Potent ASGPR-binding compounds that degrade 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 TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 331,592, filed April 15, 2022, U.S. Provisional Patent Application No. 63 / 293,447, filed December 23, 2021, U.S. Provisional Patent Application No. 63 / 228,067, filed July 31, 2021, and U.S. Provisional Patent Application No. 63 / 183,450, filed May 3, 2021, each of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention provides extracellular protein degraders and compositions having an asialoglycoprotein receptor (ASGPR) binding ligand conjugated to an extracellular protein targeting ligand that selectively degrade a target extracellular protein, such as an immunoglobulin or other extracellular protein, in vivo to treat a disorder mediated by that protein.

[0003] [Incorporated by reference] The text file is named "19121-007WO1_SequenceListing_ST25", was created on May 2, 2022, is 92.1 KB in size, and is incorporated herein by reference in its entirety. [Background technology]

[0004] Historically, therapeutic strategies to inhibit proteins have used small molecule inhibitors that bind in the enzyme pocket or at allosteric positions. These proteins, which are not enzymes, are difficult to control and some have been considered "undruggable." However, many non-enzymatic proteins remain valuable targets for drug discovery due to their role in signaling pathways. Immunoglobulins are important non-enzymatic drug targets due to their role in signaling immune responses throughout the body.

[0005] The asialoglycoprotein receptor (ASGPR) is a Ca receptor expressed primarily in parenchymal hepatocytes. 2+ ASGPR is a phospholipase A receptor-dependent lectin. Its primary role is to help regulate serum glycoprotein levels by mediating the endocytosis of desialylated glycoproteins. The receptor binds ligands with terminal galactose or N-acetylgalactosamine. After binding to ASGPR, asialoglycoproteins are cleared by receptor-mediated endocytosis. The receptor and protein dissociate in acidic endosomal compartments, and the protein is ultimately degraded by lysosomes. Publications describing various uses of the ASGPR mechanism include U.S. Patent Nos. 5,629,233, 5,629,243, 5,629,253 assigned to Pfizer Inc.; 5,629,253, 5,629,263; U.S. Patent Nos. 5,629,253, 5,629,263 assigned to Pfizer Inc. and Wave Life Sciences Ltd.; U.S. Patent No. 5,629,253, 5,629,263 assigned to Wave Sciences Ltd.; U.S. Patent Nos. 5,629,253, 5,629,263 ... and a paper from Bertozzi's group in Nature Chemical Biology entitled "LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation" (U.S. Patent No. 5,629,253).

[0006] Although some progress has been made in the field of targeted degradation of extracellular proteins, there remains a need for additional therapeutic compounds and methods of their use and production to degrade extracellular proteins and treat 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) Summary of the Invention

[0009] Novel extracellular protein degraders and pharmaceutically acceptable salts thereof, as well as compositions thereof, that degrade target extracellular proteins, such as IgG, IgA, IgE, TNF-α, Factor XIa, complement factor D, complement factor B, or other proteins described below, are provided, as well as starting materials and intermediates for such extracellular protein degraders, and methods for using and producing them. The extracellular protein degraders of the present invention comprise an ASGPR-binding ligand covalently attached to the extracellular protein targeting ligand by a linker. The ASGPR-binding ligands used in the degraders described herein include derivatives of a six-carbon pyranose moiety, specifically galactose and talose. These two sugars, shown below, are C 2 They differ only in the stereochemistry of the substituents. 2 The configuration corresponds to the stereochemistry of galactose, while the C 2 The substituents correspond to the stereochemistry of talose. 2 It has been found that certain substituents at positions improve binding of the ligand ASGPR.

[0010] [ka]

[0011] In some aspects of the 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 binder via a specific linking group. In one embodiment of the invention, the selected immunoglobulin degrader degrades IgG.

[0013] In some embodiments, other extracellular proteins can be degraded, as described further 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 in Figures 1-7, where relevant, or as otherwise known.

[0014] In some embodiments of the present invention, the extracellular protein degrader uses a ratio of ASGPR-binding ligand to extracellular protein-targeting ligand of 3: 1 or 2: 1. By using multiple ASGPR-binding ligands, the degrader can bind more tightly to ASGPR and therefore have increased degradation efficiency.

[0015] In other embodiments of the present invention, the extracellular protein degrader of the present invention has a ratio of ASGPR-binding ligand to extracellular protein-targeting ligand of 1:1. In some embodiments, the extracellular protein degrader has a C binding ligand with high binding efficiency to ASGPR. 2 With these newly discovered substituents, the ligands have sufficient ASGPR binding efficiency to allow for the resolution of molecules at a 1:1 ratio of ASGPR-binding ligand to extracellular protein-targeting ligand.

[0016] While previous medicinal chemistry approaches to treating diseases associated with extracellular proteins have been unsuccessful due to their extracellular circulation, size, and / or lack of an active site, the extracellular protein degraders of the present invention can degrade target extracellular proteins by transporting them into hepatocytes. In some embodiments, these immunoglobulin degraders feature selected ASGPR ligands characterized by high binding affinity to ASGPR (see Tables 4A and 4B for 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 and have fewer side effects, reduced side effects, increased efficacy, faster therapeutic effects, longer metabolic stability, and / or longer therapeutic efficacy than previously disclosed immunoglobulin degraders.

[0017] In some aspects of the present invention, selective degraders of immunoglobulin G (IgG) are provided. In certain embodiments, these immunoglobulin degraders comprise 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 degraders comprise: [ka] or a pharmaceutically acceptable salt thereof.

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

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

[0020] In another aspect of the invention, the IgG degrader of the invention has a ratio of ASGPR-binding ligand to IgG-binding ligand of 1:1. For example, in certain embodiments, the immunoglobulin degrader comprises: [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 aspects, there is provided a method for treating an IgG-mediated disorder, comprising administering to a patient an effective amount of an IgG degrader or a pharmaceutically acceptable salt thereof. In certain embodiments, the IgG disorder is selected from the group consisting of antiphospholipid syndrome, Behcet's syndrome, Hashimoto's thyroiditis, MGUS, necrobiotic xanthogranuloma, rheumatoid arthritis, cancer, such as multiple myeloma or peripheral multiple myeloma, dysproteinemia, chronic urticaria, scleroderma, scleromyxedema, thrombocytopenia, such as heparin-induced thrombocytopenia, cryoglobulinemia, granulomatosis with polyangiitis, such as ANCA-associated vasculitis, idiopathic thrombocytopenic purpura, thrombocytopenia, IgG4 - Selected from RD, paroxysmal nocturnal hemoglobinuria (PNH), warm autoimmune hemolytic anemia, rhabdomyolysis, lupus nephritis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Miller-Fisher syndrome, neuromyelitis optica spectrum disorder, opsoclonus-myoclonus syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), peripheral neuropathy, transverse myelitis, fibrosis, IPF / fibrosis, and transplant rejection.

[0023] In another aspect of the present invention, selective degraders of immunoglobulin A (IgA) are provided. In certain embodiments, the immunoglobulin degraders comprise IgA-targeting ligands from the Opt class of peptides. Opt class ligands are highly selective for IgA and therefore promote the selective recruitment of IgA to hepatocytes for degradation. For example, in certain embodiments, the immunoglobulin degraders comprise: [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 aspect of the invention, the IgA degrader of the invention has a ratio of ASGPR-binding ligand to IgA-binding ligand of 1:1. For example, in certain embodiments, the immunoglobulin degrader comprises: [ka] is.

[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 disorders mediated by immunoglobulins, e.g., IgG or IgA, including, for example, autoimmune disorders, other immune dysfunctions, abnormal cell proliferation such as tumors and cancers, hematology-related disorders, kidney disorders, allergic conditions, or liver disorders. In certain aspects of the invention, methods are provided for treating an immunoglobulin-mediated disorder, comprising administering to a host in need of treatment an effective amount of an immunoglobulin degrader described herein, or a pharmaceutically acceptable salt, prodrug, N-oxide thereof, and / or a pharmaceutically acceptable composition thereof, optionally in a pharmaceutically acceptable carrier.

[0028] While previous medicinal chemistry approaches to treating immunoglobulin-related diseases have been unsuccessful due to their large size, extracellular circulation, and / or lack of an active site, the immunoglobulin degraders of the present invention are capable of degrading targeted immunoglobulins. In some embodiments, these immunoglobulin degraders feature newly discovered ASGPR ligands that are characterized by high binding affinity for 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 have fewer side effects, increased efficacy, faster therapeutic effects, longer metabolic stability, and / or reduced side effects compared to previously disclosed immunoglobulin degraders.

[0029] In certain aspects, the extracellular proteolytic compound degrades TNF-α. For example, in certain embodiments, the compound of the present invention is [ka] is.

[0030] In certain embodiments, the TNF-α targeting ligand is: [ka] is selected from.

[0031] In certain aspects, the extracellular proteolytic compound degrades factor XIa. For example, in certain embodiments, the compound of the invention is [ka] is.

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

[0033] In another embodiment, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII: [ka] (In the formula, 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 alkylN3, and C0-C6 alkyl-OS(O)2R 3 each optionally substituted with 1, 2, 3, or 4 substituents; R 3 is independently, at each occurrence, hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 is selected from R 6 and R 7 is independently, at each occurrence, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R 10 is hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from R 25 is 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)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 alkylN3, and C0-C6 alkyl-OS(O)2R 3 each optionally substituted with 1, 2, 3, or 4 substituents; R 65 , R 66 , and R 67 are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, 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 alkylN3, and C0-C6 alkyl-OS(O)2R 3 each optionally substituted with 1, 2, 3, or 4 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 alkylN3, heteroaryl, aryl, and C0-C6 alkyl-OS(O)2R 3 each optionally substituted with 1, 2, 3, or 4 substituents; and When a compound is "optionally substituted," the compound may, where permitted by valence, be optionally substituted with alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR 6 , F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azido, 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] wherein any substituents are selected to result in a stable compound), or a pharmaceutically acceptable salt thereof.

[0034] In certain embodiments, the ASGPR binding ligand is [ka] or a pharmaceutically acceptable salt thereof.

[0035] In an alternative embodiment, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0036] In certain embodiments, the compound of Formula IX, Formula X, or Formula XI: [ka] (In the formula, ASPGR-binding ligands include: [ka] (In the formula, R 1 or R 5 is the linker A and all other variables are as defined herein; Linker A is the linker B , linker C , or a linker D and an ASGPR-binding ligand, Linker B is the linker A and an extracellular protein targeting ligand; Linker C is the linker A is a chemical group linking the extracellular protein targeting ligand to Linker D is the linker A and an extracellular protein targeting ligand; and An extracellular protein targeting ligand is a ligand that binds to an extracellular protein).

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

[0038] In certain embodiments, the ASGPR binding ligand is [ka] or a pharmaceutically acceptable salt thereof.

[0039] In certain embodiments, the extracellular protein degraders of the present invention are provided as isotopically enriched extracellular protein degraders, e.g., immunoglobulin degraders, having at least one desired isotopic substitution of an atom in an amount greater than the natural abundance of the isotope. For example, one or more hydrogens in the extracellular protein degrader can be replaced by deuterium, and one or more carbon atoms can be replaced by deuterium. 13 C. In one embodiment, the isotopic substitution is present at one or more positions in the ASGPR ligand. In another embodiment, the isotopic substitution is present at one or more positions in the linker portion of the molecule. In another embodiment, the isotopic substitution is present at one or more positions in the extracellular protein targeting ligand portion of the molecule.

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

[0041] (i) an extracellular protein degrader as described herein, or a pharmaceutically acceptable salt, prodrug, N-oxide thereof, and / or a pharmaceutical composition thereof as described herein; (ii) an extracellular protein degrader as described herein for use in the treatment of an immunoglobulin-related medical disorder, such as an autoimmune disorder, other immune dysfunction, hematology-related disorder, kidney disorder, allergic condition, or liver disorder; (iii) an isotopically enriched derivative of the extracellular protein degrader described herein, or a pharmaceutically acceptable salt, prodrug, N-oxide, and / or pharmaceutical composition thereof; (iv) a method for producing a medicament for therapeutic use in treating or preventing a disorder mediated by an extracellular protein, characterized in that the extracellular protein degrader described herein is used in the production; (v) an extracellular protein degrader or salt thereof as described herein in purified or substantially pure form (e.g., at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%); (vi) an extracellular protein degrader as described herein for treating a disorder as described herein; (vii) a method for producing an extracellular protein degrader as described herein; (viii) an immunoglobulin degrader as described herein, or a pharmaceutically acceptable salt, prodrug, N-oxide thereof, and / or a pharmaceutical composition thereof as described herein; (ix) an immunoglobulin degrader as described herein for use in the treatment of an immunoglobulin-related medical disorder, such as an autoimmune disorder, other immune dysfunction, hematology-related disorder, kidney disorder, allergic condition, or liver disorder; (x) an isotopically enriched derivative of an immunoglobulin degrader described herein, or a pharmaceutically acceptable salt, prodrug, N-oxide, and / or pharmaceutical composition thereof; (xi) a method for producing a medicament for therapeutic use in treating or preventing an immunoglobulin-mediated disorder, characterized in that the immunoglobulin degrader described herein is used in the production; (xii) an immunoglobulin degrader or salt thereof described herein, in purified or substantially pure form (e.g., at least 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%); (xiii) an immunoglobulin degrader as described herein for treating a disorder as described herein; (xiv) a method for producing the immunoglobulin degrader described herein, and (xv) An ASGPR-binding ligand described herein.

