).

[0241] 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).

[0242] IL-5 In some embodiments, the target extracellular 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.

[0243] 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).

[0244] 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).

[0245] IL8 In some embodiments, the target extracellular 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 tumor progression, immune evasion, epithelial-mesenchymal transition, and promotion of myeloid suppressor cell recruitment. 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.

[0246] 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.

[0247] Representative IL-8 targeting ligands are shown in Figure 1. Further IL-8 targeting ligands can be found, for example, in Bioorg Med Chem Lett 19: 4026-30 (2009) (which is incorporated herein by reference).

[0248] Cholinesterase In some embodiments, the target extracellular 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.

[0249] 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).

[0250] 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).

[0251] 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).

[0252] In some embodiments, the target extracellular 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.

[0253] CCL2 is thought to be involved in the recruitment of monocytes to the arterial wall during the disease process of atherosclerosis.

[0254] 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).

[0255] Carboxypeptidase B2 In some embodiments, the target extracellular 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.

[0256] 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).

[0257] 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.

[0258] Neutrophil elastase In some embodiments, the target extracellular 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.

[0259] 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.

[0260] 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).

[0261] 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).

[0262] Factor Xa In some embodiments, the target extracellular 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.

[0263] 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.

[0264] 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.

[0265] 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).

[0266] Factor XI In some embodiments, the target extracellular 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.

[0267] 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.

[0268] 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).

[0269] 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).

[0270] In a particular embodiment, the XI targeting ligand is [ka] Selected from.

[0271] In certain embodiments, factor XI targeting ligands are described in J Med Chem 61 (17), 7425-7447 (2018), or J Med Chem (2020) Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor Xia inhibitors: demonstrating the power of an integrated S1 protease family approach.

[0272] Non-limiting examples of XI-degradable compounds include: [ka] TIFF0007867715000096.tif179170 and TIFF0007867715000097.tif154170 are examples.

[0273] In certain non-limiting embodiments, the XI factor-degradable compound of the present invention is the following compound: [ka] Selected from TIFF0007867715000099.tif190170, TIFF0007867715000100.tif165170, TIFF0007867715000101.tif219170, or their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.

[0274] Factor XII In some embodiments, the target extracellular 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.

[0275] 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.

[0276] 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).

[0277] 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).

[0278] Factor XIII In some embodiments, the target extracellular 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.

[0279] 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.

[0280] 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).

[0281] 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).

[0282] Prothrombin In some embodiments, the target extracellular 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.

[0283] Thrombin is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0284] 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).

[0285] 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.

[0286] 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).

[0287] Coagulation factor VII In some embodiments, the target extracellular 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.

[0288] Factor VII is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0289] 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).

[0290] 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).

[0291] coagulation factor IX In some embodiments, the target extracellular 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.

[0292] Factor IX is involved in blood clot formation, as well as arterial and venous thrombosis, and thromboembolism associated with atrial fibrillation.

[0293] 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.).

[0294] 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).

[0295] Fibroblast growth factor 1 (FGF1) In some embodiments, the target extracellular 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.

[0296] 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.

[0297] 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).

[0298] Fibroblast growth factor 2 (FGF2) In some embodiments, the target extracellular 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.

[0299] 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).

[0300] 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).

[0301] Fibronectin-1 In some embodiments, the target extracellular 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.

[0302] 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).

[0303] 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).

[0304] Kallikrein-1 (KLK1) In some embodiments, the target extracellular 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).

[0305] 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).

[0306] 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).

[0307] Plasma kallikrein In some embodiments, the target extracellular 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).

[0308] 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.).

[0309] 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).

[0310] Lipoprotein lipase In some embodiments, the target extracellular 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 lipoprotein (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.

[0311] 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).

[0312] 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).

[0313] Matrix metallopeptidase 1 (MMP-1) In some embodiments, the target extracellular 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.

[0314] 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).

[0315] 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).

[0316] Macrophage migration inhibitory factor (MIF) In some embodiments, the target extracellular 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.

[0317] MIF is particularly associated with tumor progression, systemic inflammation, atherosclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

[0318] 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).

[0319] 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).

[0320] Transforming Growth Factor-β2 (TGF-β2) In some embodiments, the target extracellular 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. 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 is also associated with hematological malignancies and fibrosis.

[0321] 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.

[0322] Representative TGF-β2 targeting ligands are shown in Figure 1.

[0323] Thrombospongin-1 (TSP-1) In some embodiments, the target extracellular protein is human thrombospondin-1 (TSP-1) (UniProtKB - P61812(TGFB2_HUMAN)). TSP1 functions as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, 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.

[0324] 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.

[0325] 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).

[0326] Representative TSP-1 targeting ligands are shown in Figure 1.

[0327] CD40 ligand (CD40L) In some embodiments, the target extracellular 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.

[0328] 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).

[0329] CD40L expression is associated with HIV-related neurocognitive disorders and cardiovascular complications. Representative CD40L-targeting ligands are shown in Figure 1.

[0330] Urokinase-type plasminogen activator (UPA) In some embodiments, the target extracellular protein is human urokinase-type plasminogen activator (UPA) (UniProtKB - P00749(UROK_HUMAN)). Urokinase-type plasminogen activator (uPA) is a serine protease present in the extracellular matrix of blood and 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 have been found to correlate with tumor malignancy.

[0331] 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. al.), and 4FU7, 4FU8, 4FU9, 4FUB, 4FUC, 4FUD, 4FUE, 4FUF, 4FUG, 4FUH, 4FUI, and 4FUJ (Kang, Crystal structures of UPA bound to various searchable compounds are provided by YN et al.

[0332] 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).

[0333] Plasminogen activator, tissue type (TPA) In some embodiments, the target extracellular 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.

[0334] 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).

[0335] 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).

[0336] Plasminogen (PLG) In some embodiments, the target extracellular 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 activator, collagenase, and several complement zymogens, such as C1 and C5. Its role in tissue remodeling and tumor invasion can be regulated by CSPG4.

[0337] 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).

[0338] 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).

[0339] Plasminogen activator inhibitor-1 (PAI-1) In some embodiments, the target extracellular 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.

[0340] 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.

[0341] 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).

[0342] Placental growth factor (PIGF) In some embodiments, the target extracellular 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 PlGF-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).

[0343] 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).

[0344] 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).

[0345] Phospholipase A2, Group IB (PA21B) In some embodiments, the target extracellular 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.

[0346] 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).

[0347] 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).

[0348] Phospholipase A2, Group IIA (PA2GA) In some embodiments, the target extracellular 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.

[0349] 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).

[0350] 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).

[0351] B factor In some embodiments, the target extracellular 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.

[0352] 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).

[0353] 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).

[0354] In a particular embodiment, the extracellular targeting ligand is [ka] Selected from TIFF0007867715000103.tif203170, each is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule.

[0355] 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.

[0356] In a particular embodiment, the factor B-targeting ligand-linker is [ka] Selected from.

[0357] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, one can choose from a two-seat or three-seat configuration.

[0358] D factor In some embodiments, the target extracellular 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.

[0359] 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.

[0360] 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 Hematological 102: 466-475 (2017) (each of which is incorporated herein by reference).

[0361] 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’They 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, hydroxy 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 They came together, R 21 It may form a three-membered carbocyclic ring optionally substituted with one, two, or three substituents selected from, or R 201 and R 202 They came together, R 21 It may 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, which may be optionally substituted with one, two, or three substituents selected from the above. R 202 and R 203 They came together, R 21 It may form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, which may be optionally substituted with one, two, or three substituents selected from the above. L 100 teeth, [ka] Selected from, here, R 217 is hydrogen or a C1-C6 alkyl group, and R 218 and R 218’ m is independently selected from hydrogen, halogen, hydroxymethyl, and methyl, and m is 0, 1, 2, or 3. B 100R is a heterocyclic group having one, two, three, or four heteroatoms independently selected from cycloalkyl, N, O, and S, a C2-C6 alkenyl, a C2-C6 alkynyl group, -(C0-C4 alkyl)(aryl), -(C0-C4 alkyl)(heteroaryl), or -(C0-C4 alkyl)(biphenyl), each of which is R 21 Selected from (which are optionally substituted with one, two, three, or four substituents independently selected from the original).

[0362] In a particular embodiment, the extracellular targeting ligand is [ka] Selected from TIFF0007867715000109.tif190170TIFF0007867715000110.tif164170TIFF0007867715000111.tif190170TIFF0007867715000112.tif202170TIFF0007867715000113.tif198170TIFF0007867715000114.tif160170, each is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule.

[0363] 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.

[0364] In a particular embodiment, the complement factor D targeting ligand-linker is [ka] Selected from TIFF0007867715000116.tif192170 and TIFF0007867715000117.tif155170.

[0365] In certain embodiments, the compound of the present invention is the following compound: [ka] TIFF0007867715000119.tif163170, TIFF0007867715000120.tif255170, or their two-seat or three-seat forms are selected.

[0366] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, one can choose from a two-seat or three-seat configuration.

[0367] In a particular embodiment, the D factor targeting ligand is [ka] Selected from.

[0368] In certain non-limiting embodiments, the D-factor degradable compound of the present invention is the following compound: [ka] TIFF0007867715000124.tif187170TIFF0007867715000125.tif200170 or their two-seat or three-seat forms are selected.

[0369] Non-limiting examples of complement D factor-degrading compounds include: [ka] TIFF0007867715000127.tif186170 is one example.

[0370] H factor In some embodiments, the target extracellular protein is human complement H factor (UniProtKB - P08603(CFAH_HUMAN)). Complement H factor 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 H factor 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.

[0371] 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.

[0372] 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).

[0373] Complement component 5 (C5) In some embodiments, the target extracellular 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.

[0374] 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).

[0375] 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).

[0376] In a particular embodiment, the extracellular targeting ligand is [ka] Selected from, each is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule.

[0377] 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.

[0378] In a particular embodiment, the C5-targeting ligand is [ka] Selected from.

[0379] In a particular embodiment, the C5-targeting ligand is [ka] Selected from.

[0380] Non-limiting examples of complement C5-degrading compounds include: [ka] These are some examples.

[0381] Complement C1s In certain embodiments, the extracellular targeting ligand is a C1s targeting ligand.

[0382] 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.

[0383] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, one can choose from a two-seat or three-seat configuration.

[0384] MASP In a particular embodiment, the extracellular targeting ligand is a MASP targeting ligand.

[0385] 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.

[0386] In certain embodiments, the MSAP-1 targeting ligand is an SGMI-1 peptide linked via the N-terminus or C-terminus.

[0387] In certain embodiments, the MSAP-1 targeting ligand is an SGMI-2 peptide linked via the N-terminus or C-terminus.

[0388] In certain embodiments, the MSAP-1 targeting ligand is a TFMI-3 peptide linked via the N-terminus or C-terminus.

[0389] Factor XIa In certain embodiments, the extracellular targeting ligand is a factor XIa targeting ligand.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] In a particular embodiment, the factor XIa-targeting ligand-linker is [ka] That is the case.

[0394] In certain embodiments, the compound of the present invention is the following compound: [ka] Alternatively, one can choose from a two-seat or three-seat configuration.

[0395] 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.

[0396] [ka]

[0397] In a particular embodiment, the factor XIa targeting ligand is [ka] Selected from.

[0398] Degradation of immunoglobulins Immunoglobulins, such as IgG, can induce, regulate, or exacerbate diseases in vivo, including abnormal cell proliferation such as tumors and cancers, autoimmune disorders, inflammation, and age-related diseases. For example, immunoglobulins often bind to cell surface receptors and initiate abnormal signaling in numerous diseases, including cancer and inflammation.

[0399] Immunoglobulin degraders described herein or their pharmaceutically acceptable salts and / or pharmaceutically acceptable compositions thereof can be used to treat immunoglobulin-mediated disorders that bind to immunoglobulin-targeting ligands. The degraders described herein can target and lysosomal degradate immunoglobulins that mediate pathological disorders. Selected immunoglobulins can modulate disorders in humans through mechanisms of action such as modification of biological pathways, pathogenic signaling, or modulation of signal cascades or cellular entry. Immunoglobulins are recruited together with immunoglobulin-targeting ligands, which are ligands for immunoglobulins.