[0042] The extracellular protein targeting ligand ("EPTL") is covalently attached to the linker in the ASGPR-binding extracellular protein degrader compound via an anchor bond (which is a chemical bond between the EPTL and either Linker B, Linker C, or Linker D). This bond can be located anywhere on the ligand that does not unacceptably interfere with the ability of the EPTL to bind to the target extracellular protein. The anchor bond is shown in the non-limiting examples of extracellular protein targeting ligands in the figures: [ka] It is expressed as: [Brief explanation of the drawings]

[0043] [Figure 1A] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target immunoglobulin A (IgA). [Figure 1B] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target immunoglobulin G (IgG). [Figures 1C-1G]FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target immunoglobulin E (IgE). [Figure 1H-1M] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target tumor necrosis factor alpha (TNF-α). [Figure 1N] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-1 (IL-1). [Figures 1O-1S] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-2 (IL-2). [Figure 1T-1W] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-6 (IL-6). [Figure 1X-1AA] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interferon gamma (IFN-γ). [Figure 1BB-1KK] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target vascular endothelial growth factor (VEGF). [Figure 1LL] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target transforming growth factor β (TGF-β1). [Figure 1MM-1PP] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target proprotein convertase subtilisin / kexin type 9 (PCSK-9). [Figure 1QQ-1SS] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target carboxypeptidase B2 (CPB2). [Figure 1TT-1UU] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target cholinesterases (ChEs). [Figure 1VV-1WW] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target CC motif chemokine ligand 2 (CCL2). [Figure 1XX-1BBB]FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor VII (Factor VII). [Figure 1CCC-1FFF] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor IX (Factor IX). [Figure 1GGG] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target CD40 ligand (CD40L). [Figure 1HHH-1JJJ] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor Xa (Factor Xa). [Figure 1KKK-1MMM] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor XI (Factor XI). [Figure 1NNN-1OOO] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor XII (Factor XII). [Figure 1PPP-1QQQ] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target coagulation factor XIII (Factor XIII). [Figure 1RRR-1UUU] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target fibroblast growth factor 1 (FGF1). [Figure 1VVV-1XXX] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target fibroblast growth factor 2 (FGF2). [Figure 1YYY-1ZZZ] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target fibronectin (FN1). [Figure 1AAAA-1BBBB] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-5 (IL-5). [Figure 1CCCC] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-8 (IL-8). [Figure 1DDDD-1EEEE]FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-10 (IL-10). [Figure 1FFFF-1GGGG] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-21 (IL-21). [Figure 1HHHH-1IIII] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target interleukin-22 (IL-22). [Figure 1JJJJ-1NNNN] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target kallikrein 1. [Figure 1OOOO] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target lipoprotein lipase (LPL). [Figure 1PPPP-1QQQQ] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target matrix metalloproteinase-1 (MMP1). [Figure 1RRRR-1DDDDD] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target macrophage migration inhibitory factor (MIF), also known as glycosylation inhibitory factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase. [Figure 1EEEEE-1GGGGG] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target neutrophil elastase (NE). [Figure 1HHHHH-1IIIIII] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target prothrombin. [Figure 1JJJJJ-1NNNNN] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target plasma kallikrein (KLKB1). [Figure 1OOOOO-1SSSSS] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target plasminogen (PLG). [Figure 1TTTTTT-1XXXXX]FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target plasminogen activator inhibitor-1 (PAI-1), endothelial plasminogen activator inhibitor, or serpin E1. [Figure 1YYYYY-1AAAAAA] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target phospholipase A2, e.g., type 1B or group 1B (PLA2, PA21B, PLA2G1B, PLA2-IB). [Figure 1BBBBBB-1DDDDDD] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target phospholipase A2, e.g., type IIA or group IIA (PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA). [Figure 1EEEEEE-1NNNNNN] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target placental growth factor (PGF). [Figure 1OOOOOO-1QQQQQQ] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target plasminogen activator, tissue type (tPA, PLAT). [Figure 1RRRRRR] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target transforming growth factor beta 2 (TGF-β2, TGFB2). [Figure 1SSSSSS] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target thrombospondin 1 (TSP1, TSP-1, THBS1). [Figure 1TTTTTT-1XXXXXX] FIG. 1 shows a non-limiting list of extracellular protein targeting ligands that target urokinase or urokinase-type plasminogen activator (UPA, uPA). [Figure 2] FIG. 1 shows a non-limiting list of exemplary extracellular protein targeting ligands that target complement factor B. [Figure 3A-3B] FIG. 1 shows a non-limiting list of exemplary extracellular protein targeting ligands that target complement factor D. [Figure 4]FIG. 1 shows a non-limiting list of exemplary extracellular protein targeting ligands that target complement factor H. [Figure 5] FIG. 1 depicts a non-limiting list of exemplary extracellular protein targeting ligands that target complement component 5. [Figure 6] FIG. 1 shows a non-limiting list of exemplary extracellular protein targeting ligands that target TNF-α. [Figure 7] FIG. 1 shows a non-limiting list of exemplary extracellular protein targeting ligands that target Factor XI. [Figure 8] Figure 1 shows a graph of cellular uptake of compound 28 at various concentrations. The y-axis is mean fluorescence intensity (MFI) and the x-axis is the concentration of compound 28 measured in micromolar concentrations. The experimental procedure is described in Example 3. [Figure 9] Figure 1 shows a graph of ternary complex formation of compound 28, IgG, and ASGPR at various concentrations of compound 28. The y-axis is the ratio in the ternary complex, and the x-axis is the concentration of compound 28 measured in micromolar concentrations. The experimental procedure is described in Example 4. [Figure 10] Figure 1 shows a Western blot showing the degradation of IgG-AF488 by compound 28. The experimental procedure is described in Example 5. [Figure 11] Figure 1 shows colocalization images showing the uptake of DNP-IgG in the presence of compound 28. The experimental procedure is described in Example 4. [Figure 12] Figure 1 shows graphs of ternary complex formation of compound 4, IgG, and ASGPR and cellular uptake of IgG at various concentrations of compound 4. The y-axis is the concentration of ternary complex formation indicated by total mean fluorescence intensity (MFI) (for ternary complex formation) or the ratio of IgG+ to total cells (for uptake), and the x-axis is the concentration of compound 4 measured in micromolar concentrations. The experimental procedure is described in Example 3. [Figure 13]

[0023] Figure 1 shows a graph of ternary complex formation of Compound 4 or an inactive compound, IgG, and ASGPR at various concentrations of Compound 4 or an inactive compound. The y-axis is the concentration of ternary complex formation as indicated by total mean fluorescence intensity (MFI), and the x-axis is the concentration of Compound 4 or an inactive compound measured in micromolar concentrations. The experimental procedure is described in Example 3. [Figure 14] Figure 1 shows a graph of cellular uptake of IgG at various concentrations of Compound 4 or an inactive compound. The y-axis is the ratio of IgG+ to total cells, and the x-axis is the concentration of Compound 4 or an inactive compound measured in micromolar concentrations. The experimental procedure is described in Example 3. [Figure 15] Figure 1 shows a bar graph of surface IgG concentrations resulting from ternary complex formation of Compound 4, IgG, and ASGPR by wild-type and ASGPR knockout cells in the presence or absence of Compound 4. The y-axis is the concentration of surface IgG as indicated by total mean fluorescence intensity (MFI), and the x-axis is the presence or absence of Compound 4. The experimental procedure is described in Example 3. [Figure 16] Figure 1 shows a bar graph of cellular uptake of IgG over time in either wild-type or ASGPR knockout cells in the presence of Compound 4. The y-axis is the concentration of IgG as indicated by total mean fluorescence intensity (MFI), and the x-axis is time measured in minutes and hours. The experimental procedure is described in Example 3. [Figure 17] Figure 1 shows a Western blot showing the concentration of IgG degradation products over time in the presence of compound 21. The experimental procedure is described in Example 6. [Figure 18] Figure 1 shows a Western blot showing the concentration of full-length IgG over time in the presence of compound 21. The experimental procedure is described in Example 7. [Figure 19] 1 shows a Western blot taken from rat hepatocyte lysates showing the concentration of IgG over time in the presence of Compound 4. The experimental procedure is described in Example 8. [Figure 20]1 shows colocalization images showing the uptake of DNP-IgG in the presence of Compound 4. The experimental procedure is described in Example 9. [Figure 21] FIG. 1 is a line graph showing ASGPR binding of compound 4 measured by SPR as described in Example 1. The y-axis is response measured in units and the x-axis is time measured in seconds. [Figure 22] FIG. 1 shows a line graph showing IgG binding of compound 4 measured by SPR as described in Example 2. The y-axis is response measured in units and the x-axis is time measured in seconds. [Figure 23] FIG. 1 shows a line graph showing TNFα binding of compound 36 as measured by SPR as described in Example 2. The y-axis is response measured in units and the x-axis is time measured in seconds. [Figure 24] 1 shows a Western blot showing the time course of TNF degradation by 0.5 μM of Compound 36. The experimental procedure is described in Example 11. [Figure 25] Figure 1 shows a Western blot demonstrating ASGPR-mediated TNF uptake in the presence of compound 36. Experimental procedures are described in Example 12. [Figure 26] FIG. 1 shows non-limiting examples of formulas of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention provides novel extracellular protein degraders that degrade target extracellular proteins, such as IgG, and their pharmaceutically acceptable salts and compositions thereof, as well as starting materials and intermediates for such extracellular protein degraders, and methods for using and manufacturing them. These extracellular protein degraders are highly potent binders of both ASGPR and their respective extracellular protein targets. Some of the extracellular protein degraders of the present invention use high-binding ASGPR-binding ligands. This enhanced binding affinity for ASGPR provides the extracellular protein degraders with various advantages over previously known extracellular protein degraders. For example, the extracellular protein degraders of the present invention can be administered at lower doses, less frequently, with fewer side effects, and / or with increased efficacy compared to other extracellular protein degraders. In some embodiments, an extracellular protein degrader comprising one of the high-binding ASGPR ligands described herein may be fully active in the form of a monodentate compound (i.e., a 1:1 ratio of extracellular protein ligand to ASGPR ligand in a therapeutic molecule).

[0045] In certain embodiments, the extracellular proteolytic compound degrades immunoglobulins. The immunoglobulin degraders described herein degrade selected immunoglobulins by covalently linking the ligand of the selected immunoglobulin to a strong ASGPR binder 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, and mutants thereof. In certain aspects of the present invention, the selected immunoglobulin degrader degrades IgG.

[0046] I. Compound Terminology The extracellular protein degraders are described using their official names. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

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

[0048] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein by reference as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by context. The use of examples or illustrative language (e.g., "such as") is intended merely to better describe the present invention and does not denote a limitation on the scope of the invention unless otherwise stated. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0049] The present invention includes extracellular protein degraders having an isotopic substitution of at least one desired atom at above the natural abundance of the isotope, ie, enriched.

[0050] Examples of isotopes that can be incorporated into the extracellular protein degraders of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g. 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 In one embodiment, the isotopically labeled extracellular protein degraders are used in metabolic studies (e.g., 14 C), reaction kinetic studies (e.g. 2 H or 3 H), drug or substrate tissue distribution assays, or radiation treatment of patients, including detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). Isotopically labeled extracellular protein degraders of the present invention and prodrugs thereof can generally be prepared by following the procedures disclosed in the schemes or in the examples and preparations below, using readily available isotopically labeled reagents in place of non-isotopically labeled reagents.

[0051] General examples, but not limitation, include isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) can be optionally used at any position in the depicted structures where the desired result is achieved. Alternatively or additionally, isotopes of carbon, e.g. 13 C and 14 In one embodiment, isotopic substitution can be used to improve drug efficacy, e.g., pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, T max , C maxThis is achieved by substituting deuterium for hydrogen at one or more positions on a molecule to improve function, etc. For example, deuterium can be attached to a carbon at the site of bond cleavage during metabolism (α-deuterium kinetic isotope effect) or next to or near the site of bond cleavage (β-deuterium kinetic isotope effect).

[0052] Isotopic substitution, e.g., deuterium substitution, can be partial or complete. Partial isotopic substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched at any position of interest by 80%, 85%, 90%, 95%, or 99% or more. In certain embodiments, deuterium is enriched at a desired position by 80%, 85%, 90%, 95%, or 99%. Unless otherwise specified, enrichment at any point is above natural abundance, and in one embodiment, enrichment is sufficient to alter the detectable properties of the drug in humans.

[0053] The extracellular protein degraders of the present invention can form solvates with solvents (including water). Thus, in one embodiment, the present invention includes solvated forms of active extracellular protein degraders. The term "solvate" refers to a molecular complex of the extracellular protein degrader of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are 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 include those in which the solvent of crystallization may be isotopically substituted, for example, DO, d6-acetone, d6-DMSO. Solvates may be in liquid or solid form.

[0054] "Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injectables, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, implants, etc.

[0055] A "pharmaceutical composition" is a composition that includes at least one active agent and at least one other substance, such as a carrier. The present invention includes pharmaceutical compositions of the described extracellular protein degraders.

[0056] "Pharmaceutical combinations" are combinations of at least two active agents that can be combined in a single dosage form or given together in separate dosage forms.

[0057] "Pharmaceutically acceptable salts" refer to derivatives of the disclosed extracellular protein degraders in which the parent extracellular protein degraders have been modified by making their inorganic and organic salts, pharmaceutically acceptable acid addition salts, or base addition salts. Salts of the present extracellular protein degraders can be synthesized from parent extracellular protein degraders containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these extracellular protein degraders with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, or salt of Na, Ca, Mg, or K) or the free base form of these extracellular protein degraders with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Salts of the present 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 acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include human-consumable salts of the parent extracellular protein degrader formed, for example, 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 nitric acid, as well as those derived from 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, mesylate, esylate, besylate, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) 1~4 Included are salts prepared from organic acids such as —COOH, or with acids that generate the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0059] The term "carrier" as applied to pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient, or vehicle that provides the active extracellular protein degrader.

[0060] "Pharmaceutically acceptable excipient" means an excipient useful in preparing a pharmaceutical composition / combination that is generally safe, ingestible by humans, and not biologically or otherwise unsuitable for administration to a host (usually a human). In one embodiment, an excipient acceptable for veterinary use is used.

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

[0062] A "therapeutically effective amount" of the extracellular protein degrader, pharmaceutical composition, or combination of the present invention means an amount that, when administered to a host, brings about therapeutic benefits such as amelioration of symptoms or relief or reduction of the disease itself.

[0063] In one embodiment, the substitution of a hydrogen atom with a deuterium atom occurs within every variable. For example, if any variable is, or includes, e.g., through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (such as, in non-limiting embodiments, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3). In certain other embodiments, a variable has the symbol "'" or "a," which, in one embodiment, may be deuterated. In certain other embodiments, when two substituents on a central core ring combine to form a cyclopropyl ring, the unsubstituted methylene carbon may be deuterated.

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

[0065] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH is attached through the carbon of the keto (C=O) group.

[0066] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a moiety selected from the indicated group, provided that the normal valence of the specified atom is not exceeded and the resulting compound is stable. For example, when a substituent is oxo (i.e., ═O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.

[0067] "Alkyl" refers to a branched, straight-chain, or cyclic saturated aliphatic hydrocarbon group. In one embodiment, alkyl contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms, 1 to about 4 carbon atoms, or 1 to 3 carbon atoms. In one embodiment, alkyl contains 1 to about 8 carbon atoms. In certain embodiments, alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, specified ranges refer to alkyl groups, with each member of the range described as a unique species being considered to be expressly disclosed as an individual species. For example, the term C1-C6 alkyl, as used herein, refers to straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and also to carbocyclic alkyl groups of 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as an independent species. For example, the term C1-C4 alkyl, as used herein, refers to straight or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as an independent species. nWhen alkyl is used herein in conjunction with another group, such as (C3-C7 cycloalkyl)C0-C4 alkyl or —C0-C4 alkyl(C3-C7 cycloalkyl), the indicated group, in this case cycloalkyl, is either directly attached by a single covalent bond (C0 alkyl) or is attached through an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. The alkyl may also be attached through another group, such as a heteroatom, such as —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] It should be understood that when a term containing "alk" is used, "cycloalkyl" or "carbocyclic" can be considered part of the definition unless clearly excluded by context. For example, but not limited to, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenyloxy, haloalkyl, etc. can all be considered to include cyclic forms of alkyl, unless clearly excluded by context.