[0400] Accordingly, in some embodiments, methods are provided for treating a host with an immunoglobulin-mediated disorder, comprising administering to a host, typically a human, an effective amount of an immunoglobulin-targeting degrader or a pharmaceutically acceptable salt thereof described herein, optionally in a pharmaceutically acceptable composition.

[0401] Immunoglobulins can be either normal or abnormal forms of proteins. For example, immunoglobulins may be mutant proteins, or proteins in which partial or complete gain-of-function or loss-of-function is encoded by nucleotide polymorphisms.

[0402] Targeting of specific immunoglobulins is achieved by the present invention through the use of specific immunoglobulin targeting ligands. Target immunoglobulins of the present invention include, but are not limited to, immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE). These immunoglobulins mediate a wide range of diseases that can be treated with an effective amount of the disclosed ASGPR-binding immunoglobulin degraders described herein.

[0403] Immunoglobulin A (IgA) Abnormal expression of immunoglobulin A (IgA) mediates a wide range of autoimmune and immune-mediated disorders, particularly IgA nephropathy (also known as Buerger's disease), celiac disease, Crohn's disease, Henoch-Schönlein purpura (HSP) (also known as IgA vasculitis), 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), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis.

[0404] Specific degradation of IgA can be achieved by using IgA-specific immunoglobulin targeting ligands. In certain embodiments, the immunoglobulin targeting ligand used is the Opt peptide. Variants and derivatives of the IgA-specific Opt peptide suitable for use as IgA-specific immunoglobulin targeting ligands are described in Hatanaka et al. Journal of Biological Chemistry, 287(51) 43126-43136. In certain embodiments, the IgA-specific immunoglobulin targeting ligand is Opt-1. In certain embodiments, the IgA-specific immunoglobulin targeting ligand is Opt-2. In certain embodiments, the IgA-specific immunoglobulin targeting ligand is Opt-3.

[0405] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0406] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0407] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0408] In certain embodiments, the immunoglobulin-targeting ligand is [ka] That is the case.

[0409] 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).

[0410] Representative IgA-targeting ligands are shown in Figure 1.

[0411] Further representative IgA-targeting ligands include: Sequence ID 1, MLKKIE (Jerlstrom et al. Infect. Immun. 1996 Jul; 64(7):2787-2793), Sequence ID No. 2, Opt-1 - HMVCLAYRGRPVCFAL (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), Sequence ID 3, Opt-2 - HMVCLSYRGRPVCFSL (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), Sequence ID No. 4, Opt-3 - HQVCLSYRGRPVCFST (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), Sequence ID No. 5, QMRCLSYKGRRVCLWL (US Patent No. 9593147), Sequence ID No. 6 KRLCLQYKGSKVCFRL (US Patent No. 9593147), Sequence ID 7, RMRCLTYRGRRVCLEL (US Patent No. 9593147), SMRCLQYRGSRVCLTL (US Patent No. 9593147), Sequence ID No. 8 Sequence ID No. 9, HLRCLRYKGTRVCFSL (US Patent No. 9593147), Sequence ID No. 10, HVRCLSYKGREVCVQL (US Patent No. 9593147), Sequence ID No. 11 PRMCLFIYKGRRVCIPY (U.S. Patent No. 9593147), Sequence ID No. 12 HMRCLHYKGRRVCFLL (US Patent No. 9593147), Sequence ID No. 13 HKRCLHYRGRMVCFLI (U.S. Patent No. 9593147), Sequence ID No. 14 QKRCLKYKGSRVCFFL (US Patent No. 9593147), Sequence ID No. 15, HVRCLRYRGKNVCFLL (US Patent No. 9593147), Sequence ID No. 16, SDVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 17, RDVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 18, HDVCLRYRGRPVCFQV (U.S. Patent No. 9593147), SMVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 19 SAVCLRYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 20 Sequence ID No. 21, SDVCLNYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 22, SDVCLHYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 23, SDVCLAYRGRPVCFQV (US Patent No. 9593147), Sequence ID No. 24, SDVCLRYRGRPVCFAV (U.S. Patent No. 9593147), Sequence ID No. 25, SDVCLRYRGRPVCFQL (US Patent No. 9593147), Sequence ID No. 26, SDVCLRYRGRPVCFQA (US Patent No. 9593147), Sequence ID No. 27, HMVCLSYRGRPVCF (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 28, HMVCLSYRGRPVCFS (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 29, HQVCLSYRGQPVCFSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 30, HQVCLSYRGRPTCFSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 31, HQVCLSYRGRPVCYSL (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 32, HQVCLSYRGQPVCFST (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 33, HQVCLSYRGRPTCFST (U.S. Patent Application Publication No. 2015 / 0044701), Sequence ID No. 34, HQVCLSYRGQPTCFST (U.S. Patent Application Publication No. 2015 / 0044701), These are some examples.

[0412] In a particular embodiment, the IgA-targeting ligand is [ka] That is the case.

[0413] Non-limiting examples of IgA-degrading compounds include: [ka] Examples include TIFF0007867715000143.tif163170, TIFF0007867715000144.tif103170, TIFF0007867715000145.tif201170, TIFF0007867715000146.tif166170, and TIFF0007867715000147.tif95170.

[0414] Immunoglobulin G (IgG) Immunoglobulin G (IgG) mediates a wide range of autoimmune diseases, infectious diseases, and metabolic disorders, including systemic fibroinflammatory diseases. Furthermore, IgG4 overexpression is generally associated with multi-organ IgG4-related diseases, including, in particular, type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, matt fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumor (in various parts of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond's disease), aortitis and periaortitis, proximal bile duct stenosis, idiopathic hypocomplementemia 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, and psoriatic arthritis. These include systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammaglobulinemia, monoclonal gammaglobulinemia of unknown significance (MGUS), melanoma, bullous pemphigoid, Goodpasture's disease, encephalitis, thrombotic thrombocytopenic purpura, immune thrombocytopenia, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM sleep disorders, as well as membranous nephropathy, multiple sclerosis, hyperthyroidism-Graves disease, acquired epidermolysis bullosa, pemphigoid of pregnancy, anti-p200 pemphigoid, and paraneoplastic pemphigus.

[0415] Specific degradation of IgG can be achieved by using IgG-specific immunoglobulin targeting ligands. In certain embodiments, the immunoglobulin targeting ligand binds to the Fc region of IgG. In certain embodiments, the IgG-specific immunoglobulin targeting ligand is an Fc-binding peptide. In certain embodiments, the IgG-specific immunoglobulin targeting ligand is Fc-BP2. In certain embodiments, the IgG-specific immunoglobulin targeting ligand is Fc-III.

[0416] In certain alternative embodiments, any compound described herein that has the stereochemistry described for a targeted ligand is described herein without stereochemistry. For example, in certain embodiments, [ka] teeth, [ka] is, or, [ka] teeth, [ka] That is the case.

[0417] In certain embodiments, the compound of the present invention is [ka] or their pharmaceutically acceptable salts.

[0418] In certain embodiments, the compound of the present invention is [ka] or their pharmaceutically acceptable salts.

[0419] In certain embodiments, the compound of the present invention is [ka] TIFF0007867715000155.tif169170 or a pharmaceutically acceptable salt thereof.

[0420] In certain embodiments, the compound of the present invention is [ka] TIFF0007867715000157.tif150170, TIFF0007867715000158.tif150170, or pharmaceutically acceptable salts thereof.

[0421] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0422] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0423] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0424] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0425] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0426] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0427] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0428] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0429] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0430] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0431] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0432] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0433] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0434] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0435] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0436] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0437] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0438] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000177.tif217170(In the formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0439] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000180.tif147170(In this formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0440] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000183.tif201170TIFF0007867715000184.tif124170(In the formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0441] In certain embodiments, the immunoglobulin-targeting ligand is [ka] That is the case.

[0442] In certain embodiments, the immunoglobulin-targeting ligand is [ka] That is the case.

[0443] In certain embodiments, the immunoglobulin-targeting ligand is [ka] That is the case.

[0444] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000190.tif201170TIFF0007867715000191.tif124170(In the formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0445] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000194.tif223170 (In this formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0446] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000197.tif156170 (In this formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0447] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000200.tif199170TIFF0007867715000201.tif158170(In the formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0448] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF0007867715000204.tif201170TIFF0007867715000205.tif126170(In the formula, the extracellular protein targeting ligand is, [ka] (These are selected from their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.)

[0449] 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 are also provided, searchable by al., Science, 2001, 293: 1155-1159). 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).

[0450] Representative IgG-targeting ligands are shown in Figure 1.

[0451] 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.

[0452] In other embodiments, the IgG-targeting ligand is [ka] Selected from.

[0453] 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).

[0454] 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).

[0455] 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.

[0456] In some embodiments, the IgG-targeting ligand is a peptide. Non-limiting examples of IgG-targeting ligand peptides include: PAM(RTY)4K2KG (Sequence ID 35) (Fassina, et al, J. Mol. Recognit. 1996, 9, 564-569) [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 of sequence number 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 of SEQ ID NO: 37, Sequence ID 38, TWKTSRISIF (Krook, et al, J. Immunol. Methods 1998, 221, 151-157), Sequence ID 39, FGRLVSSIRY (Krook, et al, J. Immunol. Methods 1998, 221, 151-157), Sequence ID No. 40, Fc-III (DCAWHLGELVWCT-NH2) (DeLano et al, Science 2000, 287, 1279-1283) [ka] Sequence ID 41, FCBP-Ser DSAWHLGELWST (International Publication No. 2014 / 010813), Sequence ID 42, DCHKRSFWADNCT (see International Publication No. 2014 / 010813), Sequence ID 43, DCRTQFRPNQTCT (see International Publication No. 2014 / 010813), DCQLCDFWRTRCT, sequence number 44 (see International Publication No. 2014 / 010813), DCFEDFNEQRTCT, Sequence ID No. 45 (see International Publication No. 2014 / 010813), DCLAKFLKGKDCT, sequence number 46 (see International Publication No. 2014 / 010813), Sequence ID 47, DCWHRRTHKTFCT (see International Publication No. 2014 / 010813), DCRTIQTRSCT, Sequence ID No. 48 (see International Publication No. 2014 / 010813), DCIKLAQLHSVCT, sequence number 49 (see International Publication No. 2014 / 010813), DCWRHRNATEWCT, sequence number 50 (see International Publication No. 2014 / 010813), DCQNWIKDVHKCT, Sequence ID No. 51 (see International Publication No. 2014 / 010813), See Sequence ID No. 52 DCAWHLGELVWCT (see International Publication No. 2014 / 010813), See Sequence ID No. 53 DCAFHLGELVWCT (International Publication No. 2014 / 010813), Sequence ID 54, DCAYHLGELVWCT (see International Publication No. 2014 / 010813), Sequence ID 55, FcBP-1 PAWHLGELVWP (Kang, et al, J. Chromatogr. A 2016, 1466, 105-1 12) [ka] Sequence ID No. 56, FcBP-2 PDCAWHLGELVWCTP (Dias, et al, J. Am. Chem. Soc. 2006, 128, 2726-2732); [ka] Sequence ID No. 57, Fc-lll-4c CDCAWHLGELVWCTC (Gong, et al, Bioconjug. Chem. 2016, 27, 1569-1573) [ka] EPIHRSTLTALL (SEQ ID NO: 58, Ehrlich, et al, J. Biochem. Biophys. Method 2001, 49, 443-454), APAR of sequence number 59 (Camperi, et al, Biotechnol. Lett. 2003, 25, 1545-1548), FcRM(CFHH) 2KG (Fc receptor mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242-1253) [ka] Sequence ID 61, HWRGWV (Yang, et al., J Peptide Res. 2006, 66, 110-137), Sequence ID 62, HYFKFD (Yang, et al, J. Chromatogr. A 2009, 1216, 910-918), Sequence ID 63, HFRRHL (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104), HWCitGWV (Sequence ID 64, Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104), Sequence ID 65, HWmetCitGWmetV (US Patent No. 10,266,566), D2AAG (small synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158-167), SEQ 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] of sequence number 68 (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237), Cyclo[(Nα-Ac)-Dap(A)-RWHYFK-Lact-E] of sequence number 69 (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237), Cyclo[Link M-WFRHYK] of sequence number 70 (Menegatti, et al, Biotechnol. Bioeng. 2013, 110, 857-870), Sequence ID No. 71, NKFRGKYK (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40), NARKFYKG, sequence number 72 (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40), Sequence ID 73 FYWHCLDE (Zhao, et al, Biochem. Eng. J. 2014, 88, 1-11), Sequence ID 74, FYCHWALE (Zhao, et al, J Chromatogr. A 2014, 1355, 107-114), FYCHTIDE (SEQ ID NO: 75, Zhao, et al., Z Chromatogr. A 2014, 1359, 100-111), Dual 1 / 3 (FYWHCLDE-FYCHTIDE) of sequence number 76 (Zhao, et al, J. Chromatogr. A 2014, 1369, 64-72), RRGW of sequence number 77 (Tsai, et al, Anal. Chem. 2014, 86, 2931-2938), Sequence ID 78, KHRFNKD (Yoo and Choi, BioChip J. 2015, 10, 88-94), CPSTHWK, sequence number 79 (Sun et al. Polymers 2018, 10, 778), Sequence ID No. 80, NVQYFAV (Sun et al. Polymers 2018, 10, 778), ASHTQKS, sequence number 81 (Sun et al. Polymers 2018, 10, 778), QPQMSHM, sequence number 82 (Sun et al. Polymers 2018, 10, 778), TNIESLK, sequence number 83 (Sun et al. Polymers 2018, 10, 778), Sequence ID No. 84, NCHKCWN (Sun et al. Polymers 2018, 10, 778), SHLSKNF, sequence number 85 (Sun et al. Polymers 2018, 10, 778), These are some examples.

[0457] In some embodiments, the IgG-targeting ligand is specific to IgG4.

[0458] In some embodiments, IgG4-specific targeted ligands are described in Gunnarsson et al. Biomolecular Engineering 2006, 23, 111-117.

[0459] In some embodiments, the IgG4-specific targeted ligand is FDLLEHFY, sequence number 86, and DLLHHFDYF, sequence number 87, Selected from.

[0460] Additional IgG-targeting ligands include: [ka] TIFF0007867715000220.tif216170 and TIFF0007867715000221.tif102170 are examples.

[0461] Non-limiting examples of IgG-degrading compounds include: [ka] TIFF0007867715000223.tif204170TIFF0007867715000224.tif177170TIFF0007867715000225.tif184170TIFF00078 67715000226.tif194170TIFF0007867715000227.tif182170TIFF0007867715000228.tif240170TIFF00078677150002 29.tif179170TIFF0007867715000230.tif185170TIFF0007867715000231.tif199170TIFF0007867715000232.tif102170TIFF0007867715000233.tif201170TIFF0007867715000234.tif188170TIFF0007867715000235.tif177170 are examples.

[0462] In alternative embodiments, the hydroxyl, amine, amide, or carboxylic acid groups in the extracellular protein targeting ligands described herein are occluded with protecting groups. For example, in this embodiment, [ka] teeth, [ka] It is possible.

[0463] In alternative embodiments, instead of the depicted attachment points, hydroxyl groups, amine groups, amide groups, or carboxylic acid groups in the extracellular protein targeting ligand depicted herein are used as attachment points to the linker. For example, in this embodiment, [ka] teeth, [ka] It is possible.

[0464] Immunoglobulin E (IgE) Immunoglobulin E (IgE) is not limited to, but is particularly associated with atopic asthma, allergic rhinitis, atopic dermatitis, skin contact hypersensitivity, IgE-mediated food allergies, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, eosinophilic gastrointestinal diseases, bullous pemphigoid, chemotherapy-induced hypersensitivity reactions, seasonal allergic rhinitis, interstitial cystitis, and eosinophilic gastrointestinal diseases. It is a potent mediator of allergic diseases, including acidophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic obstructive pulmonary disease, gastroenteritis, hyper-IgE syndrome (Job's syndrome), IgE monoclonal gammaglobulinemia, monoclonal gammaglobulinemia of unknown significance (MGUS), pemphigus vulgaris, mucosal pemphigoid, chronic urticaria, autoimmune uveitis, rheumatoid arthritis, autoimmune pancreatitis, and allergic rhinoconjunctivitis.

[0465] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0466] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0467] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0468] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0469] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0470] In certain embodiments, the immunoglobulin-degrading compound is [ka] or a pharmaceutically acceptable salt thereof.

[0471] In certain embodiments, the immunoglobulin-targeting ligand is [ka] That is the case.

[0472] In a particular embodiment, the IgE-targeting ligand is [ka] Selected from TIFF0007867715000248.tif181170.

[0473] Non-limiting examples of IgE-degradable compounds include: [ka] TIFF0007867715000250.tif213170 and TIFF0007867715000251.tif187170 are examples.

[0474] Anti-MAG IgM autoantibody In some embodiments, the target extracellular protein is an anti-MAG IgM autoantibody. Myelin-associated glycoprotein (MAG) is a transmembrane glycoprotein that plays a role in glial-axon interactions in the nervous system. In some patients, IgM anti-MAG antibodies develop, leading to neuropathy. Antibody levels four times higher than normal can lead to nephropathy. A decrease in anti-MAG antibody levels is associated with a clinical response in polyneuritis.

[0475] Typical targeted ligands that bind to anti-MAG IgM autoantibodies include: HSO3-3GlcAβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer, HSO3-3GlcAβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glcβ1-Cer, HSO3-3GlcAβ1-3Galβ1-4GlcNAc-X, [ka] These are some examples.

[0476] Additional IgM autoantibodies that can be used in the present invention are described in Herrendorff, R. et al. 2017 PNAS Early Edition, doi / 10.1073 / pnas.1619386114 and International Publication No. 2018 / 167230.

[0477] Non-limiting examples of IgM autoantibody-degrading compounds include: [ka] TIFF0007867715000254.tif161170 is one example.

[0478] In certain non-limiting embodiments, the IgM autoantibody-degrading compound is the following compound: [ka] Selected from TIFF0007867715000256.tif201170, TIFF0007867715000257.tif109170, or their bidentate or tridentate forms, or pharmaceutically acceptable salts thereof.

[0479] Phospholipase A2 receptor-1 (PLA2R) autoantibody In some embodiments, the target extracellular protein is an autoantibody that binds to PLA2R. Phospholipase A2 receptor-1 (PLA2R) is a primary target in autoimmune membranous nephropathy. Membranous nephropathy is one of the main causes of nephrotic syndrome, and most patients progress to end-stage renal disease. Current treatment strategies using anti-CD20 antibodies may not be effective in achieving complete remission. PLA2R is a transmembrane glycoprotein with a cysteine-rich N-terminal extracellular domain. This domain contains an epitope to which autoantibodies bind. A reduction in autoantibody levels may bring relief to patients, but complete elimination of the autoantibodies may be necessary to achieve permanent remission.

[0480] The Protein Databank provides the crystal structure of the CTLD7 domain of PLA2R, the region to which autoantibodies bind (6JLI; Yu et al. J. Struct. Biol. 207, 295-300). Representative PLA2R autoantibody-binding ligands are not limited to these, but... Sequence ID 88, GIFVIQSESLKKC (Fresquet et al. J. Am. Soc. Nephrol 2015, 26, 302), SEQ ID NO: 89, SVLTLENCK (Fresquet et al. J. Am. Soc. Nephrol 2015, 26, 302), Sequence ID No. 90, SVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 91, SVLTLDNCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 92, SVLTEENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 93, SVLTEENS (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 94, SVLTDENC (International Publication No. 2019 / 081912 by Brenchley et al.), SEQ ID NO. 95, SVLTDENS (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 96, PIQSESLKK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 97, VIDSESLKK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 98, PIDSESLKK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 99, VIQSESLKK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 100, PIESES-PEG-K-PEG-SVLTEENC (International Publication No. 2019 / 081912 by Brenchley et al.), TLENC of VIQSES-PEG-K-PEG-SVL, SEQ ID NO. 101 (International Publication No. 2019 / 081912 by Brenchley et al.), TEENC of VIQSES-PEG-K-PEG-SVL, SEQ ID NO. 102 (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 103, PIDDES-PEG-K-PEG-SVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 104, PIDDES-PEG-KPEG-SVLTEENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 105, VIQSESLKKCKSVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 106, PIQSESLKKCKSVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 107, VIESESLKKCKSVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 108, VIDSESLKKCKSVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 109, PIESESLKKCKSVLTLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 110, VIQSESLKKCIQAGKLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 111, PIQSESLKKCIQAGKLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 112, VIESESLKKCIQAGKLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 113, VIDSESLKKCIQAGKLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 114, PIESESLKKCIQAGKLENC (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 115, PIQSESLKKCKSVLTLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 116, VIESESLKKCKSVLTLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 117, VIDSESLKKCKSVLTLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 118, PIESESLKKCKSVLTLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 119, VIQSESLKKCIQAGKLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 120, PIQSESLKKCIQAGKLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 121 VIESESLKKCIQAGKLENK (International Publication No. 2019 / 081912 by Brenchley et al.) Sequence ID 122, VIDSESLKKCIQAGKLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 123, PIESESLKKCIQAGKLENK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 124, PIESESGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 125, PIESESGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 126, PIESESGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 127, PIESESGGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 128, PIESESGGGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 129, VIQSESGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 130, VIQSESGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 131, VIQSESGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 132, VIQSESGGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 133, VIQSESGGGGGSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 134 KGCFVIQSESLKKSIQAGKSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 135, LKKCIQAGKSVLTLENCKQAN (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 136, WQDKGIFVIQSESLKKCIQAGK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID No. 137 KGIFVIQSESLKKCIQAGKSVLTLENCK (International Publication No. 2019 / 081912 by Brenchley et al.), Sequence ID 138, GIFVIQSESLKKC (International Publication No. 2015 / 185949 by Brenchley et al.), Sequence ID No. 139 WSVLTLENCK (International Publication No. 2015 / 185949 by Brenchley et al.), Sequence ID 140 WQDKGIFVIQSESLKKCIQAGKSVLTLENCK (International Publication No. 2015 / 185949 by Brenchley et al.), Sequence ID No. 141, YDWIPSSAW (Glee et al., the journal of immunology, 1999, 163:826-833), AGAIWQRDW, sequence number 142, AGAIWQKDW, sequence number 143 VIQSESLK, sequence number 144, PIQSESLK, sequence number 145, PIESESLK, sequence number 146, SVLTEENCK, sequence number 147, These are some examples.

[0481] In a particular embodiment, the following formula: [ka] Compounds of (wherein PLA2R autoantibodies are any PLA2R autoantibodies described in International Publication No. 2019 / 081912) or pharmaceutically acceptable salts thereof are provided.

[0482] In a particular embodiment, the PLA2R autoantibody is expressed by the following formula: Sequence ID 148: SVLT-XH1-EN-XH2, Sequence ID 149: XH3-I-XH4-XH5-E-XH6, Sequence ID 150: XH1-EN-XH2-K, Sequence ID 151: SVLT-XH1-ENCK, Sequence ID 152: XH3-I-XH4-XH5-E-XH6-LK, The antibody, or the peptide of SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, or SEQ ID NO: 152 linked via a linker-B group, wherein in a particular embodiment, the linked sequence is SEQ ID NO: 148 and SEQ ID NO: 149, or SEQ ID NO: 148 and SEQ ID NO: 152, In the formula, XH1, XH2, XH3, XH4, XH5, and XH6 are independently any natural amino acid or other amino acids described herein, The sequence is linked to a linker as described herein by a terminal amine or terminal carboxylic acid.

[0483] Non-limiting examples of PLA2R-degrading compounds include: [ka] Examples include TIFF0007867715000260.tif218170, TIFF0007867715000261.tif222170, TIFF0007867715000262.tif221170, and TIFF0007867715000263.tif109170.