[0069] "Alkenyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. Non-limiting examples are C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, and C2-C4 alkenyl. As used herein, specified ranges refer to alkenyl groups with each member of the range listed as an independent species, as described above for the alkyl portion. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0070] "Alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may occur at any stable point along the chain, such as a C2-C8 alkynyl or a C2-C6 alkynyl. As used herein, a specified range refers to an alkynyl group with each member of the range listed as a separate species, as described above for the alkyl portion. Examples of alkynyl 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] "Alkoxy" is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy 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 an alkyl group as defined above with the designated number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, an alkoxy group is optionally substituted as described above.

[0072] "Haloalkyl" refers to both branched and straight-chain alkyl groups substituted with one or more halogen atoms, up to the maximum permissible number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0073] "Aryl" refers to an aromatic group containing only carbon in the aromatic ring(s). In one embodiment, an aryl group contains one to three single or fused rings, has 6 to 14 or 18 ring atoms, and does not contain heteroatoms as ring members. The term "aryl" includes groups in which a saturated or partially unsaturated carbocyclic group is fused to an aromatic ring. The term "aryl" also includes groups in which a saturated or partially unsaturated heterocyclic group is fused to an aromatic ring, provided that the point of attachment is the aromatic ring. Such compounds may include an aryl ring fused to a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated cyclic group containing, optionally, one, two, or three heteroatoms independently selected from N, O, B, P, Si, and S, forming, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, 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 a phenyl group.

[0074] The term "heterocycle" refers to saturated and partially saturated heteroatom-containing ring groups, where the heteroatoms may be selected from N, S, and O. The term "heterocycle" includes monocyclic 3- to 12-membered rings as well as bicyclic 5- to 16-membered ring systems, which may include fused, bridged, or spiro bicyclic ring systems. Heterocycle does not include rings containing an -OO- or -SS- moiety. 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 include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4- ... thiazolidinyl, dihydrothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, thiazolidinyl, dihydrothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, thiazolidinyl, dihydrothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl Examples of heterocyclic rings include 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 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]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. "Bicyclic heterocycles" include groups in which a heterocyclic group is fused with an aryl group, with the point of attachment being the heterocyclic ring. "Bicyclic heterocycles" also include heterocyclic groups fused or bridged with carbocyclic groups.For example, partially unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline, partially unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated fused heterocyclic groups containing 1 to 2 oxygen atoms or sulfur atoms.

[0075] Non-limiting examples of bicyclic heterocycles include: [ka] Examples include:

[0076] Unless otherwise depicted or clear from the context, the term "bicyclic heterocycle" includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include: [ka] Examples include:

[0077] In certain alternative embodiments, the term "heterocycle" refers to saturated and partially saturated heteroatom-containing ring groups, where the heteroatoms may be selected from N, S, O, B, Si, and P.

[0078] "Heteroaryl" refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring containing 1 to 3, or in some embodiments 1, 2, or 3, heteroatoms selected from N, O, S, B, and P (typically selected from N, O, and S), with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic ring system containing at least one 5-, 6-, or 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2 heteroatoms selected from N, O, S, B, or P, with the remaining ring atoms being carbon. In one embodiment, the only heteroatoms are nitrogen. In one embodiment, the only heteroatoms are oxygen. In one embodiment, the only heteroatoms are sulfur. Monocyclic heteroaryl groups typically have 5 or 6 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-, 6-, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, and the point of attachment is the aromatic ring. If the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. 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 (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzoyl, and benzoyl. Examples of heteroaryl groups include, but are not limited to, thiazolyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. "Heteroaryloxy" refers to a heteroaryl group described above attached to the group it replaces via an oxygen (-O-) linker.

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

[0080] An "arylalkyl" is an alkyl group, as described herein, substituted with an aryl group, as described herein.

[0081] "Heterocycloalkyl" refers to an alkyl group, as described herein, 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 CH group has been replaced with a heteroatom or a carbon atom has been replaced with a heteroatom, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. In one embodiment, "heteroalkyl" is used to refer to 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-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, and the like.

[0083] When a compound is "optionally substituted," the compound may, where valence allows, be substituted with alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR 6 , F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] wherein the optional substituents are selected to result in stable compounds. For example, [ka] is an alkyl, alkenyl, alkynyl, haloalkyl, -OR, etc., as long as a stable compound is formed. 6 , F, Cl, Br, I, -NR 6 R 7, heteroalkyl, cyano, nitro, C(O)R 3 may be substituted with one or two groups independently selected from, as long as a stable compound is obtained. [ka] may be substituted with only one group selected from [ka] teeth, [ka] It may only be substituted with one or two groups selected from:

[0084] Non-limiting examples of optionally substituted CH groups include: [ka] Examples include:

[0085] Non-limiting examples of optionally substituted -S- groups include: [ka] Examples include:

[0086] "Alkyl" Embodiments In one embodiment, "alkyl" is C1-C 10 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 1 carbon.

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

[0089] In one embodiment, the "alkyl" has 3 carbons.

[0090] In one embodiment, the "alkyl" has 4 carbons.

[0091] In one embodiment, the "alkyl" has 5 carbons.

[0092] In one embodiment, the "alkyl" has 6 carbons.

[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 an alternative embodiment, the "alkyl" group is optionally substituted.

[0099] In an alternative embodiment, an "alkenyl" group is optionally substituted.

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

[0101] "Haloalkyl" Embodiments In one embodiment, "haloalkyl" is C1-C 10haloalkyl, 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 1 carbon.

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

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

[0105] In one embodiment, the "haloalkyl" has 1 carbon and 3 halogens.

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

[0107] In one embodiment, the "haloalkyl" has 3 carbons.

[0108] In one embodiment, the "haloalkyl" has 4 carbons.

[0109] In one embodiment, the "haloalkyl" has 5 carbons.

[0110] In one embodiment, the "haloalkyl" has 6 carbons.

[0111] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0112] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0113] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0114] Further non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0115] "Heteroaryl" Embodiments Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0116] Further non-limiting examples of 5-membered "heteroaryl" groups include: [ka] Examples include:

[0117] In one embodiment, "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0118] Non-limiting examples of 6-membered "heteroaryl" groups containing one or two nitrogen atoms include: [ka] Examples include:

[0119] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0120] Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0121] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka] Examples include:

[0122] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka] Examples include:

[0123] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka] Examples include:

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

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

[0126] Further non-limiting examples of "heteroaryl" groups that are bicyclic include: [ka] Examples include:

[0127] Heterocycle Embodiments In one embodiment, "heterocycle" refers to a ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0128] In one embodiment, "heterocycle" refers to a ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

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

[0130] In one embodiment, "heterocycle" refers to a ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0131] In one embodiment, "heterocycle" refers to a ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0132] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0133] Further non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

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

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

[0136] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the points of attachment of each group are on the heterocycle.

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

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

[0139] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0140] Further non-limiting examples of "heterocycle" include: [ka] Examples include:

[0141] Further non-limiting examples of "heterocycle" include: [ka] Examples include:

[0142] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0143] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0144] Further non-limiting examples of "heterocycle" include: [ka] Examples include:

[0145] Further non-limiting examples of "heterocycle" include: [ka] Examples include:

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

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

[0148] In one embodiment, an "aryl" is a six-carbon aromatic group fused to a heterocycle, where the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring.

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

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

[0151] "Arylalkyl" Embodiments Non-limiting examples of "arylalkyl" include: [ka] Examples include:

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

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

[0154] Non-limiting examples of "arylalkyl" include: [ka] Examples include:

[0155] II. Extracellular proteolysis A wide range of known and characterized extracellular proteins can cause, regulate, or propagate diseases in vivo, such as abnormal cell proliferation, including tumors and cancer, 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 aberrant signaling in many diseases, including cancer and inflammation.

[0156] The extracellular protein degraders described herein, or pharmaceutically acceptable salts thereof and / or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by target extracellular proteins that bind to extracellular protein targeting ligands. The described degraders can target specific extracellular proteins that mediate pathological disorders for lysosomal degradation. The target extracellular proteins can regulate disorders in humans through mechanisms of action such as altering biological pathways, pathogenic signaling, or modulating signal cascades or cell invasion. In one embodiment, the target extracellular protein is a protein that is not druggable in the classical sense, in that it does not have a binding pocket or active site that can be inhibited or otherwise bound and cannot be easily allosterically controlled. In another embodiment, the target extracellular protein is a protein that is druggable in the classical sense, but for therapeutic purposes, protein degradation is preferred over inhibition. The target extracellular protein is recruited 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 an alternative embodiment, the target extracellular protein is covalently bound to the extracellular protein targeting ligand in a manner that may be irreversible or reversible.

[0157] Thus, in some embodiments, there is provided a method of 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 that targets 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 comprising an extracellular protein targeting ligand can bind, resulting in a beneficial therapeutic effect through its degradation. 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 can be an endogenous protein that mediates a disorder. The endogenous protein can be either a normal or abnormal form of the protein. For example, the target extracellular protein can be an extracellular mutant protein, or a protein in which, for example, a partial or complete gain or loss of function is encoded by a nucleotide polymorphism. In some embodiments, the degrader targets the abnormal form of the protein rather than the normal form of the protein.

[0159] An extracellular protein targeting ligand is a ligand that binds covalently or non-covalently to a target extracellular protein selected for lysosomal degradation. 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 a 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 figures.

[0160] Anchor binding The extracellular protein targeting ligand ("EPTL") is covalently attached to the linker in the ASGPR-binding extracellular protein degrader compound via an anchor bond (which is a chemical bond between the EPTL and either Linker B, Linker C, or Linker D). This bond can be placed anywhere on the ligand that does not unacceptably interfere with the ability of the EPTL to bind to the target extracellular protein. The anchor bond is shown in the non-limiting examples of extracellular protein targeting ligands in Figure 1 as follows: [ka] It is expressed as:

[0161] Many exemplary target extracellular proteins for medical therapy described below have structural information featured 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, e.g., www.rcsb.org, www.wwpdb.org, and www.uniprot.org. See, e.g., Section ** Using the PDB codes provided in the databank itself, and the technical references set forth herein or otherwise published, one skilled in the art can determine suitable positions at which EPTL can be linked to the ASGPR binding moiety via an anchor attachment to linker B, linker C, or linker D. For many of these proteins, published references describe how a wide range of ligands bind to target extracellular proteins, and from this information, reasonable anchor attachment positions 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 position at which the extracellular protein targeting ligand docks to the target extracellular protein. A person skilled in the art can also import the crystal structure and the selected extracellular protein targeting ligand of interest into modeling software (e.g., 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 is attached via a linker and anchor bond at a point that does not excessively adversely affect binding to the target extracellular protein.

[0163] Optional Substituents In certain embodiments, the extracellular protein targeting ligands described herein, for example, in one of the figures, are selected from the group consisting of alkyl (including C1-C4 alkyl), alkenyl (including C2-C4 alkenyl), alkynyl (including C2-C4 alkynyl), haloalkyl (including C1-C4 haloalkyl), -OR 6 , F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0164] In certain embodiments, the target extracellular protein 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 elastase. , prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpin E1, phospholipase A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), transforming growth factor beta 2 (TGF-β2, TGFB2), thrombospondin 1, urokinase, urokinase-type plasminogen activator, complement factor B, complement factor D, target of 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 selected from the group consisting of 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 elastase, and the like. thrombospondin 1, urokinase, urokinase-type plasminogen activator, complement factor B, complement factor D, target 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 contemplates using natural amino acids, unnatural amino acids, or any combination thereof to achieve the desired targeting ligand properties.

[0168] The term "naturally occurring amino acid" refers to an amino acid 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 unnatural amino acid, e.g., phenylalanine is replaced with 4-chloro-phenylalanine, non-limiting examples of unnatural amino acids include 4-chloro-phenylalanine, 3-fluoro-phenylalanine, 4-trifluoromethyl-phenylalanine, 3,4-dichloro-phenylalanine, 4-phenyl-phenylalanine, N-methylalanine, N-methylglutamic acid, N-methylphenylalanine, and homoserine.

[0170] Additional examples of unnatural amino acids include: [ka] TIFF2024517812000057.tif130170 is an example.

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

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

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

[0174] Non-limiting examples of extracellular protein targeting ligands that 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 any particular chirality, hi other embodiments, the amino acid sequence is all D-amino acids, all L-amino acids, or a mixture of D- and L-amino acids.

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

[0177] [ka]

[0178] For clarity, the NH that is part of the amide is part of the proline, and the CO 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] For clarity, the NH attached to the lysine is part of the linker, and the lysine is attached to the NH by a carbonyl that 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 serious inflammatory diseases. TNF-α has been implicated in a number of disorders, including, but not limited to, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupus erythematosus, diabetes, and the induction of cachexia.

[0183] The Protein Data Bank website provides the crystal structure of TNF-α, searchable by 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), and 5TSW (Cha, SS, J Biol Chem., 1998, 273 2153-2160), as well as 5YOY (Ono et al., Protein Sci., 2018, 27 1038-1046), 2AZ5 (He., MM, et al., Science, 2005, 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. Additional TNF-α targeting ligands can be found, for example, in U.S. Pat. No. 8,541,572, 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] is selected from.

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

[0187] Non-limiting examples of TNFα degrading compounds include: [ka] Examples include TIFF2024517812000064.tif190170, TIFF2024517812000065.tif170170, TIFF2024517812000066.tif193170, and TIFF2024517812000067.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 the 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 synergizes with IL12 / interleukin-12 to induce IFN-glucan synthesis from T helper 1 (Th1) cells. IL-1 has been implicated in a number of autoinflammatory and autoimmune disorders, including, but not limited to, Blau syndrome, cryopyrin-associated periodic syndrome, familial Mediterranean fever, Majeed syndrome, mevalonate kinase deficiency syndrome, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, tumor necrosis factor receptor-associated periodic syndrome, Behcet's disease, Sjogren'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 Data Bank website provides the crystal structure of IL-1, searchable by 9ILB (Yu, B., et al., Proc Natl Acad Sci USA, 1999, 96 103-108), 1I1B (Finzel, B.C., 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 et al., MAbs, 2015, 7 1151-1160), and 3LTQ (Barthelmes, K., et al., J Am Chem. Soc., 2011, 133, 808-819), crystal structures of IL-1 bound to various compounds are also available. Furthermore, Guy et al. provide insight into the crystal structure of a small antagonist peptide bound to the 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 described in Figure 1. Additional IL-1 targeting ligands can be found, for example, in U.S. Patent No. 9,694,015 (each of which is incorporated herein by reference). Additional binding ligands include rilonacept or a binding fragment thereof (J Rheumatol. 2012;39:720-727 (2012)), and canakinumab or a binding fragment thereof (J Rheumatol. 2004;31:1103-1111).