[0484] Complement C3 In some embodiments, the target extracellular protein is complement C3. Complement C3 is one of the major proteins involved in the complement response and is a crucial factor in both innate and adaptive immunity. Elevated C3 levels are associated with paroxysmal nocturnal hemoglobinuria (PNH), membranoproliferative glomerulonephritis (IC-MPGN), C3 nephropathy (C3G), geographic (GA), age-related macular degeneration (AMD), periodontitis, amyotrophic lateral sclerosis (ALS), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), cold agglutinin disease (CAD), and host attack in gene therapy. Lowering C3 levels may improve some of the symptoms or complications arising from these inflammatory diseases.

[0485] The Protein Data Bank website provides the crystal structure of complement C3, searchable by 2A73 (Janssen, BJ Nature, 2005, 505-511). Complement C3 bound to nanobody inhibitors can be found using PDB accession code 6EHG (Jensen, RK et al. J Biol Chem, 2018, 293, 6269-6281). Non-limiting examples of complement C3-binding ligands include: D-Tyr-Ile-[Cys-Val-1MeTrp-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-meIle of SEQ ID NO: 153 (Zhang, Y. et al. 2015, Immunobiology, 220, 993-998), Sequence ID 154, ICVVQDWGHHRCTAGMANLTSHASAI, (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), Sequence ID 155, ICVVQDWGHHRCT, (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), Sequence ID No. 156, CVVQDWGHHAC (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), Sequence ID 157, Ac-ICVVQDWGHHRCT-NH2, (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Sequence ID 158, CVVQDWGHHRCT-NH2, (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Sequence ID 159, CVVQDWGHHRC-NH2, (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-ICVVGDWGHHRCT-NH2, SEQ ID NO: 160 (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-I of sequence number 161 * CVVQPWGHHRC * T-NH2,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Biotin-KYSSI, sequence number 162 * CVVQDWGHHRC * T-NH2,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-I of sequence number 163 * CVVQDWGHHRC *TAGHMANLTSHASAK-Biotin,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Sequence ID 164, Ac-ICV(1mW)QDWGAHRCT, (Risitano et al. Blood, 2014, 123, 2094) Sequence ID 165, yICV(1mW)QDW-Sar-AHRC-mI, (Risitano et al. Blood, 2014, 123, 2094) Sequence ID 166 PEG-yICV(1mW)QDW-Sar-AHRC-mI (Risitano et al. Blood, 2014, 123, 2094) [ka] Sequence ID No. 167, Ac-Ile-[Cys-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-Thr-NH2 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Sequence ID 168, Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-Ile-NH2 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Sequence ID 169, Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-mIle-NH2 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Sequence ID No. 170, Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-Thr-NH2) (Qu, H. et al. Molecular Immunology, 2011, 48, 481), Sequence ID No. 171, Ac-Xaa1-[Cys2-Val3-Xaa4-Gln5-Asp6-Trp7-Gly8-Xaa9-Xaa10-Xaa11-Cys12]-Thr13-NH2 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVVQDWGHHRC]T-NH2 (Sequence ID 172, Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVVQDWGAHRC]T-NH2 (Sequence ID 173, Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVTQDWGHHRC]T-NH2 (Sequence ID 174, Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVSQDWGHHRC]T-NH2 (Sequence ID 175, Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVHQDWGHHRC]T-NH2, SEQ ID NO: 176 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVFQDWGHHRC]T-NH2, SEQ ID NO: 177 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVYQDWGAHRC]T-NH2, SEQ ID NO: 178 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGWHRC]T-NH2 of SEQ ID NO: 179, (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGHHRC]T-NH2 of SEQ ID NO: 180, (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]T, of sequence number 181, (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]T-NH2 of SEQ ID NO: 182, (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAdHRC]T, SEQ ID NO: 183 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGdAHRC]T, with SEQ ID NO: 184 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-dI[CVWQDWGAHRC]T, of sequence number 185 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]dT, of sequence number 186, (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]T-NH2, SEQ ID NO: 187 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Sequence ID No. 188, W[CVWQDWGTNRC]W-NH2, (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Sequence ID No. 189, Ac-D[CVWQDWGTNKC]W-NH2, (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Sequence ID No. 190, Q[CVWQDWGQNQC]W-NH2, (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-I[CVWQDWGAHRC]W-NH2, sequence number 191 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-W[CVWQDWGAHRC]T-NH2, sequence number 192 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-W[CVWQDWGAHRC]W-NH2, sequence number 193 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Sequence ID No. 194, Ac-Ile-[Ala-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Hcy]-Thr-NH2, (Knerr, P. et al. ACS Chem. Biol., 2011, 6, 753-760), Sequence ID No. 195, Ac-Ile-[Cys-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-(NMeIle)-NH2, (Knerr, P. et al. ACS Chem. Biol., 2011, 6, 753-760), Ac-Ile-[Ala-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Hcy]-(NMeIle)-NH2, (Knerr, P. et al. ACS Chem. Biol., 2011, 6, 753-760), Sequence ID No. 197, Ac-ICV(5fW)QDWGAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID No. 198, Ac-ICV(5MeW)QDWGAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID No. 199, Ac-ICV(2Nal)QDWGAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID No. 200, Ac-ICVWQD(5fW)GAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID No. 201, Ac-ICVWQD(5MeW)GAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID No. 202, Ac-ICVWQD(1MeW)GAHRCT-NH2, (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Sequence ID 203, Ac-ICVYQDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 204, Ac-ICVWQDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID No. 205, Ac-ICVWQDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 206, Ac-ICVWQDWGAHRCdT-COOH, (International Publication No. 2021 / 007111), Sequence ID No. 207, Ac-ICV(2-Nal)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 208, Ac-ICV(2-Nal)QDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID 209, Ac-ICV(1-Nal)QDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID No. 210, Ac-ICV(2-lal)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 211, Ac-ICV(2-lal)QDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID No. 212, Ac-ICVDhtQDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID 213, Ac-ICV(Boa)QDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID 214, Ac-ICV(Bpa)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 215, Ac-ICV(Bta)QDWGAHRCT-COOH, (International Publication No. 2021 / 007111), Sequence ID No. 216, Ac-ICV(Bta)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 217, Ac-ICVWQDWG(2-Abu)HRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 218, H-GICVWQDWGAHRCTAN-COOH, (International Publication No. 2021 / 007111), CONH2 of Ac-ICV(5fW)QDWGAHRCT-, sequence number 219 (International Publication No. 2021 / 007111), SEQ ID NO: 220, Ac-ICV(5-methyl-W)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), SEQ ID NO: 221, Ac-ICV(1-methyl-W)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 222, Ac-ICVWQD(5fW)GAHRCT-CONH2, (International Publication No. 2021 / 007111), CONH2 of Ac-ICV(5fW)QD(5fW)GAHRCT-, sequence number 223 (International Publication No. 2021 / 007111), SEQ ID NO: 224, Ac-ICV(5-methyl-W)QD(5fW)GAHRCT-CONH2, (International Publication No. 2021 / 007111), SEQ ID NO: 225, Ac-ICV(1-methyl-W)QD(5fW)GAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID No. 226, H-GICV(6fW)QD(6fW)GAHRCTN-COOH, (International Publication No. 2021 / 007111), Sequence ID 227, Ac-ICV(1-formyl-W)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID No. 228, Ac-ICV(1-methyloxy-W)QDWGAHRCT-CONH2, (International Publication No. 2021 / 007111), Sequence ID 229, H-GICV(5fW)QD(5fW)GAHRCTN-COOH, (International Publication No. 2021 / 007111), These are some examples.

[0486] In a particular embodiment, the complement C3-targeting ligand is [ka] That is the case.

[0487] In a particular embodiment, the complement C3-targeting ligand is [ka] Selected from TIFF0007867715000267.tif186170.

[0488] Non-limiting examples of complement C3-degrading compounds include: [ka] TIFF0007867715000269.tif216170TIFF0007867715000270.tif212170 are examples.

[0489] In certain non-limiting embodiments, the complement C3-degrading compound of the present invention is the following compound: [ka] TIFF0007867715000272.tif178170TIFF0007867715000273.tif171170TIFF0007867715000274.tif170170TIFF0007867715000275.tif180170TIFF0007867715000276.tif184170TIFF0007867715000277.tif88170 or selected from their two-seat or three-seat forms.

[0490] Complement C1q In some embodiments, the target extracellular protein is complement C1q. The complement system is part of the innate immune system and clears apoptotic cells and pathogens. Activation of this pathway begins with the binding of the C1 complex to an antigen-bound immunoglobulin. The C1 complex consists of a tetramer of C1q and proteases (C1r and C1s). C1q mediates the binding of complement to IgG or IgM. Following the binding event, the proteases are activated, and they cleave C4, initiating the remainder of the pathway which ends in opsonization. Overactivity of this pathway can cause many inflammatory pathologies, including allograft rejection, neuromyelitis optica, generalized myasthenia gravis, and cold agglutinin disease. Degradation of C1q may alleviate the symptoms associated with these inflammatory diseases.

[0491] The Protein Databank website provides crystal structures of complement C1q, searchable by 2JG9 (Paidassi, H. et al., J. Immunol, 2008, 180, 2329-2338), 1PK6 (Gaboriaud, C., J. Biol. Chem, 2003, (278) 46974-46982), 5HZF (Moreau, C. et al., Front. Immunol, 2016, (7) 79), 2WNV, and 2WNU (Garlatti, V. et. al., J. Immunol. 2010, (185), 808). Additionally, the PDB website provides structures of complement C1q bound to ligands, which can be searched using 6Z67 (Laursen, N. et al. Front. Immunol., 2020, (11), 1504).

[0492] Non-restrictive examples of complement C1q-binding ligands include: Ac-Ala-Glu-Ala-Lys-Ala-Lys-Ala-CONH2 (International Publication No. 88 / 07054), Sequence ID No. 230 IALILEPICCQERAA, sequence number 231 (Sharp, JA et al. PLoS ONE 10(7), e0132446), IALILEPICCQERAA-dPEG24, sequence number 232 (Sharp, JA et al. PLoS ONE 10(7), e0132446), dPEG24-IALILEPICCQERAA, sequence number 233 (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 234, RALILEPICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 235, IRLILEPICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), IARILEPICCQERAA, sequence number 236 (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 237, IALIREPICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), IALILEPICCRERAA, sequence number 238 (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 239, IALILEPICCQRRAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 240, IELILEPICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 241, IAEILEPICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 242, IALILEPICCQEEAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 243, IALILEPICCQEREA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 244, IALILEEICCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 245, IALILEPECCQERAA (Sharp, JA et al. PLoS ONE 10(7), e0132446), Sequence ID 246, PAICQRATATLGTVGSNTSGTTAIEACILL (Sharp, JA et al. Frontiers in Immunology (2014) 5, 406), Sequence ID No. 247, CEGPFGPRHDLTFCW (Roos, A. et al. The Journal of Immunology, 2001, 167, 7052), Sequence ID No. 248, XbEGPFGPRHDLTFCW (Roos, A. et al. The Journal of Immunology, 2001, 167, 7052), Sequence ID 249, QYYPFSX (Messmer BT et al. Molecular Immunology, 2000, 37, 343), NPFNLAR, sequence number 250 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID 251, QLQDMTSSPFWL (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 252, NPFVIGRWHPPH (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SEQ ID NO: 253, SLAKFLNPFLYR (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 254, ASTPRFEPFQLD (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 255, SLHSQPYSPFML (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 256, NILSSWSSPFVF (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 257, NLPSSWTNPFYL (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SPFMLHP, sequence number 258 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), PSPFMLT of sequence number 259 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), IGPFHLH, sequence number 260 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), TNPFMLN, sequence number 261 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), NTTFLYP, sequence number 262 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SHYTQYL, sequence number 263 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID 264, NHHPNYW (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID 265, VHYPLSW (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 266, HHLKYSDTSPPI (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SHMHERWDTSPPI, sequence number 267 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID 268, SHMHERWDTSYQ (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SHIHSNAAWRIT, sequence number 269 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID 270, WHYPHWQ (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SHYLYTQ, sequence number 271 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), AHYSFTQ, sequence number 272 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), THYPTFY, sequence number 273 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 274, EHNTSFW (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 275, NHYKLTW (Messmer BT et al. Molecular Immunology, 2000, 37, 343), Sequence ID No. 276, NHSPYFQ (Messmer BT et al. Molecular Immunology, 2000, 37, 343), SHYQHYQ, sequence number 277 (Messmer BT et al. Molecular Immunology, 2000, 37, 343), PAICQRATATLGTVGSNTSGTTEIEACILL (Gronemus, JQ et al. Molecular Immunology, 2010, 48, 305), SEQ ID NO: 278 Sequence ID 279, WLGLGGGYGW (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 280, FYGPFFLNDSLRGIW (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 281, LRFLNPFSLDGSGFW (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 282, HSPFCLGVLECFGLV (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 283, TCGAFYLYHDPFICG (Lauvrak V., Biol. Chem. 1997, 378, 1509), MQHCLASHELYLPWC (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 284, Sequence ID 285, FFVFGSGDAFAFSDM (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 286, PCVIIDTGSSRWCYL (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 287, HSPFCLGVLECFGLV (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 288, HAAFEPRGDVRHTLL (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 289, CRWDGSWGEVRC (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 290, CYWVGTWGEAVC (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 291, RWFPCPNKEGCCSISV (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 292, RSTYCNKNKDSCHIPE (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 293, QPPQCIKDGGFVICRV (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 294, KGKKCKPEEHPCNEPM (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 295, NKMTCSDDGKLCWEHL (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 296, PLGRPCPTCPLAPS (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 297, QRMRPCPSCPLAPW (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID 298, WPSRPCPSCPEVPP (Lauvrak V., Biol. Chem. 1997, 378, 1509), SCTKDCPTCPLVPV (Lauvrak V., Biol. Chem. 1997, 378, 1509), Sequence ID No. 299, Nanobody of C1qNb75 (Laursen, NS et al. Frontiers in Immunology, 2020, 11, 1504), Sequence ID No. 300, IALILEPICCQERAA (US Patent No. 8,906,845), PAICQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 301 PAIAQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 302 PAICQRATATLGTVGSNTSGTTEIEAAILL (US Patent No. 8,906,845), Sequence ID No. 303 PAICQRATATLGTVGSNTSGTTAIEACILL (US Patent No. 8,906,845), Sequence ID No. 304 PAICQRATATLGTVGSNTSGTTEIAACILL (US Patent No. 8,906,845), Sequence ID No. 305 PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 306, PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 307 PAIAQRAEIEAAILL (US Patent No. 8,906,845), Sequence ID No. 308 Sequence ID No. 309, IALILEPICCQERAA (US Patent No. 8,906,845), Sequence ID No. 310 PAICQRATATLGTNTSGTTEIEACILL (U.S. Patent No. 8,906,845), PAICQRATATLSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 311 PAICQRATATTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 312 PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 313 Sequence ID No. 314, AICQRATATLGTVGSNTSGTTEIEACILL (U.S. Patent No. 8,906,845), Sequence ID No. 315, ICQRATATLGTVGSNTSGTTEIEACILL (U.S. Patent No. 8,906,845), Sequence ID No. 316, CQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), PAICQRATATLGTVGSNTSGTTEIEACIL (US Patent No. 8,906,845), Sequence ID No. 317 PAICQRATATLGTVGSNTSGTTEIEACI (US Patent No. 8,906,845), Sequence ID No. 318, Sequence ID No. 319 PAICQRATATLGTVGSNTSGTTEIEAC (U.S. Patent No. 8,906,845), Sequence ID No. 320, Ac-IALILEPICCQERAA (U.S. Patent No. 8,906,845), Ac-PAICQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 321, Sequence ID No. 322, Ac-PAIAQRATATLGTVGSNTSGTTEIEACILL (U.S. Patent No. 8,906,845), Ac-PAICQRATATLGTVGSNTSGTTEIEAAILL (US Patent No. 8,906,845), Sequence ID No. 323, Ac-PAICQRATATLGTVGSNTSGTTAIEACILL (US Patent No. 8,906,845), Sequence ID No. 324 Sequence ID No. 325, Ac-PAICQRATATLGTVGSNTSGTTEIAACILL (U.S. Patent No. 8,906,845), Ac-PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 326 Ac-PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 327 Ac-PAIAQRAEIEAAILL (US Patent No. 8,906,845), Sequence ID No. 328 Sequence ID No. 329, Ac-IALILEPICCQERAA (U.S. Patent No. 8,906,845), Sequence ID No. 330, Ac-PAICQRATATLGTNTSGTTEIEACILL (U.S. Patent No. 8,906,845), Ac-PAICQRATATLSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 331 Ac-PAICQRATATTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 332 Ac-PAICQRAEIEACILL (US Patent No. 8,906,845), Sequence ID No. 333 Ac-AICQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 334, Ac-ICQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Sequence ID No. 335 Sequence ID No. 336, Ac-CQRATATLGTVGSNTSGTTEIEACILL (US Patent No. 8,906,845), Ac-PAICQRATATLGTVGSNTSGTTEIEACIL (US Patent No. 8,906,845), Sequence ID No. 337 Ac-PAICQRATATLGTVGSNTSGTTEIEACI (US Patent No. 8,906,845), Sequence ID No. 338, Sequence ID No. 339, Ac-PAICQRATATLGTVGSNTSGTTEIEAC (U.S. Patent No. 8,906,845), These are some examples.

[0493] In a particular embodiment, the linker is an amino acid sequence, for example, sequence number 231 [ka] It is bound via the C-terminus.

[0494] In a particular embodiment, the linker is, for example, SEQ ID NO: 231 [ka] It is attached to the N-terminus of

[0495] Non-limiting examples of complement C1q-degrading compounds include: [ka] These are some examples.

[0496] IL-17 In some embodiments, the target extracellular protein is human interleukin-17 (IL-17) (UniProtKB-Q16552(IL17_HUMAN)). Interleukin-17 is a 35 kDa homodimeric glycoprotein and a key cytokine for the inflammatory response. IL-17 is secreted by different classes of helper T cells (known as Th17 cells) that mediate tissue inflammation. A characteristic effect of IL-17 production is neutrophil proliferation, which is responsible for neutrophil homeostasis in healthy tissues. IL-17 is thought to be involved as a major factor not only in psoriasis but also in other autoimmune diseases. Other diseases in which IL-17 therapy may be beneficial include, but are not limited to, asthma, rheumatoid arthritis, psoriatic arthritis, Crohn's disease, and inflammatory bowel disease. Inflammation caused by IL-17 has been shown to hinder recovery after stroke.

[0497] The Protein Databank website lists the following proteins: 4NUX (Zhang, B. et al. (2014) Acta Crystallogr D Biol Crystallogr 70: 1476-1483), 4HSA (Liu, S. et al. (2013) Nat Commun 4: 1888-1888), 4QHU (unpublished), 6WIR (Lieu, R. et al. (2020) PLoS One 15: e0232311-e0232311), 5VB9 (Ting, JP et al. (2018) PLoS One 13: e0190850-e0190850), 4NUX (Zhang, et al. (2014) Acta Crystallogr D Biol Crystallogr 70: 1476-1483), 3JVF (Ely, LK et al. Crystal structures of IL-17 are available for retrieval via (2009) Nat Immunol 10: 1245-1251), 5N9B (unpublished), and 2VXS (Gerhardt, S. et al. (2009) J Mol Biol 394: 905).

[0498] Non-limiting examples of IL-17 targeting ligands include, for example, International Publications 2012 / 101263, 2020 / 163554, 2021 / 055376, 2020 / 146194, 2020 / 127685, U.S. Patent Application Publication 2015 / 0005319, 2014 / 066726, 2019 / 223718, and 2020 / 135872. International Publication No. 2020 / 146194, International Publication No. 2021 / 027721, International Publication No. 2021 / 027724, International Publication No. 2021 / 027729, International Publication No. 2021 / 067191, Chinese Published Patent No. 104069102, Chinese Announced Patent No. 105601617, Chinese Announced Patent No. 108299256, Liu et al., "Elucidation of the binding site and structural induction design of macrocyclic IL-17A antagonists (Binding "Site elucidation and structure-guided design of macrocyclic IL-17A antagonists" 2016, Scientific Reports, 6:30859; "Inhibiting complex IL-17AA and IL-17RA interactions with a linear peptide" by Liu et al. 2016, Scientific Reports 6:26071; "Artificial macrocycles as IL-17A / IL-17RA antagonists" by Wang, W. et al. Med. Chem. Comm. 2018, 9, 22; Liu, C.This can be found in the article "The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo" by et al., Science Signaling 10, eaaf8823 (2017).

[0499] Additional binding ligands include: Sequence ID 340, IVVTAPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 341, ITVTMPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 342, IVVTIPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 343, IVVTLPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 344, IVVTVPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 345, IVVTMPADLWDWIMA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID No. 346, IVVTMPADLWDWINA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 347, IVVTMPADLWDWIQA (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 348, IHVTIPADLWDWINK (Liu et al. 2016, Scientific Reports 6:26071), Sequence ID 349, IHVTIPADLWDWIN (Liu et al. 2016, Scientific Reports 6:26071), [ka] TIFF0007867715000282.tif214170TIFF0007867715000283.tif169170TIFF0007867715000284.tif197170TIFF0007867715000285.tif86170 are listed, and each is R 21 It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule.

[0500] In a particular embodiment, [ka] (In the formula, IL-17 targeted ligands are provided as compounds of any IL-17 ligand described in International Publication No. 2020 / 146194, International Publication No. 2020 / 163554, International Publication No. 2020 / 127685, and International Publication No. 2021 / 055376 (each of which constitutes part of this Specified Publication by reference), or as pharmaceutically acceptable salts thereof.

[0501] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] (In the formula, X D is CH or N, R D1-CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2CF3, -CH(CH3)2, CH2CHF2, CH2CH2F, -CF(CH3)2, CF2CH3, -OCH3, [ka] And, R D2 It is a ligand (which is -H or -CH2OCH3).

[0502] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] (In the formula, R E1 This includes alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, -OR E8 , or -NR E9 R E10 , or an F-pocket substituent, R E2 These are alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, condensed cycloalkylaryl, substituted condensed cycloalkylaryl, heteroaryl, substituted heteroaryl, or D-pocket substituent. Each R E3 These are independently hydrogen, (C1-C7) alkyl, substituted (C1-C7) alkyl, or -OR E32 And, m E is 0, 1, or 2, Each R E4 These are independently hydrogen, (C1-C7) alkyl, substituted (C1-C7) alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, or substituted heterocycle. k E is 0 or 1, X E1 , XE2 , X E3 , and X E4 These are independently -N- or -CR E11 -However, X E1 , X E2 , X E3 , and X E4 Two or fewer of these are nitrogen atoms. Each R E5 These are independently hydrogen, (C1-C7) alkyl, substituted (C1-C7) alkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, heterocyclic alkyl, substituted heterocyclic alkyl, -NR E12 R E13 , -NR E14 C(O)R E15 , -NHSO2R E31 , OH, or B pocket substituent, R E6 is hydrogen or alkyl, R E7 is a hetero ring, a substituted hetero ring, -(CHR E16 ) o R E17 , or -(CHR E18 ) p R E19 is or R E6 and R E7 These, together with the nitrogen atom to which they are attached, form piperazine, substituted piperazine, heterocycle, or substituted heterocycle. [ka] Alternatively, form an A pocket substituent, R E8 These are (C1-C7) alkyl, substituted (C1-C7) alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Each R E11 These are independently hydrogen, alkyl, substituted alkyl, -OR E20 , -N RE21 R E22 , Halo, -CN, -CO2R E23 ,-CONR E24 R E25, or -SR E26 And, n E is 1, 2, or 3, o E is 1, 2, or 3, p E is 1, 2, or 3, Each R E16 These are independently hydrogen, (C1-C7) alkyl, or substituted (C1-C7) alkyl. R E17 teeth, [ka] And, Each R E18 These are independently hydrogen, (C1-C7) alkyl, or substituted (C1-C7) alkyl. R E19 -NR E27 R E28 And, R E27 and R E28 These, together with the nitrogen atom to which they are attached, form a heterocycle or a substituted heterocycle or [ka] Forming, R E9 , R E10 , R E12 , R E13 , R E14 , R E15 , R E18 , R E19 , R E20 , R E21 , R E22 , R E23 , R E24 , R E25 , R E26 , R E30 , R E31 , and R E32 Independently, in each case, is selected from hydrogen, alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, or alternatively, independently, RE9 and R E10 , R E21 and R E22 , and R E24 and R E25 These, together with the attached atoms, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. R E28 is hydrogen or alkyl, A pocket substituent is [ka] Selected from the group consisting of, B pocket substituent is [ka] Selected from the group consisting of, D-pocket substituents are [ka] Selected from the group consisting of, F pocket substituent is [ka] Selected from the group consisting of, In the formula, each of the substituents in the above formula is independently a halogen, -OR F12 , -SR F12 , -N(R F12 )2, -C(O)R F12 ,-C(O)N(R F12 )2, N(R F12 )C(O)R F12 , -C(O)OR F12 ,-OC(O)R F12 ,-S(O)R F12 -S(O)2R F12 -NO2, =O, =S, =N(R F12 ), -CN, C 3~10 Selected from carbon rings and 3- to 10-membered heterorings, where C 3~10Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F12 , -N(R F12 )2, -C(O)R F12 ,-C(O)N(R F12 )2, -N(R F12 )C(O)R F12 , -C(O)OR F12 ,-OC(O)R F12 -NO, =O, =N(R F11 It is a ligand of (which is optionally substituted with one or more substituents selected from -CN).