[0191] In certain embodiments, the IL-1 targeting ligand is [ka] is 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 has been implicated in host-versus-graft rejection and other autoimmune disorders.

[0193] The Protein Data Bank website provides the crystal structure of IL-2, searchable by 1M4C and 1M47 (Arkin, MR, et al., Proc. Natl. Acad. Sci. USA, 2003, 100: 1603-1608), as well as 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), 1NBP (Hyde, J., et al., Biochemistry, 2003, 42 Crystal structures of IL-2 bound to various compounds searchable by IL-2 receptors (Arkin, MR, et al., Proc Natl Acad Sci USA, 2003, 100 1603-1608), as well as IL-2 receptors 1M48, 1M49, 1M4A, 1M4B, and 1M4C (Arkin, MR, et al., Proc Natl Acad Sci USA, 2003, 100 1603-1608), have also been provided. Furthermore, Stauber, DJ, et al. have provided insights into the crystal structure of the IL-2 signaling complex: a paradigm for heterotrimeric cytokine receptors (Stauber, DJ, et al., PNAS, 2006, 103(8), 2788-2793).

[0194] Representative IL-2 targeting ligands are shown in Figure 1. Additional IL-2 targeting ligands can be found, for example, in U.S. Patent No. 8,802,721, U.S. Patent No. 9,682,976, U.S. Patent No. 9,708,268, Eur J Med Chem 83: 294-306 (2014), J Med Chem 60: 6249-6272 (2017), Nature 450: 1001-1009 (2007), each of which is incorporated herein by reference.

[0195] In certain embodiments, the IL-2 targeting ligand is [ka] is 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 diverse biological functions. IL-6 is a potent inducer of the acute phase response and plays a key role in the terminal differentiation of B cells into Ig-secreting cells. IL-6 is also involved in lymphocyte and monocyte differentiation. IL-6 also acts on B cells, T cells, hepatocytes, hematopoietic progenitor cells, and cells of the CNS, and is required for the generation of T(H)17 cells. IL-6 has been implicated in a number of inflammatory diseases and cancers, including, but not limited to, Castleman's disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large cell lung cancer, ovarian cancer, rheumatoid arthritis, and asthma.

[0197] The Protein Data Bank website provides not only the crystal structure of IL-6, which can be searched for 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 U S A., 2002, 99 15959-15964), but also the crystal structure of 4CNI (Shaw, S., et al., Mabs, 2014, 6: 773), and 4NI7 and 4NI9 (Gelinas et al., J Biol Chem. 2014, 289(12), 8720-8734), also provide crystal structures of IL-6 bound to various compounds. Furthermore, Gelinas et al. provide insights into the crystal structure of interleukin-6 complexed with a modified nucleic acid ligand (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: a novel form of receptor dimerization and its impact on signal transduction.

[0198] Potential direct or indirect inhibitors of IL-6 are shown in Figure 1. Additional potential direct or indirect inhibitors of IL-6 can be found, for example, in U.S. Patent Nos. 8,901,310, 10,189,796, and 9,694,015 (each of which is incorporated herein by reference). In another embodiment, the extracellular targeting ligand of IL-6 is Avimar C326 or a binding fragment thereof, 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 has been implicated in a number of autoimmune disorders, including but not limited to rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, and acne vulgaris.

[0200] The Protein Data Bank website provides not only the crystal structure of IFN-γ, searchable by 1HIG (Ealick, SE, et al., Science 252, 1991, 698-702), but also 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. have provided 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 set forth in Figure 1. Additional 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 endothelial growth factor (VEGF) (UniProtKB - P15692(VEGFA_HUMAN)). VEGF is a growth factor active in angiogenesis, vasculogenesis, and endothelial cell growth. VEGF induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis, and induces vascular permeability. VEGF has been implicated in tumor vascularization and angiogenesis.

[0203] The Protein Data Bank website provides the crystal structures of VEGF searchable by 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, 2002, 23 57-61) also provides crystal structures of VEGF bound to various searchable compounds. 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 U S A., 1997 Jul 8; 94(14): 7192-7197).

[0204] A representative VEGF targeting ligand is shown in Figure 1. Additional VEGF targeting ligands include, but are not limited to, the peptide VEPNCDIHVMWEWECFERL-NH2 (Biochemistry 1998, 37, 17754-177764) (all cited references are incorporated herein by reference). Additional VEGF targeting ligands are described, for example, in J Med Chem 57: 3011-29 (2014), U.S. Patent No. 9,884,843, U.S. Patent No. 9,446,026, J Med Chem 53: 1686-99 (2010), J Med Chem 48: 8229-36 (2005), J Nat Prod 76: 29-35 (2013) (each of which is incorporated herein 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 multifunctional 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 responses to neurodegeneration. TGF-β1 can promote the differentiation of either T helper 17 cell (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 has been implicated in TGF-β1-mediated tumor suppression via T cell elimination. TGF-β1 expression has also been implicated in hematological malignancies and fibrosis.

[0206] The Protein Data Bank website provides the crystal structures of TGF-β1 searchable by 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 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) have also been provided.Furthermore, Hinck et al. provide insights into the structural studies of TGF-βs and their receptors, providing further insight into the evolution of the TGF-β superfamily (Hinck, A., FEBS, 2012, 586(14), 1860-1870).

[0207] A representative TGF-β1 targeting ligand is 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. Additional TGF-β1 targeting ligands are described, for example, in Bioorg Med Chem Lett 21: 5642-5 (2011), which is incorporated herein by reference.

[0208] Proprotein convertase subtilisin / kexin type 9 (PCSK-9) In some embodiments, the target extracellular protein is human proprotein convertase subtilisin / kexin type 9 (PCSK-9) (UniProtKB - Q8NBP7(PCSK9_HUMAN)). PCSK-9 plays an important role in regulating plasma cholesterol homeostasis. PCSK-9 binds to members of the low-density lipid receptor family, i.e., 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 intracellular acidic compartments. PCSK-9 acts via a non-proteolytic mechanism to promote the degradation of hepatic LDLR via the clathrin-LDLRAP1 / ARH-mediated pathway, preventing the recycling of LDLR from endosomes to the cell surface or targeting it to lysosomes for degradation. PCSK-9 has been implicated in the development of high blood cholesterol levels and cardiovascular disease.

[0209] The Protein Data Bank website provides not only the crystal structure of PCSK-9, searchable by 2P4E (Cunningham, D., et al., Nat Struct Mol Biol., 2007, 14 413-419), but also the crystal structures of 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 4OV6 (Mitchell, T., et al., J Pharmacol Exp Ther., 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) have also been provided. Additionally, Piper et al. have provided insight into the crystal structure of PCSK9 (Piper, DE, et al., Structure, 2007, 15(5), 545-52).

[0210] A representative PCSK-9 targeting ligand is 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, incorporated herein by reference). Additional PCSK-9 targeting ligands are set forth, for example, in U.S. Pat. No. 9,227,956, J Biol Chem 289: 942-55 (2014), each of which is incorporated herein by reference.

[0211] In certain embodiments, the PCSK-9 ligand is any PCSK-9 ligand described in WO 2021 / 156792, which is incorporated herein by reference.

[0212] In certain embodiments, the formula: [ka] (In the formula, The ASGPR ligand is an ASGPR ligand described herein, The PCSK-9 targeting ligand is any PCSK-9 ligand described in WO 2021 / 156792), or a pharmaceutically acceptable salt 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] TIFF2024517812000072.tif195170TIFF2024517812000073.tif195170TIFF2024517812000074.tif209170TIFF2024517812000075.tif36170 (in the formula, L A1 is a bond, NR 8 , or O).

[0214] In certain embodiments, the PCSK9 targeting ligand has the formula: [ka] (In the formula, R B1 is H, R B2 is (C1-C6)alkoxy, -L B1 - or (C1-C6) alkyl substituted with -C(=O)OH; 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 together with the carbon atom to which they are attached form a (C3-C7)cycloalkyl, R B9 is H or one or more R B27 is (C1-C6) alkyl optionally substituted with R B9’ is H or (C1-C6) alkyl, R B10 is OR B13 and one or more R B14 Optionally substituted (C6-C 10 ) aryl, R 11 is (C1-C6) alkyl or L B1 and R B12 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —OH, or CN; R B13 is R B16 (C6~C 10 ) aryl, Each R B14 is independently at each occurrence 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 is a 5- to 7-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S optionally substituted with Each R B26 independently, in each case, one or more R B29is (C1-C6) alkyl optionally substituted with Each R B27 are independently, in each case, (C6~C 10 ) aryl, Each R B29 are, independently in each case, -NR B31 R B32 or a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; Each R B31 is independently selected from H and (C1-C6) alkyl; Each R B32 is independently selected from H and (C1-C6) alkyl; L B1 is -(CH2) p NH- * where L B1 of * is the linker (L A ) and R B11 , R B6 , or R B7 At least one of the -L B1 -and n is 1).

[0215] In certain embodiments, the PCSK9 targeting ligand has the formula: [ka] (In the formula, R C1 -OR C10 and one or more R C11 (C6~C 10 ) aryl, R C2 is H, (C1-C6) alkyl, -L C1 or (C-C)carbocyclyl, where alkyl is selected from one R C18 and the carbocyclyl is substituted with one or more R C19 is replaced by R C3is H or (C1-C6) alkyl, R C4 is H or (C1-C6) alkyl, or R C3 and R C4 together with the atoms to which they are attached 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 wherein the alkyl is optionally substituted with one or more substituents each independently selected from —OH or (C1-C6)alkoxy; R C8 is H, (C1-C6) alkyl, or -L C1 and R C9 is a halogen, R C10 is one R C22 (C6~C 10 ) aryl, Each R C11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, or CN; R C18 (C6~C 10 ) aryl, Each R C19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —OH, or CN; R C22 is one or more R C23 is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S substituted with Each R C23 are, independently in each case, -NR C24 R C25or (C1-C6) alkyl optionally substituted with a 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; R C24 is H, (C1-C6) alkyl, R C25 is H, (C1-C6) alkyl, L C1 is -(CH2) p NH- * where L C1 of * is the linker (L A ) and R C2 , R C6 , or R C8 At least one of the -L C1 and 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 invention include: [ka] Examples include:

[0217] In certain embodiments, PCSK-9 targeting ligands that can be used in any of the formulas of the invention include: [ka] Examples include:

[0218] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2024517812000081.tif201170TIFF2024517812000082.tif68170.

[0219] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2024517812000084.tif180170TIFF2024517812000085.tif92170.

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

[0221] Non-limiting examples of PCSK-9 degrading compounds include: [ka] Examples include:

[0222] FHR3 Human complement factor H-related protein 3 (FHR-3) belongs to the complement factor H (FH) family. FH, the major negative regulator of alternative complement pathway activation, also belongs to a family that includes five other related family members thought to have arisen from non-allelic homologous recombination and interlocus gene conversion, including 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 isoform 4A and isoform 4B, and complement factor H-related protein 5 (FHR5).

[0223] Unlike factor H, FHR3 lacks the complement regulatory domain essential for complement inactivation and competes with factor H, resulting in excessive complement activation. Thus, the present invention provides compounds that modulate the concentration of complement factor H proteins, particularly FHR3, to remove competitors for factor H, thereby restoring factor H-mediated regulation and used to treat disorders caused by excessive complement activation.

[0224] Because of the central role that factor H plays in complement regulation, many clinical associations result 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), whereas polymorphic variants of complement factor H are strongly associated with important human diseases, including age-related macular degeneration (AMO) and meningococcal sepsis (Clin Exp Immunol 151(2):210-230; Immunobiology 217(11):1034-1046).

[0225] In certain embodiments, the present invention provides for use in the treatment of an FHR3-mediated disease or disorder.

[0226] In certain embodiments, the FHR3-mediated disease or disorder is a complement-related disease, a disorder of complement dysregulation, an autoimmune disease, a kidney disease, a retinal degenerative disease, a rheumatic disease, associated degenerative diseases, an autoimmune kidney disease, dense deposit disease (ODD), and a systemic autoimmune disease.

[0227] In certain embodiments, non-limiting examples of FHR3-mediated diseases or disorders 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 SLE (systemic lupus erythematosus).

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

[0229] In certain embodiments, the FHR3 targeting ligand is [ka] Selected from TIFF2024517812000089.tif185170TIFF2024517812000090.tif88170.

[0230] In certain embodiments, the FHR3 compound is [ka] Selected from TIFF2024517812000092.tif185170TIFF2024517812000093.tif182170.

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

[0232] Non-limiting examples of tau protein targeting ligands include: [ka] Examples include:

[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 has been implicated in a number of autoimmune disorders, including Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

[0234] The Protein Data Bank 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 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 set forth in Figure 1. Additional IL-21 targeting ligands can be found, for example, in U.S. Patent No. 9,701,663, which is incorporated herein 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 those of both the innate and adaptive immune systems. IL-22 has been implicated in a number of autoimmune disorders, including, but not limited to, graft-versus-host disease (GVHD), psoriasis, rheumatoid arthritis, atopic dermatitis, and asthma.

[0237] The Protein Data Bank 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 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 set forth in Figure 1. Additional 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 a pro-inflammatory cytokine. IL-10 has been implicated in tumor survival and protection against cytotoxic chemotherapy drugs.

[0240] The Protein Data Bank website provides the crystal structure 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, S. I. et al., J. Biol. Chem., 2006, 281, 35088-35096), and 3LQM (Yoon, S. I. et al., Structure, 2010, 18, 638-648). Furthermore, Zdanov, A. et al. have provided insights into the crystal structure of IL-10 (Zdanov, A., Current Pharmaceutical Design, 2004, 10, 3873-3884).

[0241] Representative IL-10 targeting ligands are set forth in Figure 1. Additional 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 has been implicated in a number of allergic disorders, including, but not limited to, asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, hypereosinophilic syndrome, and Churg-Strauss syndrome.

[0243] The Protein Data Bank 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 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. Additional 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), 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 factor that attracts neutrophils, basophils, and T cells, but not monocytes. IL-8 is also involved in neutrophil activation. IL-8 is released by several cell types in response to inflammatory stimuli. IL-8 has been implicated in promoting tumor progression, immune evasion, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that elevated serum IL-8 levels correlate with poor prognosis in many malignancies. Preclinical studies have shown that blocking IL-8 reduces mesenchymal characteristics in tumor cells, potentially leading to less resistance to therapy.

[0246] The Protein Data Bank website provides the crystal structures of IL-8 searchable 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), as well as 1ILP and 1ILQ (Skelton, N, J., et al., Structure, 1999, 7, 157-168), and 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, 111-121) also provide crystal structures of IL-8 bound to various compounds that can be retrieved.

[0247] Representative IL-8 targeting ligands are set forth in Figure 1. Additional 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 is responsible for the inactivation of the neurotransmitter acetylcholine. Inhibiting cholinesterase results in increased levels of acetylcholine in the synaptic cleft (the space between two nerve endings). The primary use of cholinesterase inhibitors is the treatment of dementia in patients with Alzheimer's disease. People with Alzheimer's disease have reduced levels of acetylcholine in the brain. Cholinesterase inhibitors have been shown to be effective against symptoms of dementia, such as cognition.

[0249] The Protein Data Bank website provides not only the crystal structure of cholinesterase, searchable by 1P0I and 1P0Q (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147), but also the crystal structures of 1P0M and 1P0P (Nicolet, Y., et al., J Biol Chem., 2003, 278, 41141-41147), 2J4C (Frasco, M.F., 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 cholinesterase bound to various compounds are also provided, searchable by the search engines 2Y1K (Carletti, E., et al., Chem Res Toxicol., 2011, 24, 797), 2WIG, 2WIJ, 2WIK, 2WIL, and 2WSL (Carletti, E., et al., Biochem J., 2009, 421, 97-106).Additionally, Ahmad et al. have provided insights into the isolation, crystal structure determination, and cholinesterase inhibitory activity of isotalatididine 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. Additional 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), 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. provide insights into the synthesis and crystal structure of human CCL2 by native 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 and activation of CCR2, inducing a potent chemotactic response and mobilization of intracellular calcium ions. CCL2 exhibits chemotactic activity for monocytes and basophils, but not for neutrophils or eosinophils.

[0253] CCL2 has been implicated in the recruitment of monocytes to the arterial wall during the atherosclerotic disease process.

[0254] Representative CCL2 targeting ligands are set forth in Figure 1. Additional 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-activatable fibrinolysis inhibitor (TAFIa), cleaves C-terminal arginine or lysine residues from biologically active peptides, such as circulating kinins or anaphylatoxins, thereby regulating their activity. Human carboxypeptidase B2 downregulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin. Carboxypeptidase B2 has been implicated and targeted in the inhibition of thrombosis.

[0256] The Protein Data Bank website provides the crystal structures of carboxypeptidase B2 (also known as thrombin-activatable fibrinolysis inhibitor (TAFI)), searchable by 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), as well as 3D67 (Marx, PF, et al., Blood, 2008, 112, 2803-2809), 5HVF, 5HVG, and 5HVH (Zhou, X., et al., J Thromb Haemost., 2016, 14, 1629-1638), and the crystal structures of TAFI bound to various compounds searchable by 3LMS (Sanglas, L., et al., J Thromb Haemost., 2010, 8, 1056-1065) have also been provided. Furthermore, Schreuder et al. have provided insight into the interaction of TAFI with 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 FIG. Additional carboxypeptidase B2 targeting ligands are described, for example, in 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 is incorporated herein by reference.

[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 has been implicated in a number of disorders, including pulmonary disease, chronic obstructive pulmonary disease, pneumonia, respiratory distress, and acute lung injury (ALI), as well as cystic fibrosis, and chronic kidney disease.

[0260] The Protein Data Bank website lists the following: 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), 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., ACS Chem Biol., 2015, 10, 945-951) provides crystal structures of human neutrophil elastase bound to various compounds that can be searched for.

[0261] Representative neutrophil elastase targeting ligands are shown in FIG. Additional neutrophil elastase targeting ligands are described, for example, in 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), Bioorg Med Chem Lett 25: 4370-81 (2015), 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 incorporated herein 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 clotting.

[0263] Factor X has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[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), 2P9, 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 the ELISA kits are provided, including 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).

[0265] Representative factor Xa targeting ligands are shown in FIG. 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), which are incorporated herein by reference.

[0266] Factor XI In some embodiments, the target extracellular protein is human Factor XI (UniProtKB - P03951(FA11_HUMAN)). Factor XI initiates an intermediate step in the intrinsic pathway of blood coagulation by activating Factor IX.

[0267] Factor XI has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[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., (2016, 24, 2257-2272) provides searchable crystal structures of factor XI bound to various compounds. Additionally, 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. Additional Factor XI targeting ligands can be found, for example, in U.S. Patent No. 9,783,530, U.S. Patent No. 10,143,681, U.S. Patent No. 10,214,512, 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), J Med Chem 57: 955-69 (2014), each of which is incorporated herein by reference.

[0270] In certain embodiments, the Factor XI targeting ligand is: [ka] is selected from.

[0271] In certain embodiments, the Factor XI targeting ligand is 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 Group XI degradable compounds include: [ka] Examples include TIFF2024517812000097.tif179170 and TIFF2024517812000098.tif154170.

[0273] In certain non-limiting embodiments, the Factor XI degrading compound of the present invention is the following compound: [ka] TIFF2024517812000100.tif190170TIFF2024517812000101.tif165170TIFF2024517812000102.tif219170, or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt 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 first to α-factor XIIa, which is then cleaved by trypsin to β-factor XIIa. α-factor XIIa activates factor XI to factor XIa.

[0275] Factor XII has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[0276] The Protein Data Bank 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. have provided 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. Additional 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), 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 to become a transglutaminase that catalyzes the formation of γ-glutamyl-ε-lysine crosslinks between fibrin chains, thus stabilizing the fibrin clot. It also crosslinks α2-plasmin inhibitor or fibronectin to the α chains of fibrin.

[0279] Factor XIII has been implicated in the development of deep vein thrombosis and acute pulmonary embolism, as well as the risk of stroke and embolism in people with non-valvular atrial fibrillation.

[0280] The Protein Data Bank website provides not only the crystal structures of factor XIII, which can be searched using 1FIE (Yee, V.C., et al., Thromb Res., 1995, 78, 389-397) and 1F13 (Weiss, M.S., et al., FEBS Lett., 1998, 423, 291-296), but also the crystal structures of factor XIII bound to various compounds, which can be searched using 1DE7 (Sadasivan, C., et al., J. Biol. Chem., 2000, 275, 36942-36948), and 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. Additional 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), 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 converts fibrinogen to fibrin by cleaving bonds after Arg and Lys, activates factors V, VII, VIII, and XIII, and activates protein C in a complex with thrombomodulin. It functions in blood homeostasis, inflammation, and wound healing.

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

[0284] The Protein Data Bank website provides the crystal structure of prothrombin, searchable by 3NXP (Chen, Z. et al., Proc Natl Acad Sci USA, 2010, 107, 19278-19283), as well as the crystal structures of 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), 3K65 (Adams, TE, et al., Biochimie, 2016, 122, Crystal structures of prothrombin bound to various compounds searchable by 6BJR and 6C2W (Chinnaraj, M. et al., Sci Rep., 2018, 8, 2945-2945) have also been provided. Furthermore, Pozzi et al. have provided insights into the mechanism and conformational flexibility of the crystal structure of prothrombin (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),Crystal structures of thrombin bound to compounds searchable by 1HAO and 1HAP (Padmanabhan, K. et al., Acta Crystallogr D Biol Crystallogr., 1996, 52, 272-282), and 1HBT (Rehse, P. H. et al., Biochemistry, 1995, 34, 11537-11544) have been provided.

[0286] Representative prothrombin targeting ligands are shown in Figure 1. Additional 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), 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 a zymogen. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, 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 clot formation and arterial and venous thrombosis, as well as 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 Chem, 2019, 295, 517-528), 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.), and 5L0S (Li, Z., et al., Nat Commun., 2017, 8, 185-185). Furthermore, Kemball-Cook et al. have provided insight into the crystal structure of active-site-inhibited factor VIIa (Kemball-Cook, G., et al., J Struct Biol., 1999, 127(3), 213-23).

[0290] Representative Factor VII targeting ligands are shown in Figure 1. Additional Factor VII targeting ligands can be found, for example, in U.S. Pat. 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), 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 a Ca 2+ It is a vitamin K-dependent plasma protein that participates 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 clot formation and in arterial and venous thrombosis, as well as thromboembolism associated with atrial fibrillation.

[0293] The Protein Data Bank website lists the following proteins: 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, (E. et al.) provide crystal structures of factor IX bound to a variety of retrievable compounds.

[0294] Representative Factor IX targeting ligands are shown in Figure 1. Additional Factor IX targeting ligands can be found, for example, in U.S. Pat. No. 9,409,908, Bioorg Med Chem Lett 25: 5437-43 (2015), and U.S. Pat. No. 10,189,819, 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 an important role in regulating cell survival, cell division, angiogenesis, cell differentiation, and cell migration. FGF1 functions as a ligand for FGFR1 and integrins, and in the presence of heparin, binds to FGFR1, causing dimerization and activation of FGFR1 through sequential autophosphorylation at tyrosine residues that serve as docking sites for interacting proteins, resulting in the activation of several signal transduction cascades. FGF1 induces the phosphorylation and activation of FGFR1, FRS2, MAPK3 / ERK1, MAPK1 / ERK2, and AKT1. FGF1 can induce angiogenesis. FGF1 has been implicated in carcinogenesis, cancer cell proliferation, resistance to anticancer therapy, and angiogenesis.

[0296] The Protein Data Bank website provides the crystal structure of FGF1, searchable by 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), 1E0O (Pellegrini, L., et al., Nature, 2000, 407, 1029), as well as crystal structures of FGF1 bound to various compounds searchable by 2ERM (Canales, A., et al., FEBS J, 2006, 273, 4716-4727).

[0297] Representative FGF1 targeting ligands are shown in Figure 1. Additional 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), 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 an important role in regulating cell survival, cell division, cell differentiation, and cell migration. FGF2 also induces angiogenesis. FGF2 has been implicated in carcinogenesis, cancer cell proliferation, resistance to anticancer therapy, and angiogenesis.

[0299] The Protein Data Bank 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. Additional FGF2 targeting ligands can be found, for example, in U.S. Pat. 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 the primary driver of increased myocardial fibroblast (MF) abundance after cardiac injury. Interfering with FN polymerization may attenuate MF and fibrosis and improve cardiac function after ischemia / reperfusion (I / R) injury.

[0302] The Protein Data Bank 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. Additional 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 Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. Kallikrein has been implicated in adverse reactions in hereditary angioedema (HAE).

[0305] The Protein Data Bank website provides not only the crystal structure of KLK1, searchable by 1SPJ (Laxmikanthan, G., et al., Proteins, 2005, 58, 802-814), but also 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. Additional 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. 10,221,161, 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), U.S. Patent No. 10,214,512 (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. Plasma kallikrein activates factor XII in the reverse reaction after it binds to negatively charged surfaces. 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 has been implicated in the development of retinal dysfunction, diabetic macular edema, and hereditary angioedema (HAE).

[0308] The Protein Data Bank website provides crystal structures of plasma kallikrein 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), and 5F8T, 5F8X, and 5F8Z (Xu, M., et al.).

[0309] Representative plasma kallikrein targeting ligands are shown in Figure 1. Additional 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. 10,144,746, 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 key enzyme in triglyceride metabolism. Lipoprotein lipase catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), thereby playing a key role in lipid clearance from the bloodstream, lipid utilization, and storage. Lipoprotein lipase mediates the marginal movement of triglyceride-rich lipoprotein particles within capillaries. Lipoprotein lipase has been implicated in the development of cardiovascular disease and obesity.

[0311] The Protein Data Bank website provides crystal structures of lipoprotein lipase 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. Additional 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 types I, II, and III collagen at a single site in the helical domain. MMP-1 also cleaves types VII and X collagen. MMP-1 has been implicated in cardiovascular disease.

[0314] The Protein Data Bank 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 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 insight 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 insight into the crystal structure of MMP1 and the selectivity of collagenase inhibitors (Lovejoy, B., et al., Nat Struct Mol Biol., 1999, 6, 217-221).

[0315] Representative MMP-1 targeting ligands are shown in FIG. 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 (1998), which is incorporated herein by reference.

[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 proinflammatory cytokine involved in the innate immune response to bacterial pathogens. Expression of MIF at sites of inflammation suggests a role as a mediator regulating macrophage function in host defense. MIF counteracts the anti-inflammatory activity of glucocorticoids.

[0317] MIF has been implicated in tumor progression, systemic inflammation, atherosclerosis, rheumatoid arthritis, and systemic lupus erythematosus, among others.

[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 2OOH, 2OOW, and 2OOZ (Crichlow, G. V. et al., J. Biol. Chem., 2007, 282, 23089-23095), 1GCZ and 1GD0 (Orita, M. et al., J. Med. Chem., 2001, 44, 540-547), and 1CA7, 1CGQ, and 1P1G (Lubetsky, J. B. et al., Biochemistry, 1999, 38, 7346-7354) have also been provided. Furthermore, Sun et al. have provided insight into the crystal structure of MIF (Proc. Natl. Acad. Sci. USA, 2007, 38, 7346-7354)., 1996, 28;93(11), 5191-6).

[0319] Representative MIF targeting ligands are shown in Figure 1. Additional 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), 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 multifunctional protein that regulates various processes, such as angiogenesis and cardiac development. Once activated after release of LAP, TGF-β2 functions by binding to TGF-β receptors (TGFBR1 and TGFBR2), thereby transducing signals. TGF-β2 expression in the tumor microenvironment is associated with poor prognosis and has been implicated in TGF-β2-mediated tumor suppression via T cell elimination. TGF-β2 expression has also been implicated in hematological malignancies and fibrosis.

[0321] The Protein Data Bank website not only contains the crystal structure of TGF-β2, searchable by 6I9J (Del Amo-Maestro L. et al., Sci Rep. 2019, 9, 8660-8660), but also 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 4XJJ (Wangkanont et al.), and 1KTZ (Hart, PJ, et al., Nat Struct Biol., 2002, 9, 203-208) have also been provided.

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

[0323] Thrombospondin-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 response, adhesion, invasion, migration, apoptosis, and proliferation.

[0324] TSP-1 expression has been implicated in the promotion of certain cancers, such as breast cancer, prostate cancer, melanoma, SCLC, osteosarcoma, cutaneous squamous cell carcinoma, oral squamous cell carcinoma, papillary thyroid carcinoma, thyroid carcinoma, and medulloblastoma, as well as a number of diseases, including diabetes, fibrotic disorders such as liver fibrosis, and multiple myeloma.