[0503] In a particular embodiment, the I-17 targeted ligand is of formula: [ka] It is a ligand for [the substance / function].

[0504] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] (In the formula, [ka] is an arbitrarily substituted C 3~12 Selected from carbon rings and optionally substituted 3- to 12-membered heterocycles, where substituents on ring AF are independently, in each case, Halogen, -OR F11 , -SR F11 , -N(R F11 )2, -C(O)R F11 ,-C(O)N(R F11 )2, N(R F11 )C(O)R F11 , -N(R F11 )S(O)2R F11 , -C(O)OR F11 ,-OC(O)R F11 ,-S(O)R F11 -S(O)2R F11 -NO2, =O, =S, =N(R F11 ), -CN, and, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl (each is a halogen, -OR) F11 , -SR F11 , -N(R F11 )2, -C(O)R F11 ,-C(O)N(R F11 )2, N(R F11 )C(O)R F11 , -C(O)OR F11 ,-OC(O)R F11 ,-S(O)R F11 -S(O)2R F11 -NO2, =O, =S, =N(R F11 ), -CN, C 3~10 It is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle, where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F11 , -N(R F11 )2, -C(O)R F11 ,-C(O)N(R F11 )2, -N(R F11 )C(O)R F11 -C(O)OR11, -OC(O)R11, -NO2, =O=N (each optionally substituted with one or more substituents selected from R11 and -CN'), and C 3~12 Carbon rings and 3- to 12-membered heterocycles (each containing halogens, -OR compounds) F11 , -SR F11 , -N(R F11 )2, -C(O)R F11 ,-C(O)N(R F11 )2, N(R F11 )C(O)R F11 , -C(O)OR F11 ,-OC(O)R F11 -NO2, -CN, C 1~6 Alkyl and C 1~6 (Optionally substituted with one or more substituents independently selected from the haloalkyl group), Selected from, [ka] is an arbitrarily substituted C 3~10 Selected from carbon rings and optionally substituted 3- to 12-membered heterocycles, each substituent on ring B is independently, in each case, Halogen, -OR F12 , -SR F12 , -N(R F12 )2, -C(O)R F12 ,-C(O)N(R F12 )2, -N(R F12 )C(O)R F12 , -C(O)OR F12 ,-OC(O)R F12 ,-S(O)R F12 -S(O)2R F12 -NO2, =O, =S, =N(R F12 ), -CN, and, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl (each is a halogen, -OR) F12 , -SR F12 , -N(R F12 )2, -C(O)R F12 ,-C(O)N(R F12 )2, N(R F12 )C(O)R F12 , -C(O)OR F12 ,-OC(O)R F12 ,-S(O)R F12 -S(O)2R F12 -NO2, =O, =S, =N(R F12 ), -CN, C 3~10 It is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle, where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F12 , -N(R F12 )2, -C(O)R F12 ,-C(O)N(R F12 )2, -N(R F12 )C(O)R F12 , -C(O)OR F12 ,-OC(O)R F12 -NO, =O, =N(R F11), and (each optionally substituted with one or more substituents selected from -CN), Selected from, R F4 teeth, -C(O)N(R F23 )(R F24 ) and C(O) heterocycle (where the heterocycle is a halogen, -OR F13 , -SR F13 , -N(R F13 )2, -C(O)R F13 ,-C(O)N(R F13 )2, -N(R F13 )C(O)R F13 , -C(O)OR F13 ,-OC(O)R F13 ,-S(O)R F13 -S(O)2R F13 -NO2, =O, =S, =N(R F13 ), optionally substituted with one, two, three, or four substituents selected from -CN), and, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl (each is a halogen, -OR) F13 , -SR F13 , -N(R F13 )2, -C(O)R F13 ,-C(O)N(R F13 )2, N(R F13 )C(O)R F13 , -C(O)OR F13 ,-OC(O)R F13 ,-S(O)R F13 -S(O)2R F13 -NO2, =O, =S, =N(R F13 ), -CN, C 3~10 It is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle, where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F13 , -N(R F13 )2, -C(O)R F13 ,-C(O)N(R F13 )2, -N(R F13 )C(O)RF13 , -C(O)OR F13 ,-OC(O)R F13 -NO2, =O, =N(R F13 ), and (each optionally substituted with one or more substituents selected from -CN), Selected from, L F is either a bond or selected from -O- and -NH-, R FA is hydrogen, halogen, -OR F14 , -N(R F14 )2, -C(O)R F14 ,-C(O)N(R F14 )2, N(R F14 )C(O)R F14 ,-C(O)O RF14 ,-OC(O)R F14 , -NO2, -CN, and C 1~6 Selected from alkyl, where C 1~6 Alkyl is a halogen, OR F14 , -N(R F14 )2, -C(O)R F14 It is optionally substituted with one or more substituents selected from NO2, =O, and -CN. R FB is hydrogen, halogen, -OR F15 , -N(R F15 )2, -C(O)R F15 ,-C(O)N(R F15 )2, N(R F15 )C(O)R F15 , -C(O)OR F15 ,-OC(O)R F15 , -NO2, -CN, and C 1~6 Selected from alkyl, where C 1~6 Alkyl is a halogen, OR F15 , -N(R F15 )2, -C(O)R F15 , NO2, =O, and -CN are optionally substituted with one or more substituents selected from R A or R B At least one of them is not hydrogen, R F 'and R F'' independently of hydrogen, halogen, -OR F16 , and C 1~6 Selected from alkyl, where C 1~6 Alkyl is a halogen, -OR F16 , -N(R F16 )2, -C(O)R F16 It is optionally substituted with one or more substituents selected from -NO2, =O, and -CN. R F1 is -OR F21 , -N(R F21 )(R F22 ), -N(R F21 )C(O)R F22 , -N(R F21 )C(O)O RF22 , -N(R F21 )C(O)N(R F21 )(R F22 ), -N(R F21 )S(=O)2N(R F21 )(R F22 ), and -N(R F21 )S(=O)2(R F22 ) are selected from, Each R F2 and R F3 These are independently hydrogen, halogen, and -OR F17 , C 1~6 Alkyl and C 3~6 Selected from cycloalkyl, where C 1~6 Alkyl and C 3~6 Cycloalkyls are halogens, -OR F17 , -N(R F17 )2, -C(O) RF17 It is optionally substituted with one or more substituents selected from -NO2, =O, and -CN, or R bonded to the same carbon F2 and R F3 Together, halogen, -OR F17 , -N(R F17 )2, -C(O)R F17 C optionally substituted with one or more substituents selected from -NO2, =O, and -CN 3~6 Forming a cycloalkyl group, R F21Independently, in each case, hydrogen, as well as halogens, -OR F17 , -N(R F17 )2, -C(O)R F17 Selected from C1-C6 alkyl groups, optionally substituted with one or more substituents independently selected from -NO2, =O, and -CN. R F22 teeth, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl (each is a halogen, -OR) F18 , -SR F18 , -N(R F18 )2, -C(O) RF18 ,-C(O)N(R F18 )2, -N(R F18 )C(O)R F18 , -C(O)OR F18 ,-OC(O)R F18 ,-S(O)R F18 -S(O)2R F18 -NO2, =O, =S, =N(R F18 ), -CN, C 3~10 It is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle, where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F18 , -N(R F18 )2, -C(O)R F18 ,-C(O)N(R F18 )2, N(R F18 )C(O)R F18 , -C(O)OR F18 ,-OC(O)R F18 -NO2, =O, =N(R F18 ), and (each optionally substituted with one or more substituents selected from -CN), C 3~12 Carbon rings and 3- to 12-membered heterocycles, Selected from, C 3~12 Each of the carbon rings and the 3- to 12-membered heterocycles is, Halogen, -OR F18 , -SR F18 , -N(R F18)2, -C(O)R F18 ,-C(O)N(R F18 )2, -N(R F18 )C(O)R F18 , -C(O)OR F18 ,-OC(O)R F18 ,-S(O)R F18 -S(O)2R F18 -NO2, =O, =S, =N(R F18 ), -CN, and, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl (each is a halogen, -OR) F18 , -SR F18 , -N(R F18 )2, -C(O)R F18 ,-C(O)N(R F18 )2, -N(R F18 )C(O)R F18 , -C(O)OR F18 ,-OC(O)R F18 ,-S(O)R F18 -S(O)2R F18 -NO2, =O, =S, =N(R F18 ), -CN, C 3~10 It is optionally substituted with one or more substituents independently selected from a carbon ring and a 3- to 10-membered heterocycle, where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F18 , -N(R F18 )2, -C(O)R F18 ,-C(O)N(R F18 )2, -N(R F18 )C(O)R F18 , -C(O)OR F18 ,-OC(O)R F18 -NO, =O, =N(R F18 ), and -CN, each optionally substituted with one or more substituents selected from C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F18 , -N(R F18 )2, -C(O)R F18 ,-C(O)N(R F18 )2, N(R F18 )C(O)RF18 , -C(O)OR F18 ,-OC(O)R F18 -NO2, =O, =N(R F18 ), and (each optionally substituted with one or more substituents selected from -CN), It is optionally substituted with one or more substituents independently selected from the original, R F23 teeth, Halogen, -OR F19 , -SR F19 , -N(R F19 )2, -NO2, -CN, C 3~10 C 1~6 Alkyl (where C 3~10 Carbon rings and 3- to 10-membered heterocycles are halogens, -OR F19 , -N(R F19 )2, =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN (each optionally substituted with one or more substituents selected from these), and, C 3~12 Carbon rings and 3- to 10-membered heterocycles (each containing halogens, -OR compounds) F19 , -N(R F19 )2, optionally substituted with one or more substituents independently selected from =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN), Selected from, R F24 This includes hydrogen, as well as halogens, -OR F19 , -SR F19 , -N(R F19 )2, -NO2, -CN, C 3~6 C is optionally substituted with one or more substituents independently selected from carbon rings and 3- to 6-membered heterocycles. 1~6 Selected from alkyl groups, R F11 , R F12 , R F13 , R F14 , R F15 , R F16 , R F17 , R F18 , and R F19These are independent, in each case, Hydrogen, and, Halogen, -OH, -O-C1~C6alkyl, -O-C1~C6 haloalkyl-NH2, -NO2, =O, -CN, C 3~10 C 1~6 Alkyl (where C 3~10 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents selected from halogens, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl-NH2, -NO2, =O, and -CN, and, C 3~12 Carbon rings, and heterocycles with 3 to 12 members, Selected from, C 3~12 Each of the carbon rings and the 3- to 12-membered heterocycles is, Halogens, -OH, -O-C1~C6alkyl, -O-C1~C6 haloalkyl-NH2, -NO2, =O, -CN, and C optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1~C6 alkyl, -O-C1~C6 haloalkyl-NH2, -NO2, =O, and -CN 1~6 Alkyl, It is optionally substituted with one or more substituents independently selected from the original, n F is selected from 0 and 1, and m F is a ligand (selected from 0, 1, and 2).