[0325] The Protein Data Bank website provides the crystal structure of TSP-1 searchable by 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., Protein Expr Purif., 2011, 80, 253-259). al., Structure, 2006, 14, 33-42) also provide crystal structures of TSP-1 bound to various compounds that can be searched.

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

[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 costimulates T cell proliferation and cytokine production. Its crosslinking in T cells generates a costimulatory signal that, in combination with TCR / CD3 ligation and CD28 costimulation, enhances IL4 and IL10 production. CD40L induces activation of NF-κB and the kinases MAPK8 and PAK2 in T cells. CD40L also induces tyrosine phosphorylation of CD28 isoform 3. CD40L not only mediates B cell proliferation in the absence of costimulation, but also mediates IgE production in the presence of IL4 and is involved in immunoglobulin class switching.

[0328] The Protein Data Bank 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 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 has been implicated in HIV-associated 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 blood and in the extracellular matrix of many tissues. The enzyme's primary physiological substrate is plasminogen, the inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade involved in thrombolysis or extracellular matrix degradation, depending on the physiological environment. This cascade has been implicated in vascular disease and cancer progression. Increased expression levels of urokinase and several other components of the plasminogen activation system have been found to correlate with tumor aggressiveness.

[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, YN et al. provide crystal structures of UPA bound to various compounds that can be searched.

[0332] Representative UPA targeting ligands are shown in FIG. 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 (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 is incorporated herein 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 the abundant but inactive zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By regulating plasmin-mediated proteolysis, TPA plays an important role in tissue remodeling and degradation, cell migration, and many other physiopathological 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 Data Bank website provides not only the crystal structure of TPA, which can be searched using 1VR1 (Dekker, RJ et al., J. Mol. Biol., 1999, 293, 613-627), but also crystal structures of TPA bound to various compounds, which can be searched using 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. Additional TPA targeting ligands are described, 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. 10,118,930, 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 embryonic development, 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 may be regulated by CSPG4.

[0337] The Protein Data Bank website provides the crystal structure of PLG, searchable by 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. Additional PLG targeting ligands are described, for example, in 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. 8,598,206, U.S. Patent No. 8,921,319, 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 (1997), each of which is incorporated herein by reference.

[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 is the primary inhibitor of tissue-type plasminogen activator (PLAT) and urokinase-type plasminogen activator (PLAU). As a PLAT inhibitor, PAI-1 is required for downregulation of fibrinolysis and is responsible for controlling clot degradation. As a PLAU inhibitor, PAI-1 is involved in regulating cell adhesion and spreading and functions as a regulator of cell migration, independent of its role as a protease inhibitor. Overexpression of PAI-1 promotes angiogenesis, metastasis, and poor prognosis in tumors, including, but not limited to, oral and breast cancer.

[0340] The Protein Data Bank website provides the crystal structure of PAI-1 searchable by 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 Haemost, 2019), as well as crystal structures of PAI-1 bound to various compounds, which can be searched using 4IC0 (Hong, ZB et al.).

[0341] Representative PAI-1 targeting ligands are shown in Figure 1. Additional PAI-1 targeting ligands are described, 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 a growth factor that is effective in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. PGF binds to the receptor FLT1 / VEGFR-1. The isoform PlGF-2 binds NRP1 / neuropilin-1 and NRP2 / neuropilin-2 in a heparin-dependent manner. PGF also promotes cell tumor growth and has been implicated in age-related macular degeneration (AMD) and choroidal neovascularization (CNV).

[0343] The Protein Data Bank 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 crystal structures of PIGF bound to various compounds, searchable by 1RV6 (Christinger, HW, J. Biol. Chem., 2004, 279, 10382-10388). Furthermore, De Falco has provided 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. Additional PGF targeting ligands are shown, for example, in J Med Chem 54: 1256-65 (2011), 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, liberating free fatty acids and lysophospholipids. PA21B has been implicated in a number of diseases, including cardiovascular disease, atherosclerosis, immune disorders, and cancer.

[0346] The Protein Data Bank website provides the crystal structure of PA21B, searchable by 3FVJ and 3FVI (Pan, YH et al., Biochim. Biophys. Acta., 2010, 1804, 1443-1448).

[0347] Representative PA21B targeting ligands are shown in Figure 1. Additional PA21B targeting ligands are described, 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 the regulation of phospholipid metabolism in biological membranes, including eicosanoid biosynthesis. Independent of its catalytic activity, PA2GA also functions as a ligand for integrins. PA2GA induces cell proliferation in an integrin-dependent manner. PA2GA has been implicated in numerous diseases, including cardiovascular disease, atherosclerosis, immune disorders, and cancer.

[0349] The Protein Data Bank 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 a complex between group IIA phospholipase A2 and two natural anti-inflammatory agents, anisic acid and atropine, which exhibit 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 a human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032 (Kitadokoro, K. et al., J Biochem., 1998, 123(4), 619-23).

[0350] Representative PA2GA targeting ligands are shown in Figure 1. Additional PA2GA targeting ligands are shown, for example, in J Med Chem 48: 893-6 (2005), 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, which is part of the alternative pathway of the complement system, is cleaved by factor D into two fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate C3 or C5 convertase. Factor B has also been implicated in the proliferation and differentiation of preactivated B lymphocytes, the rapid proliferation of peripheral blood monocytes, the stimulation of lymphocyte blastogenesis, and the lysis of red blood cells. Ba inhibits the proliferation of preactivated B lymphocytes.

[0352] The Protein Data Bank website provides the crystal structure of complement factor B, searchable by 2OK5 (Milder, FJ, et al., Nat Struct Mol Bio 2007, 14, 224-228), as well as 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. Additional complement factor B targeting ligands are provided, for example, in U.S. Patent No. 9,682,968, U.S. Patent No. 9,475,806, U.S. Patent No. 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 certain embodiments, the extracellular targeting ligand is: [ka] TIFF2024517812000104.tif203170, each of which is 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[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, WO 2020 / 016749, WO 2018 / 005552, WO 2013 / 192345, or WO 2015 / 009616.

[0356] In certain embodiments, the factor B targeting ligand-linker is [ka] is selected from.

[0357] In certain embodiments, the compound of the present invention is the following compound: [ka] or a bidentate or tridentate form thereof.

[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 it forms a complex with factor C3b, activating the C3bbb complex and then becoming the C3 convertase of the alternative pathway. Its function is consistent with that of C1s in the classical pathway.

[0359] The Protein Data Bank 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 are provided, which can be searched using 6QMR and 6QMT (Karki, RG, et al., J Med Chem 2019, 62, 4656-4668).

[0360] Representative complement factor D targeting ligands are shown in Figure 6. Additional complement factor D targeting ligands are described, for example, in J Med Chem 60: 5717-5735 (2017), Nat Chem Biol 12: 1105-1110 (2016), US Patent No. 9598446, US Patent No. 9643986, US Patent No. 9663543, US Patent No. 9695205, US Patent No. 9732103, US Patent No. 9732104, US Patent No. 9758537, US Patent No. 9796741, US Patent No. 9828396, US Patent No. 10000516, US Patent No. 10005802, US Patent No. 10011612, US Patent No. 10081645, US Patent No. 10087203, US Patent No. 10092584, US Patent No. 10100072, US Patent No. 10106563, US Patent No. 101 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 certain embodiments, the extracellular targeting ligand is: [ka] (In the formula, R 21a , R 21b , R 21c , R 21d , R 21e , R 21f , and R 21gis independently, in each occurrence, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, 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 and heterocycles, R 201 , R 202 , R 202 ', and R 203 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, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, -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 , C1-C2 haloalkyl, —C0-C4 alkyl(C3-C7 cycloalkyl) and —O—C0-C4 alkyl(C3-C7 cycloalkyl), and C1-C2 haloalkoxy, wherein R 209 and R 210 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, and (C3-C7 cycloalkyl)C0-C4 alkyl; or R 202 and R 202’may together form a 3- to 6-membered spiro ring optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, —COOH, C1-C4 alkyl (especially including methyl), C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C2-C4 alkanoyl, hydroxyC1-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 Together, R 21 or may form a 3-membered carbocyclic ring optionally substituted with 1, 2, or 3 substituents selected from R 201 and R 202 Together, R 21 and may form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected from R 202 and R 203 Together, R 21 and may form a 3- to 6-membered carbocyclic or 3- to 6-membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents selected from L 100 teeth, [ka] where R 217 is hydrogen or C1-C6 alkyl, and R 218 and R 218’ is independently selected from hydrogen, halogen, hydroxymethyl, and methyl, and m is 0, 1, 2, or 3; B 100is a cycloalkyl, a heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from 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 selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0362] In certain embodiments, the extracellular targeting ligand is: [ka] TIFF2024517812000110.tif190170TIFF2024517812000111.tif164170TIFF2024517812000112.tif190170TIFF2024517812000113.tif202170TIFF2024517812000114.tif198170TIFF2024517812000115.tif160170, each selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0363] In certain embodiments, the Factor D targeting ligand is selected from the ligands described in U.S. Pat. No. 9,796,74, U.S. Pat. No. 10,011,612, WO 2018 / 160889, WO 2019 / 195720, WO 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., WO 2015 / 009977.

[0364] In certain embodiments, the complement factor D targeting ligand-linker is [ka] Selected from TIFF2024517812000117.tif192170TIFF2024517812000118.tif155170.

[0365] In certain embodiments, the compound of the present invention is the following compound: [ka] TIFF2024517812000120.tif163170TIFF2024517812000121.tif255170 or their bidentate or tridentate forms.

[0366] In certain embodiments, the compound of the present invention is the following compound: [ka] or a bidentate or tridentate form thereof.

[0367] In certain embodiments, the Factor D targeting ligand is: [ka] is selected from.

[0368] In certain non-limiting embodiments, the Factor D degrading compound of the present invention is the following compound: [ka] TIFF2024517812000125.tif187170TIFF2024517812000126.tif200170 or bidentate or tridentate forms thereof.

[0369] Non-limiting examples of complement factor D degrading compounds include: [ka] TIFF2024517812000128.tif186170 is an example.

[0370] H factor In some embodiments, the target extracellular protein is human complement factor H (UniProtKB - P08603(CFAH_HUMAN)). Complement factor H is a glycoprotein that plays an essential role in maintaining a balanced immune response by regulating complement activation. It acts as a soluble inhibitor of complement, binding to self-markers such as glycan structures and preventing complement activation and amplification on cell surfaces. Complement factor H accelerates the decay of the 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 for serine protease factor I, CFH also regulates the proteolysis of already deposited C3b. Furthermore, CFH mediates several cellular responses through interaction 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 Data Bank website provides the crystal structures of closely related mutants of complement factor H, searchable by 3KXV and 3KZJ (Bhattacharjee, A., et al., Mol Immunol 2010, 47, 1686-1691), as well as 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), 4ONT (Blaum, BS, et al., Nat Chem Biol 2015, 11, 2016), and 4ONT (Blaum, BS, et al., Nat Chem Biol 2015, 11, 2017). 77-82), as well as the crystal structure of wild-type complement factor H bound to various compounds searchable by 4ZH1 (Blaum, BS, et al., Glycobiology 2016, 26, 532-539).

[0372] Representative complement factor H targeting ligands are shown in Figure 7. Additional complement factor H targeting ligands are described, for example, in J Immunol 182: 6394-6400 (2009), PLoS Pathogens 4: e1000250 (2008), PLoS Pathogens 6: e1001027 (2010), U.S. Patent No. 10,865,238, U.S. Patent No. 8,962,795, 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)). Activation of C5 by C5 convertase initiates spontaneous assembly of the late complement components C5-C9 into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the substrate for assembly of the lytic complex.

[0374] The Protein Data Bank website provides not only the crystal structure of complement component 5, which can be searched for using 3CU7 (Fredslund, F., Nat Immunol 2008, 9, 753-760), but also crystal structures of complement component 5 bound to various compounds, which can be searched for using 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. Additional complement component 5 targeting ligands are described, 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 No. 2017 / 0342139, and U.S. Patent Application Publication No. 2020 / 0095307 (each of which is incorporated herein by reference).

[0376] In certain embodiments, the extracellular targeting ligand is: [ka] each selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0377] In certain embodiments, the complement C5 targeting ligand is selected from the 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, T. W. L.; He, P.-L.; Zhu, F.-H.; Li, J.; Lu, W.; Blom, A. M.; 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 certain embodiments, the C5 targeting ligand is [ka] is selected from.

[0379] In certain embodiments, the C5 targeting ligand is [ka] is selected from.

[0380] Non-limiting examples of complement C5 degrading compounds include: [ka] Examples include:

[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 the ligands described in WO 2020 / 198062 or U.S. Pat. No. 6,683,055.

[0383] In certain embodiments, the compound of the present invention is the following compound: [ka] or a bidentate or tridentate form thereof.

[0384] MASP In certain embodiments, the extracellular targeting ligand is a MASP targeting ligand.

[0385] In certain embodiments, the MASP targeting ligand is selected from the 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 WO 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, the Factor XIa targeting ligand-linker is [ka] is.

[0394] In certain embodiments, the compound of the present invention is the following compound: [ka] or a bidentate or tridentate form thereof.

[0395] In certain embodiments, a factor Xia targeting ligand is selected in which the anchor bond is placed in any suitable position, with or without functionalization.

[0396] [ka]

[0397] In certain embodiments, the Factor XIa targeting ligand is [ka] is selected from.

[0398] Immunoglobulin degradation Immunoglobulins, such as IgG, can cause, regulate, or propagate diseases in vivo, such as abnormal cell proliferation, including tumors and cancer, autoimmune disorders, inflammation, and age-related diseases. For example, immunoglobulins bind to cell surface receptors and often initiate aberrant signaling in many diseases, such as cancer and inflammation.

[0399] The immunoglobulin degraders described herein, or their pharmaceutically acceptable salts and / or their pharmaceutically acceptable compositions, can be used to treat disorders mediated by immunoglobulins that bind to immunoglobulin targeting ligands. The described degraders can target immunoglobulins that mediate pathological disorders for lysosomal degradation. The selected immunoglobulins can regulate disorders in humans through mechanisms of action such as altering biological pathways, pathogenic signal transduction, or regulating signal cascades or cell invasion. The immunoglobulins are recruited together with immunoglobulin targeting ligands, which are ligands for the immunoglobulins.

[0400] Thus, in some embodiments, there is provided a method of treating a host with an immunoglobulin-mediated disorder, comprising administering to the host, typically a human, an effective amount of an immunoglobulin-targeted degrader described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0401] An immunoglobulin can be either a normal or abnormal form of the protein, for example, an immunoglobulin can be a mutant protein or a protein in which, for example, a partial or complete gain or loss of function is encoded by a nucleotide polymorphism.