[0505] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] It is a ligand for [the substance / function].

[0506] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] (In the formula, R G1 These include 5- or 6-membered heteroaryls, 9- or 10-membered bicyclic heteroaryls, phenyls, (C1-C6) alkoxys, (C3-C7) cycloalkoxys, (C1-C6) alkyls, phenyl-(C1-C4) alkyls, (C3-C7) cycloalkyls, 4- to 6-membered heterocycloalkyls, and -NRs. GC R GD Selected from the group consisting of, where the above 5-membered or 6-membered heteroaryl, 9-membered or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl, and 4-membered to 6-membered heterocycloalkyl are R GA It is optionally substituted with one or more substituents independently selected from the original, R GA Deuterium, halogen, hydroxyl, -NR GC R GD , (C1~C6)alkyl, (C1~C6)alkylcarbonyl, (C3~C7)cycloalkyl, phenyl, 5-membered or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, where the above (C1~C6)alkyl, (C1~C6)alkylcarbonyl, (C3~C7)cycloalkyl, phenyl, 5-membered or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl are deuterium, halogen, hydroxy, cyano, (C1~C4)alkyl, (C3~C7)cycloalkyl, (C1~C4)alkoxy, -SO2-(C1~C4)alkyl, and -NR GC R GD It is optionally substituted with one or more substituents independently selected from the original, R G2 R is selected from the group consisting of 5-membered or 6-membered heteroaryls, where the above 5-membered or 6-membered heteroaryl is R GB The 5-membered or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from the above, where the 5-membered or 6-membered heteroaryl may optionally contain -CO- as a ring member, and if the 5-membered heteroaryl contains nitrogen as a ring atom, the nitrogen is RG8 They may be optionally substituted with substituents selected from the following: R GB Deuterium, halogen, cyano, hydroxy, -NR GC R GD (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)alkyl-CO-O-(CH2) n - represents a (C3-C7) cycloalkyl group, where n is 1-4, and the above (C1-C6) alkyl, (C1-C6) alkoxy, or (C3-C7) cycloalkyl group may contain deuterium, halogen, cyano, hydroxy, or -NR. GC R GD , and are optionally substituted with one or more substituents independently selected from (C1~C4) alkoxys, R GC and R GD Each of these is independently selected from the group consisting of hydrogen and (C1-C6) alkyl, or R GC and R GD These combine to form pyrrolidinyl or piperidinyl, where the (C1-C6) alkyl, pyrrolidinyl, or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and hydroxy. R G8 is, -L G -PO(OH)2 and -CHR GG O-(CO-A-NR GH )) 0又は1) -CO-A-NR GH R GI Selected from the group consisting of, L G is a combination or -CHR GG Selected from the group consisting of O-, Here, each of the -CO-A-NR GH - independently represents an amino acid residue, which is selected from native amino acids as either the D-form, the L-form, or a mixture of the D-form and L-form, and the amino acid residue has a substituent R at the α-amino group. GH It may also be replaced with R GG , RGH , and R GI These are independently selected from hydrogen and (C1-C6) alkyl groups. R G3 It is selected from the group consisting of hydrogen, deuterium, hydroxyl, and halogens. R G4 It is selected from the group consisting of hydrogen, deuterium, and halogens. R G5 -CHR G6 R G7 , (C3~C 10 ) Selected from the group consisting of cycloalkyl and GG, where the above (C3~C 10 )Cycloalkyl and GG are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, (C1-C4)alkyl, and halo(C1-C4)alkyl. GG is [ka] It represents, and, R G6 and R G7 Each of these independently represents hydrogen, phenyl, (C1-C6)alkyl, or (C3-C7)cycloalkyl, where the phenyl, (C1-C6)alkyl, or (C3-C7)cycloalkyl is a ligand (which is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, and (C1-C4)alkyl).

[0507] In a particular embodiment, the IL-17 targeting ligand is of the formula: [ka] It is a ligand for [the substance / function].

[0508] Interleukin-6 (IL-6) In some embodiments, the target extracellular 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.

[0509] 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.

[0510] Non-limiting examples of direct or indirect inhibitors of IL-6 are shown in Figure 1. Further direct or indirect inhibitors of IL-6 may be found, for example, in U.S. Patent No. 8,901,310, U.S. Patent No. 1,018,9796, and U.S. Patent No. 9,694,015 (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).

[0511] In some embodiments, the target extracellular protein is interleukin-6. Interleukin-6 (IL-6) is a cytokine that is a crucial component of the acute phase immune response. After the IL-6 ligand binds to the IL-6 receptor, the heterodimer associates with IL6ST and gp130 to stimulate the response. During infection, certain molecules derived from the pathogen bind to Toll-like receptors, which activate macrophages to produce IL-6. In addition to stimulating the differentiation of B cells and neutrophils, IL-6 mediates the fever response.

[0512] IL-6 is thought to be associated with many inflammatory diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, diabetes, atherosclerosis, depression, Alzheimer's disease, systemic lupus erythematosus, multiple myeloma, prostate cancer, Behçet's disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman disease.

[0513] IL-6 signaling is also important in the musculoskeletal system. In bone, IL-6 interacts with VEGF to stimulate angiogenesis. In muscle cells, large amounts of IL-6 are produced during exercise. In contrast to its role in stimulating the immune system, IL-6 is anti-inflammatory during exercise.

[0514] The Protein Databank website provides crystal structures of interleukin-6 searchable by 1ALU (Somers, WS et al. 1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling. (1997) EMBO J. 16: 989-997) and 1IL6 (Xu, GY et al. Solution structure of recombinant human interleukin-6 (1997) J Mol Biol 268: 468-481), as well as the structure of IL-6 bound in the active hexameric complex searchable by 1P9M (Boulanger, MJ et al. Hexameric Structure and Assembly of the Interleukin-6 / IL-6-alpha-Receptor / gp130 Complex. (2003) Science 300: 2101-2104).

[0515] Non-limiting examples of IL-6 targeting ligands can be found, for example, in U.S. Patent No. 10,633,423, U.S. Patent No. 10,669,314, U.S. Patent Application Publication No. 2004 / 0092720, and Ranganath, S. et al. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo. PLoS ONE 10(11):e0141330.

[0516] Sequence ID 350 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWEKIGlaKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 351 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG30L)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 352 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG20Br)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 353 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG40Br)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 354, FDhLDCIHRLLEAFLDPNLTEQQRWEKIDKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 355, QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 356 SWQSDChaDCIHRLLEAFLDK-AcNLTEEQRWERIDKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) Sequence ID 357 SWQSDChaDCIHRLLEAFLDK-PEG40BrNLTEEQRWERIDKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330)

[0517] In a particular embodiment, the IL-6 targeting ligand is SEQ ID NO: 343, which is bound to the linker via a PEGylated lysine residue.

[0518] Sequence ID 358 EEX3X4AWX7EIHX 11 LPNLX 16 X17 X 18 QX 20 X 21 AFIX 25 X 26 LX 28 X 29 (US Patent No. 10,633,423) (Here, independently of each other, X3 is selected from A, F, H, K, Q, R, S, W, and Y. X4 is selected from A, D, E, F, H, I, K, L, M, N, Q, R, S, T, V, and Y. X7 is selected from F, H, I, K, L, M, N, R, S, T, V, W, and Y. X 11 It is selected from A, I, K, L, M, N, R, S, T, and V. X 16 It is selected from N and T, X 17 It is selected from A, I, T, and V. X 18 It is selected from D, E, G, H, K, N, Q, R, S, and T. X 20 It is selected from I, L, M, R, T, and V. X 21 It is selected from A, S, T, and V. X 25 It is selected from I, M, Q, S, T, V, and W. X 26 It is selected from K and S, X 28 is selected from F, L, M, and Y, and X 29 (This is selected from D and R).

[0519] Sequence ID 359 EEX3X4AWX7EIHX 11 LPNLX 16 X 17 X 18 QX 20 X 21 AFIX 25 X 26 LX 28 X 29(US Patent No. 10,669,314) (Here, independently of each other, X3 is selected from A, F, H, K, Q, R, S, W, and Y. X4 is selected from A, D, E, F, H, I, K, L, M, N, Q, R, S, T, V, and Y. X7 is selected from F, H, I, K, L, M, N, R, S, T, V, W, and Y. X 11 It is selected from A, I, K, L, M, N, R, S, T, and V. X 16 It is selected from N and T, X 17 It is selected from A, I, T, and V. X 18 It is selected from D, E, G, H, K, N, Q, R, S, and T. X 20 It is selected from I, L, M, R, T, and V. X 21 It is selected from A, S, T, and V. X 25 It is selected from I, M, Q, S, T, V, and W. X 26 It is selected from K and S, X 28 is selected from F, L, M, and Y, and X 29 (This is selected from D and R).

[0520] In certain embodiments, the targeted ligand for treating IL-6-mediated diseases binds to gp130. Non-limiting examples of gp130-targeting ligands can be found, for example, in Ahn, SH. et al. In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor 2020 Asian-Australas J Anim Sci.33:670-677, Aqel, SI Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development. (2019) Clinical and Experimental Immunology, 196:215-225, and Hong, S.-S. et al. A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor beta Subunit, Glycoprotein 130. 2015 J Immunol 195:237-245.

[0521] In a particular embodiment, the gp130-targeting ligand is [ka] Selected from.

[0522] Immunoglobulin A1 (IgA1) Immunoglobulin A is a class of antibodies that are normally found in secretions but are also present in serum. IgA is a dimeric form containing four heavy chains and four light chains. IgA exists in two isotypes: IgA1 and IgA2. IgA1 contains more repeats in the hinge region and is the main form found in serum. While IgA production maintains strong mucosal immunity and defense against pathogens, it can be toxic. IgA nephropathy, also known as Buerger's disease, is a pathological accumulation of IgA antibodies that impairs kidney function. The etiology of this disease remains unknown, but the glycosylation pattern in the hinge region has been suggested to be a contributing factor. Because proper kidney function is important for overall health, IgA nephropathy is associated with systemic diseases such as liver failure, cancer, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, heart failure, reactive arthritis, and ankylosing spondylitis.

[0523] The Protein Data Bank website provides crystal structures of IgA1, with representative examples including the PDB accession codes 1IGA (Boehm, MK 1999, J. Mol. Bio. 286 1421-1447), 2ESG (Almogren, A. 2006 J. Mol. Biol. 356, 413-431), 6XJA, 7JGJ (Eisenmesser, EZ 2020, Nat. Commun, 11, 6063-6063), and 3CHN (Bonner, A. 2009, Mucosal Immunol., 2, 74-84).

[0524] Examples of directly or indirectly IgA1-binding molecules include jakarin and YYALSDAKEEEPRYKALRGENQDLREKERKYQDKIKKLEEKEKNLEKKS (SEQ ID NO: 360).

[0525] Linker Embodiment 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, unsaturated or saturated monocarboxylic acids, or divalent residues of 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 21Independently, 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 variable parts are selected from (as defined herein).

[0526] In one embodiment, the linker A It is a bond and a linker B teeth, [ka] That is the case.

[0527] In one embodiment, the linker B It is a bond and a linker A teeth, [ka] That is the case.

[0528] 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 in the L-form or D-form) are selected from the following.

[0529] In one embodiment, the divalent residue of the dicarboxylic acid undergoes a nucleophilic addition reaction: [ka] It is generated from.

[0530] Non-limiting embodiments of the divalent residue of a dicarboxylic acid produced by a nucleophilic addition reaction include: [ka] These are some examples.

[0531] 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.

[0532] 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.

[0533] In one embodiment, the divalent residue of the dicarboxylic acid undergoes a condensation reaction: [ka] It is generated from.

[0534] Non-limiting embodiments of the divalent residues of the dicarboxylic acid produced by condensation include: [ka] These are some examples.

[0535] A non-limiting embodiment of the divalent residue of a saturated dicarboxylic acid is: [ka] These are some examples.

[0536] A non-limiting embodiment of the divalent residue of a saturated dicarboxylic acid is: [ka] These are some examples.

[0537] 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-).

[0538] 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.

[0539] Non-limiting embodiments of the divalent residue of a fatty acid 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-), 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-), paulic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)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 CHCH(CH2)7CH2-) and are selected from.

[0540] In certain embodiments, the linker C is

Chemical formula

[0541] D is

Chemical Structure

[0542] In certain embodiments, the linker A is

Chemical Structure

[0543] In certain embodiments, the linker A is

Chemical Structure

[0544] In a particular embodiment, the linker A teeth, [ka] Selected from the above, each is optionally substituted with any one, two, three, or four substituents as defined herein.

[0545] In a particular embodiment, the linker A teeth, [ka] Selected from the above, each is optionally substituted with any one, two, three, or four substituents as defined herein.

[0546] In a particular embodiment, the linker A teeth, [ka] Selected from the above, each is optionally substituted with any one, two, three, or four substituents as defined herein.

[0547] In a particular embodiment, the linker A teeth, [ka] Selected from the above, each is optionally substituted with any one, two, three, or four substituents as defined herein.

[0548] 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.)

[0549] 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.)

[0550] 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.)

[0551] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0552] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0553] 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)

[0554] 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:

[0555] In a particular embodiment, the linker B Linker C , or linker D teeth, [ka] TIFF0007867715000333.tif215170TIFF0007867715000334.tif215170TIFF0007867715000335.tif215170TIFF0007867715000336.tif215170 (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).

[0556] In a particular embodiment, the linkerB Linker C , or linker D teeth, [ka] TIFF0007867715000338.tif191170 (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).

[0557] 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)

[0558] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0559] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0560] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0561] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0562] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0563] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0564] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0565] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0566] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0567] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0568] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0569] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0570] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0571] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0572] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0573] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0574] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0575] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0576] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0577] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0578] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0579] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0580] In certain embodiments, the linker D is

Chemical formula

[0581] In certain embodiments, the linker A is

Chemical formula

[0582] In certain embodiments, the linker A is

Chemical formula

[0583] In certain embodiments, the linker A is

Chemical formula

[0584] In certain embodiments, the linker A is

Chemical formula

[0585] In certain embodiments, the linker A is

Chemical formula

[0586] In certain embodiments, the linker A is [ka] Selected from.

[0587] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0588] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0589] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0590] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0591] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0592] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0593] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0594] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0595] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0596] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0597] In a particular embodiment, the linker A teeth, [ka] Selected from.

[0598] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0599] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0600] In a particular embodiment, the linker B teeth, [ka] Selected from, in the formula, each is R 21 It is optionally substituted with one, two, three, or four substituents selected from the following.

[0601] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0602] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0603] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0604] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0605] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0606] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0607] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0608] In a particular embodiment, the linker B teeth, [ka] Selected from.

[0609] In a particular embodiment, the linker B - Linker A teeth, [ka] Selected from.

[0610] In a particular embodiment, the linker B - Linker A teeth, [ka] Selected from.

[0611] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0612] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0613] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0614] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0615] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0616] In a particular embodiment, the linker C teeth, [ka] Selected from TIFF0007867715000399.tif235170, in the formula, each is R 21 It is optionally substituted with one, two, three, or four substituents selected from the following.

[0617] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0618] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0619] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0620] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0621] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0622] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0623] In a particular embodiment, the linker C teeth, [ka] Selected from.

[0624] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0625] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0626] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0627] In a particular embodiment, the linker C -(Linker A )2 is, [ka] Selected from.

[0628] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0629] In a particular embodiment, the linker D teeth, [ka] Selected from.

[0630] In a particular embodiment, the linker D teeth, [ka] Selected from, in the formula, each is R 21 It is optionally substituted with one, two, three, or four substituents selected from the following.

[0631] In a particular embod...

Claims

1. formula: 【Chemistry 1】 (In the formula, ASGPR-binding ligands are, 【Chemistry 2】 (In the formula, R １ or R ５ is a linker Ａ Replaced by binding to, R １ is replaced by a linker Ａ and replaced, R ５ is, independently, hydrogen, heteroalkyl, C ０ to C ６ alkyl - cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C ０ to C ６ alkyl - OR ６ C ０ to C ６ alkyl - SR ６ C ０ to C ６ alkyl - NR ６ R ７ C ０ to C ６ alkyl - C(O)R ３ C ０ to C ６ alkyl - N(R ８ )-C(O)R ３ C ０ to C ６ alkyl - O - C(O)R ３ and C ０ to C ６ alkyl N3 selected from R ５ Linker Ａ When combined with and replaced by R, １ These are independently hydrogen, heteroalkyl, and C ０ ~C ６ Alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, C ０ ~C ６ Alkyl-OR ６ , C ０ ~C ６ Alkyl-SR ６ , C ０ ~C ６ Alkyl-NR ６ R ７ , C ０ ~C ６ Alkyl-C(O)R ３ , C ０ ~C ６ Alkyl-N(R) ８ )-C(O)R ３ , C ０ ~C ６ Alkyl-O-C(O)R ３ , and C ０ ~C ６ Selected from alkyl N3, R ３ Independently, in each case, hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR ８ , and -NR ８ R ９ Selected from the group consisting of, 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) ２ 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, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle. R １０ This includes hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and C(O)R. ３ S(O)R ３ , C(S)R ３ , or S(O) ２ R ３ And, R ６５ 、 R ６６ 、 and R ６７ are, independently, hydrogen, heteroalkyl, C ０ -C ６ -alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocyclic ring, heterocycloalkyl, haloalkoxy, C ０ -C ６ -alkyl-OR ６ 、 C ０ -C ６ -alkyl-SR ６ 、 C ０ -C ６ -alkyl-NR ６ R ７ 、 C ０ -C ６ -alkyl-C(O)R ３ 、 C ０ -C ６ -alkyl-N(R ８ )-C(O)R ３ 、 C ０ -C ６ -alkyl-O-C(O)R ３ 、 and C ０ -C ６ -alkyl N3 selected from), or a pharmaceutically acceptable salt thereof, Extracellular protein-targeting ligands are ligands that bind to immunoglobulin G proteins. Linker Ａ teeth, 【Transformation 3】 And, Linker B is a bond, Linker Ｃ teeth, 【Chemistry 4】 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 linked in each case: bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ６ -, -NR ６ C(O)-, -O-, -S-, -NR ６ -, -C(R ２１ R ２１ )-,-P(O)(R ３ )O-, -P(O)(R ３ ) - Divalent residues of natural or unnatural amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocyclic, heteroaryl, -CH ２ CH ２ -[O-(CH ２ ) ２ ] ｎ -O-, -CH ２ CH ２ -[O-(CH ２ ) ２ ] ｎ -NR ６ -ien-CH ２ CH ２ -[O-(CH ２ ) ２ ] ｎ -, -[-(CH ２ ) ２ -O-] ｎ -, -[O-(CH ２ ) ２ ] ｎ -, -[O-CH(CH ３ ) C(O)] ｎ -, -[C(O)-CH(CH ３ )-O] ｎ -, -[O-CH ２ C(O)] ｎ -, and -[C(O)-CH ２ -O] ｎ -, each is R ２１ It is optionally substituted with one, two, or three substituents independently selected from the original compound. n is independently selected in each case from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 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 SO ２ R ３ , -NR ８ S(O)R ３ Selected from the group consisting of haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocyclic compounds, 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 ASGPR-binding extracellular protein degrader compound (which is optionally substituted with one, two, three, or four substituents independently selected from the above).

2. R ６５ , R ６６ , and R ６７ These are, independently, hydrogen and C ０ ~C ６ The compound according to claim 1, selected from alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocyclic, heterocycloalkyl, and haloalkoxy.

3. R ６７ CF ３ The compound according to claim 1.

4. R ６５ The compound according to claim 1, wherein is hydrogen.

5. R ６６ The compound according to claim 1, wherein is hydrogen.

6. The ASGPR-binding ligand is 【Transformation 5】 The compound according to claim 1.

7. The ASGPR-binding ligand is 【Transformation 6】 The compound according to claim 1.

8. The ASGPR-binding ligand is 【Transformation 7】 The compound according to claim 1.

9. R １ is a linker Ａ It is not homologous to hydrogen, heteroalkyl, alkyl, alkenyl, alkynyl, arylalkyl, C ０ ~C ６ Alkyl-OR ６ , C ０ ~C ６ Alkyl-SR ６ , and C ０ ~C ６ Alkyl-NR ６ R ７ A compound according to claim 1, selected from the following.

10. R ５ is a linker Ａ It is not homologous to hydrogen, heteroalkyl, alkyl, alkenyl, alkynyl, arylalkyl, C ０ ~C ６ Alkyl-OR ６ , C ０ ~C ６ Alkyl-SR ６ , and C ０ ~C ６ Alkyl-NR ６ R ７ A compound according to claim 1, selected from the following.

11. Linker Ａ teeth, 【Transformation 8】 The compound according to claim 1, selected from (wherein xx is 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, or 25).

12. Linker Ａ teeth, 【Chemistry 9】 The compound according to claim 1, wherein each is selected from and optionally substituted with one, two, three, or four substituents as defined in claim 1.

13. Linker Ａ teeth, 【Chemistry 10】 A compound according to claim 1, selected from the following.

14. The aforementioned compound has the formula: 【Chemistry 11】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound has the formula: 【Chemistry 12】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

16. R ２２ is selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, heterocyclic, and heteroaryl, and each is R ２１ The compound according to claim 15, which is optionally substituted with one, two, three, or four substituents independently selected from the above.

17. Linker Ｃ teeth, 【Chemistry 13】 A compound according to claim 15, selected from the above.

18. The compound according to any one of claims 1 to 17, wherein the extracellular protein targeting ligand that binds to IgG is Fc-BP-2.

19. The compound according to any one of claims 1 to 17, wherein the extracellular protein targeting ligand that binds to IgG is Fc-III.

20. The aforementioned compound has the formula: 【Chemistry 14】 【change】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

21. The aforementioned compound has the formula: 【Chemistry 15】 【change】 【change】 【change】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof. 【Request Item 22】 【Chemistry 16】 【change】 【change】 【change】 Compounds selected from, or pharmaceutically acceptable salts thereof.

23. The compound according to claim 1, wherein the extracellular protein targeting ligand binds to IgG4.

24. The compound according to claim 1, wherein the extracellular protein-targeting ligand binds to an IgG autoantibody.

25. The autoantibody is the compound according to claim 24, wherein the autoantibody binds to a TSH receptor.

26. The autoantibody is the compound according to claim 24, wherein the autoantibody binds to a citrullinated protein.

27. structure: 【Chemistry 17】 Compounds thereof, or pharmaceutically acceptable salts thereof.

28. structure: [Chemistry 18] Compounds thereof, or pharmaceutically acceptable salts thereof.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier for treating an immunoglobulin G-mediated disorder.

30. The aforementioned compound, 【Chemistry 19】 The pharmaceutical composition according to claim 29, or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound, 【Chemistry 20】 The pharmaceutical composition according to claim 29, or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition according to claim 29, wherein the disorder is rheumatoid arthritis.

33. The pharmaceutical composition according to claim 29, wherein the disorder is an autoimmune thyroid disease.

34. The pharmaceutical composition according to claim 33, wherein the autoimmune thyroid disease is autoimmune thyroid eye disease.

35. The pharmaceutical composition according to claim 29, wherein the disorder mediated by IgG is asymptomatic myasthenia gravis.

36. The pharmaceutical composition according to claim 29, wherein the disorder mediated by IgG is dilated cardiomyopathy.

37. The pharmaceutical composition according to claim 29, wherein the disorder mediated by IgG is lupus.

38. The pharmaceutical composition according to claim 29, wherein the disorder mediated by IgG is multiple sclerosis.

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