[0402] Targeting of specific immunoglobulins is achieved according to 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 effective amounts of the disclosed ASGPR-binding immunoglobulin degraders described herein.

[0403] Immunoglobulin A (IgA) Aberrant expression of immunoglobulin A (IgA) mediates a wide range of autoimmune and immune-mediated disorders, including IgA nephropathy (also known as Buerger's disease), celiac disease, Crohn's disease, Henoch-Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic cirrhosis, acquired immune deficiency syndrome, IgA multiple myeloma, alpha chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis, among others.

[0404] Specific degradation of IgA can be achieved by using an IgA-specific immunoglobulin targeting ligand. In certain embodiments, the immunoglobulin targeting ligand used is an Opt peptide. Variants and derivatives of IgA-specific Opt peptide suitable for use as an IgA-specific immunoglobulin targeting ligand 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] is.

[0409] The Protein Data Bank website provides not only the crystal structure of IgA but also crystal structures of IgA bound to various compounds, searchable by 5E8E (Baglin, T. P., 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. have provided excellent insight 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 FIG.

[0411] Further representative IgA targeting ligands include: MLKKIE of SEQ ID NO: 1 (Jerlstrom et al. Infect. Immun. 1996 Jul; 64(7):2787-2793), Opt-1 - HMVCLAYRGRPVCFAL of SEQ ID NO: 2 (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), Opt-2 - HMVCLSYRGRPVCFSL of SEQ ID NO: 3 (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), Opt-3 - HQVCLSYRGRPVCFST of SEQ ID NO: 4 (Hatanaka et al. J. Biol. Chem. Vol. 287, No. 51, pp. 43126-43136, December 14, 2012), QMRCLSYKGRRVCLWL of SEQ ID NO: 5 (U.S. Patent No. 9,593,147); KRLCLQYKGSKVCFRL of SEQ ID NO: 6 (U.S. Patent No. 9,593,147); RMRCLTYRGRRVCLEL of SEQ ID NO: 7 (U.S. Patent No. 9,593,147); SMRCLQYRGSRVCLTL (U.S. Patent No. 9,593,147) of SEQ ID NO: 8; HLRCLRYKGTRVCFSL of SEQ ID NO: 9 (U.S. Patent No. 9,593,147); HVRCLSYKGREVCVQL of SEQ ID NO: 10 (U.S. Patent No. 9,593,147); PRMCLFIYKGRRVCIPY of SEQ ID NO: 11 (U.S. Patent No. 9,593,147); HMRCLHYKGRRVCFLL of SEQ ID NO: 12 (U.S. Patent No. 9,593,147); HKRCLHYRGRMVCFLI of SEQ ID NO: 13 (U.S. Patent No. 9,593,147); QKRCLKYKGSRVCFFL of SEQ ID NO: 14 (U.S. Patent No. 9,593,147); HVRCLRYRGKNVCFLL of SEQ ID NO: 15 (U.S. Patent No. 9,593,147); SDVCLRYRGRPVCFQV of SEQ ID NO: 16 (U.S. Patent No. 9,593,147); RDVCLRYRGRPVCFQV of SEQ ID NO: 17 (U.S. Patent No. 9,593,147); HDVCLRYRGRPVCFQV of SEQ ID NO: 18 (U.S. Patent No. 9,593,147); SMVCLRYRGRPVCFQV of SEQ ID NO: 19 (U.S. Patent No. 9,593,147); SAVCLRYRGRPVCFQV of SEQ ID NO: 20 (U.S. Patent No. 9,593,147); SDVCLNYRGRPVCFQV of SEQ ID NO: 21 (U.S. Patent No. 9,593,147); SDVCLHYRGRPVCFQV of SEQ ID NO: 22 (U.S. Patent No. 9,593,147); SDVCLAYRGRPVCFQV of SEQ ID NO: 23 (U.S. Patent No. 9,593,147); SDVCLRYRGRPVCFAV of SEQ ID NO: 24 (U.S. Patent No. 9,593,147); SDVCLRYRGRPVCFQL of SEQ ID NO: 25 (U.S. Patent No. 9,593,147); SDVCLRYRGRPVCFQA of SEQ ID NO: 26 (U.S. Patent No. 9,593,147); HMVCLSYRGRPVCF of SEQ ID NO: 27 (U.S. Patent Application Publication No. 2015 / 0044701); HMVCLSYRGRPVCFS of SEQ ID NO: 28 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGQPVCFSL of SEQ ID NO: 29 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGRPTCFSL of SEQ ID NO: 30 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGRPVCYSL of SEQ ID NO: 31 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGQPVCFST of SEQ ID NO: 32 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGRPTCFST of SEQ ID NO: 33 (U.S. Patent Application Publication No. 2015 / 0044701); HQVCLSYRGQPTCFST of SEQ ID NO: 34 (U.S. Patent Application Publication No. 2015 / 0044701); Examples include:

[0412] In certain embodiments, the IgA targeting ligand is: [ka] is.

[0413] Non-limiting examples of IgA degrading compounds include: [ka] Examples include TIFF2024517812000144.tif163170, TIFF2024517812000145.tif103170, TIFF2024517812000146.tif201170, TIFF2024517812000147.tif166170, and TIFF2024517812000148.tif95170.

[0414] Immunoglobulin G (IgG) Immunoglobulin G (IgG) mediates a wide range of autoimmune, infectious, and metabolic diseases, including systemic fibroinflammatory disorders. Moreover, overexpression of IgG4 is commonly associated with multiorgan IgG4-related disorders, including, among others, type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Kuttner's tumor, inflammatory pseudotumor (at various sites in the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond's disease), aortitis and peri-aortic inflammation, proximal bile duct stenosis, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, mass lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren's syndrome, and psoriatic arthritis. , systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture's disease, encephalitis, thrombotic thrombocytopenic purpura, immune thrombocytopenia, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan's syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM parasomnias, and membranous nephropathy, multiple sclerosis, hyperthyroid Graves' disease, epidermolysis bullosa acquisita, gestational pemphigoid, anti-p200 pemphigoid, and paraneoplastic pemphigus.

[0415] By using IgG-specific immunoglobulin targeting ligand, specific degradation of IgG can be achieved.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 depicted herein with the stereochemistry depicted in the targeting ligand is depicted herein without the stereochemistry. For example, in certain embodiments, [ka] teeth, [ka] or [ka] teeth, [ka] is.

[0417] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0418] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0419] In certain embodiments, the compounds of the present invention are [ka] TIFF2024517812000156.tif169170 or a pharmaceutically acceptable salt thereof.

[0420] In certain embodiments, the compounds of the present invention are [ka] TIFF2024517812000158.tif150170TIFF2024517812000159.tif150170 or a pharmaceutically acceptable salt 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] TIFF2024517812000178.tif217170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0439] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000181.tif147170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0440] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000184.tif201170TIFF2024517812000185.tif124170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0441] In certain embodiments, the immunoglobulin targeting ligand is: [ka] is.

[0442] In certain embodiments, the immunoglobulin targeting ligand is: [ka] is.

[0443] In certain embodiments, the immunoglobulin targeting ligand is: [ka] is.

[0444] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000191.tif201170TIFF2024517812000192.tif124170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0445] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000195.tif223170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0446] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000198.tif156170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0447] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000201.tif199170TIFF2024517812000202.tif158170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0448] In certain embodiments, the immunoglobulin-degrading compound is the following compound: [ka] TIFF2024517812000205.tif201170TIFF2024517812000206.tif126170 (wherein the extracellular protein targeting ligand is [ka] or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0449] The Protein Data Bank website provides the crystal structures of IgG searchable by 1H3X (Krapp, S., et al., J. Mol. Biol., 2003, 325: 979) and 5V43 (Lee, CH, et al., Nat. Immunol., 2017, 18: 889-898), as well as 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., 2017, 12: 1335-1345). al., Science, 2001, 293: 1155-1159), crystal structures of IgG bound to various compounds are also provided. Furthermore, Kiyoshi, M. et al. have provided insight into the structural basis for human IgG1 binding to its high-affinity human receptor, FcγRI (Kiyosi M., et al., Nat Commun., 2015, 6, 6866).

[0450] Representative IgG targeting ligands are shown in FIG.

[0451] Further exemplary IgG targeting ligands include: [ka] (In the formula, X R is O, S, NH, or N-C1-C3 alkyl, and X M is O, S, NH, or N-C1 to C3 alkyl).

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

[0453] In some embodiments, the IgG targeting ligand has the chemical structure: [ka] (In the formula, R N02 is a dinitrophenyl group optionally linked via CH, 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 is selected from O, CH2, NH, N-C1-C3 alkyl, NC(O)C1-C3 alkyl, 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 chemical structure: [ka] where k"" is 1 to 4 (preferably 2 to 3, most often 3), or [ka] It is the base.

[0456] In some embodiments, the IgG targeting ligand is a peptide. Non-limiting examples of IgG targeting ligand peptides include: PAM(RTY)4K2KG of SEQ ID NO: 35 (Fassina, et al., J. Mol. Recognit. 1996, 9, 564-569) [ka] D-PAM (wherein all amino acids in the PAM sequence are D-amino acids) (Verdoliva, et al, J. Immunol. Methods, 2002, 271, 77-88) (RTY)4K2KG of SEQ ID NO: 36; D-PAM-Φ (wherein all amino acids in the PAM sequence are D-amino acids, with the additional modification that the four N-terminal arginines are acetylated with phenylacetic acid) (Dinon, et al J. Mol. Recognit. 2011, 24, 1087-1094) (RTY)4K2KG of SEQ ID NO: 37; TWKTSRISIF of SEQ ID NO: 38 (Krook, et al., J. Immunol. Methods 1998, 221, 151-157), FGRLVSSIRY of SEQ ID NO: 39 (Krook, et al, J. Immunol. Methods 1998, 221, 151-157), Fc-III (DCAWHLGELVWCT-NH2) of SEQ ID NO: 40 (DeLano et al., Science 2000, 287, 1279-1283) [ka] FCBP-Ser DSAWHLGELWST of SEQ ID NO: 41 (WO 2014 / 010813), DCHKRSFWADNCT of SEQ ID NO: 42 (see WO 2014 / 010813), SEQ ID NO: 43 DCRTQFRPNQTCT (see WO 2014 / 010813), DCQLCDFWRTRCT of SEQ ID NO: 44 (see WO 2014 / 010813), DCFEDFNEQRTCT of SEQ ID NO: 45 (see WO 2014 / 010813), DCLAKFLKGKDCT of SEQ ID NO: 46 (see WO 2014 / 010813), DCWHRRTHKTFCT of SEQ ID NO: 47 (see WO 2014 / 010813), DCRTIQTRSCT of SEQ ID NO: 48 (see WO 2014 / 010813), DCIKLAQLHSVCT of SEQ ID NO: 49 (see WO 2014 / 010813), DCWRHRNATEWCT of SEQ ID NO: 50 (see WO 2014 / 010813), SEQ ID NO: 51 DCQNWIKDVHKCT (see WO 2014 / 010813), DCAWHLGELVWCT of SEQ ID NO: 52 (see WO 2014 / 010813), DCAFHLGELVWCT of SEQ ID NO: 53 (see WO 2014 / 010813), DCAYHLGELVWCT of SEQ ID NO: 54 (see WO 2014 / 010813), FcBP-1 PAWHLGELVWP of SEQ ID NO: 55 (Kang, et al, J. Chromatogr. A 2016, 1466, 105-1 12) [ka] FcBP-2 PDCAWHLGELVWCTP of SEQ ID NO: 56 (Dias, et al., J. Am. Chem. Soc. 2006, 128, 2726-2732); [ka] Fc-lll-4c CDCAWHLGELVWCTC of SEQ ID NO: 57 (Gong, et al., Bioconjug. Chem. 2016, 27, 1569-1573) [ka] EPIHRSTLTALL of SEQ ID NO: 58 (Ehrlich, et al, J. Biochem. Biophys. Method 2001, 49, 443-454), APAR of SEQ ID NO: 59 (Camperi, et al., Biotechnol. Lett. 2003, 25, 1545-1548), FcRM(CFHH)2KG of SEQ ID NO: 60 (Fc receptor mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242-1253) [ka] HWRGWV of SEQ ID NO: 61 (Yang, et al., J Peptide Res. 2006, 66, 110-137), HYFKFD of SEQ ID NO: 62 (Yang, et al, J. Chromatogr. A 2009, 1216, 910-918), HFRRHL of SEQ ID NO: 63 (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104), HWCitGWV of SEQ ID NO: 64 (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104), HWmetCitGWmetV of SEQ ID NO: 65 (U.S. Patent No. 10,266,566), D2AAG of SEQ ID NO: 66 (small synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158-167), DAAG of SEQ ID NO: 67 (small synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158-167), Cyclo[(Nα-Ac)S(A)-RWHYFK-Lact-E] of SEQ ID NO: 68 (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237), Cyclo[(Nα-Ac)-Dap(A)-RWHYFK-Lact-E] of SEQ ID NO: 69 (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237), Cyclo[Link M-WFRHYK] of SEQ ID NO: 70 (Menegatti, et al, Biotechnol. Bioeng. 2013, 110, 857-870), NKFRGKYK of SEQ ID NO: 71 (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40), NARKFYKG of SEQ ID NO: 72 (Sugita, et al, Biochem. Eng. J. 2013, 79, 33-40), FYWHCLDE of SEQ ID NO: 73 (Zhao, et al, Biochem. Eng. J. 2014, 88, 1-11), FYCHWALE of SEQ ID NO: 74 (Zhao, et al, J Chromatogr. A 2014, 1355, 107-114), FYCHTIDE of SEQ ID NO: 75 (Zhao, et al., Z Chromatogr. A 2014, 1359, 100-111), Dual 1 / 3 (FYWHCLDE-FYCHTIDE) of SEQ ID NO: 76 (Zhao, et al, J. Chromatogr. A 2014, 1369, 64-72), RRGW of SEQ ID NO: 77 (Tsai, et al, Anal. Chem. 2014, 86, 2931-2938), KHRFNKD of SEQ ID NO: 78 (Yoo and Choi, BioChip J. 2015, 10, 88-94), CPSTHWK of SEQ ID NO: 79 (Sun et al. Polymers 2018, 10, 778), NVQYFAV of SEQ ID NO: 80 (Sun et al. Polymers 2018, 10, 778), ASHTQKS of SEQ ID NO: 81 (Sun et al. Polymers 2018, 10, 778), QPQMSHM of SEQ ID NO: 82 (Sun et al. Polymers 2018, 10, 778), TNIESLK of SEQ ID NO: 83 (Sun et al. Polymers 2018, 10, 778), NCHKCWN of SEQ ID NO: 84 (Sun et al. Polymers 2018, 10, 778), SHLSKNF of SEQ ID NO: 85 (Sun et al. Polymers 2018, 10, 778), Examples include:

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

[0458] In some embodiments, the IgG4-specific targeting ligand is described in Gunnarsson et al. Biomolecular Engineering 2006, 23, 111-117.

[0459] In some embodiments, the IgG4-specific targeting ligand is FDLLEHFY of SEQ ID NO: 86, and DLLHHFDYF of SEQ ID NO: 87, is selected from.

[0460] Additional IgG targeting ligands include: [ka] Examples include TIFF2024517812000221.tif216170 and TIFF2024517812000222.tif102170.

[0461] Non-limiting examples of IgG degrading compounds include: [ka] TIFF2024517812000224.tif204170TIFF2024517812000225.tif177170TIFF2024517812000226.tif184170TIFF20245 17812000227.tif194170TIFF2024517812000228.tif182170TIFF2024517812000229.tif240170TIFF20245178120002 Examples include 30.tif179170TIFF2024517812000231.tif185170TIFF2024517812000232.tif199170TIFF2024517812000233.tif102170TIFF2024517812000234.tif201170TIFF2024517812000235.tif188170TIFF2024517812000236.tif177170.

[0462] In an alternative embodiment, the hydroxyl, amine, amide, or carboxylic acid groups in the extracellular protein targeting ligands depicted herein are blocked with protecting groups. For example, in this embodiment, [ka] teeth, [ka] It could be.

[0463] In an alternative embodiment, instead of the depicted points of attachment, a hydroxyl group, an amine group, an amide group, or a carboxylic acid group on the extracellular protein targeting ligand depicted herein is used as the point of attachment to the linker. For example, in this embodiment: [ka] teeth, [ka] It could be.

[0464] Immunoglobulin E (IgE) Immunoglobulin E (IgE) is a known inflammatory cytokine that is involved in, among other things, but not limited to, atopic asthma, allergic rhinitis, atopic dermatitis, cutaneous contact hypersensitivity, IgE-mediated food allergies, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, eosinophilic gastrointestinal disease, bullous pemphigoid, chemotherapy-induced hypersensitivity reactions, seasonal allergic rhinitis, interstitial cystitis, and eosinophilic steroids. It is a potent mediator of allergic diseases, including eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic obstructive pulmonary disease, gastroenteritis, hyper-IgE syndrome (Jobs syndrome), IgE monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), pemphigus vulgaris, mucous membrane 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] is.

[0472] In certain embodiments, the IgE targeting ligand is: [ka] Selected from TIFF2024517812000249.tif181170.

[0473] Non-limiting examples of IgE degrading compounds include: [ka] Examples include TIFF2024517812000251.tif213170 and TIFF2024517812000252.tif187170.

[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-axonal interactions in the nervous system. In some patients, IgM anti-MAG antibodies develop and cause neuropathy. Antibody levels four times higher than normal can cause nephropathy. Decreased levels of anti-MAG antibodies are associated with clinical responses in polyneuropathy.

[0475] Representative targeting 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] Examples include:

[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 WO 2018 / 167230.

[0477] Non-limiting examples of IgM autoantibody degrading compounds include: [ka] TIFF2024517812000255.tif161170 is an example.

[0478] In certain non-limiting embodiments, the IgM autoantibody degrading compound is the following compound: [ka] TIFF2024517812000257.tif201170TIFF2024517812000258.tif109170 or a bidentate or tridentate form thereof, or a pharmaceutically acceptable salt thereof.

[0479] Phospholipase A2 receptor-1 (PLA2R) autoantibodies In some embodiments, the target extracellular protein is an autoantibody that binds to PLA2R. Phospholipase A2 receptor-1 (PLA2R) is a major target in autoimmune membranous nephropathy. Membranous nephropathy is one of the major causes of nephrotic syndrome, and most patients progress to end-stage renal disease. Current treatment regimens using anti-CD20 antibodies may not be effective in inducing complete remission. PLA2R is a transmembrane glycoprotein with a cysteine-rich N-terminal extracellular domain. This domain contains the epitope to which the autoantibody binds. Reduction of autoantibody levels may provide relief to patients, but complete removal of the autoantibody may be required to achieve durable remission.

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

[0481] In certain embodiments, the compound has the formula: [ka] (wherein the PLA2R autoantibody is any PLA2R autoantibody described in WO 2019 / 081912), or a pharmaceutically acceptable salt thereof.

[0482] In certain embodiments, the PLA2R autoantibody has the following formula: SEQ ID NO: 148: SVLT-XH1-EN-XH2, SEQ ID NO: 149: XH3-I-XH4-XH5-E-XH6, SEQ ID NO: 150: XH1-EN-XH2-K, SEQ ID NO: 151: SVLT-XH1-ENCK, SEQ ID NO: 152: XH3-I-XH4-XH5-E-XH6-LK, or a 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, in certain embodiments the linked sequences are SEQ ID NO: 148 and SEQ ID NO: 149, or SEQ ID NO: 148 and SEQ ID NO: 152; wherein XH1, XH2, XH3, XH4, XH5, and XH6 are independently any naturally occurring amino acid or other amino acid described herein; and The sequences are linked at a terminal amine or terminal carboxylic acid to a linker described herein.

[0483] Non-limiting examples of PLA2R degrading compounds include: [ka] Examples include TIFF2024517812000261.tif218170, TIFF2024517812000262.tif222170, TIFF2024517812000263.tif221170, and TIFF2024517812000264.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 an important factor in both innate and adaptive immunity. Elevated C3 levels are associated with host attack in paroxysmal nocturnal hemoglobinuria (PNH), immune complex membranoproliferative glomerulonephritis (IC-MPGN), C3 nephropathy (C3G), geographic glomerulonephritis (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 gene therapy. Reducing C3 levels may improve some of the symptoms or complications resulting 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 under 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), ICVVQDWGHHRCTAGMANLTSHASAI of SEQ ID NO: 154 (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), ICVVQDWGHHRCT of SEQ ID NO: 155 (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), CVVQDWGHHAC of SEQ ID NO: 156 (Sahu, A. et al. The Journal of Immunology, 1996, 157, 884-891), Ac-ICVVQDWGHHRCT-NH2 of SEQ ID NO: 157 (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), CVVQDWGHHRCT-NH2 of SEQ ID NO: 158 (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), CVVQDWGHHRC-NH2 of SEQ ID NO: 159 (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-ICVVGDWGHHRCT-NH2 of SEQ ID NO: 160 (Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-I of SEQ ID NO: 161 * CVVQPWGHHRC * T-NH2,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Biotin-KYSSI of SEQ ID NO: 162 * CVVQDWGHHRC * T-NH2,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-I of SEQ ID NO: 163 * CVVQDWGHHRC *TAGHMANLTSHASAK-Biotin,(Sahu, The Journal of Immunology, 2000, 165, 2491-2499), Ac-ICV (1 mW) QDWGAHRCT of SEQ ID NO: 164 (Risitano et al. Blood, 2014, 123, 2094) yICV(1mW)QDW-Sar-AHRC-mI of SEQ ID NO: 165 (Risitano et al. Blood, 2014, 123, 2094) PEG-yICV(1mW)QDW-Sar-AHRC-mI of SEQ ID NO: 166 (Risitano et al. Blood, 2014, 123, 2094) [ka] Ac-Ile-[Cys-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-Thr-NH2 of SEQ ID NO: 167 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-Ile-NH2 of SEQ ID NO: 168 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-mIle-NH2 of SEQ ID NO: 169 (Qu, H. et al. Immunobiology (2012) http: / / dx.doi.org / 10.1016 / j.imbio.2012.06.003), Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-Thr-NH2) of SEQ ID NO: 170 (Qu, H. et al. Molecular Immunology, 2011, 48, 481), Ac-Xaa1-[Cys2-Val3-Xaa4-Gln5-Asp6-Trp7-Gly8-Xaa9-Xaa10-Xaa11-Cys12]-Thr13-NH2 of SEQ ID NO: 171 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVVQDWGHHRC]T-NH2 of SEQ ID NO: 172 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVVQDWGAHRC]T-NH2 of SEQ ID NO: 173 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVTQDWGHHRC]T-NH2 of SEQ ID NO: 174 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVSQDWGHHRC]T-NH2 of SEQ ID NO: 175 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVHQDWGHHRC]T-NH2 of SEQ ID NO: 176 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVFQDWGHHRC]T-NH2 of SEQ ID NO: 177 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVYQDWGAHRC]T-NH2 of 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 SEQ ID NO: 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 of 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 SEQ ID NO: 185 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]dT of SEQ ID NO: 186 (Mallik et al. J. Med. Chem., 2005, 48, 274-286), Ac-I[CVWQDWGAHRC]T-NH2 of SEQ ID NO: 187 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), SEQ ID NO: 188 W[CVWQDWGTNRC]W-NH2 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-D[CVWQDWGTNKC]W-NH2 of SEQ ID NO: 189 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Q[CVWQDWGQNQC]W-NH2 of SEQ ID NO: 190 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-I[CVWQDWGAHRC]W-NH2 of SEQ ID NO: 191 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-W[CVWQDWGAHRC]T-NH2 of SEQ ID NO: 192 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-W[CVWQDWGAHRC]W-NH2 of SEQ ID NO: 193 (Lopez de Victoria, A. et al. Chem Biol Drug Des 2011, 77, 431-440), Ac-Ile-[Ala-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Hcy]-Thr-NH2 of SEQ ID NO: 194 (Knerr, P. et al. ACS Chem. Biol., 2011, 6, 753-760), Ac-Ile-[Cys-Val-Trp-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-(NMeIle)-NH2, SEQ ID NO: 195 (Knerr, P. et al. ACS Chem. Biol., 2011, 6, 753-760), SEQ ID NO: 196 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), Ac-ICV(5fW)QDWGAHRCT-NH2 of SEQ ID NO: 197 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICV(5MeW)QDWGAHRCT-NH2 of SEQ ID NO: 198 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICV(2Nal)QDWGAHRCT-NH2 of SEQ ID NO: 199 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICVWQD(5fW)GAHRCT-NH2 of SEQ ID NO: 200 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICVWQD(5MeW)GAHRCT-NH2 of SEQ ID NO: 201 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICVWQD(1MeW)GAHRCT-NH2 of SEQ ID NO: 202 (Katragadda et al. J. Med. Chem. 2006, 49, 4616-4622), Ac-ICVYQDWGAHRCT-CONH2 of SEQ ID NO: 203 (WO 2021 / 007111), Ac-ICVWQDWGAHRCT-COOH of SEQ ID NO: 204 (WO 2021 / 007111), Ac-ICVWQDWGAHRCT-CONH2 of SEQ ID NO: 205 (WO 2021 / 007111), Ac-ICVWQDWGAHRCdT-COOH of SEQ ID NO: 206 (WO 2021 / 007111), Ac-ICV(2-Nal)QDWGAHRCT-CONH2 of SEQ ID NO: 207 (WO 2021 / 007111), Ac-ICV(2-Nal)QDWGAHRCT-COOH of SEQ ID NO: 208 (WO 2021 / 007111), Ac-ICV(1-Nal)QDWGAHRCT-COOH of SEQ ID NO: 209 (WO 2021 / 007111), Ac-ICV(2-lal)QDWGAHRCT-CONH2 of SEQ ID NO: 210 (WO 2021 / 007111), Ac-ICV(2-lal)QDWGAHRCT-COOH of SEQ ID NO: 211 (WO 2021 / 007111), Ac-ICVDhtQDWGAHRCT-COOH of SEQ ID NO: 212 (WO 2021 / 007111), Ac-ICV(Boa)QDWGAHRCT-COOH of SEQ ID NO: 213 (WO 2021 / 007111), Ac-ICV(Bpa)QDWGAHRCT-CONH2 of SEQ ID NO: 214 (WO 2021 / 007111), Ac-ICV(Bta)QDWGAHRCT-COOH of SEQ ID NO: 215 (WO 2021 / 007111), Ac-ICV(Bta)QDWGAHRCT-CONH2 of SEQ ID NO: 216 (WO 2021 / 007111), Ac-ICVWQDWG(2-Abu)HRCT-CONH2 of SEQ ID NO: 217 (WO 2021 / 007111), H-GICVWQDWGAHRCTAN-COOH of SEQ ID NO: 218 (WO 2021 / 007111), CONH2 of Ac-ICV(5fW)QDWGAHRCT- of SEQ ID NO: 219 (WO 2021 / 007111), Ac-ICV(5-methyl-W)QDWGAHRCT-CONH2 of SEQ ID NO: 220 (WO 2021 / 007111), Ac-ICV(1-methyl-W)QDWGAHRCT-CONH2 of SEQ ID NO: 221 (WO 2021 / 007111), Ac-ICVWQD(5fW)GAHRCT-CONH2 of SEQ ID NO: 222 (WO 2021 / 007111), CONH2 of Ac-ICV(5fW)QD(5fW)GAHRCT- of SEQ ID NO: 223 (WO 2021 / 007111), Ac-ICV(5-methyl-W)QD(5fW)GAHRCT-CONH2 of SEQ ID NO: 224 (WO 2021 / 007111), Ac-ICV(1-methyl-W)QD(5fW)GAHRCT-CONH2 of SEQ ID NO: 225 (WO 2021 / 007111), H-GICV(6fW)QD(6fW)GAHRCTN-COOH of SEQ ID NO: 226 (WO 2021 / 007111), Ac-ICV(1-formyl-W)QDWGAHRCT-CONH2 of SEQ ID NO: 227 (WO 2021 / 007111), Ac-ICV(1-methyloxy-W)QDWGAHRCT-CONH2 of SEQ ID NO: 228 (WO 2021 / 007111), H-GICV(5fW)QD(5fW)GAHRCTN-COOH of SEQ ID NO: 229 (WO 2021 / 007111), Examples include:

[0486] In certain embodiments, the complement C3 targeting ligand is: [ka] is.

[0487] In certain embodiments, the complement C3 targeting ligand is: [ka] Selected from TIFF2024517812000268.tif186170.

[0488] Non-limiting examples of complement C3 degrading compounds include: [ka] Examples include TIFF2024517812000270.tif216170 and TIFF2024517812000271.tif212170.

[0489] In certain non-limiting embodiments, the complement C3 degrading compound of the present invention is the following compound: [ka] TIFF2024517812000273.tif178170TIFF2024517812000274.tif171170TIFF2024517812000275.tif170170TIFF2024517812000276.tif180170TIFF2024517812000277.tif184170TIFF2024517812000278.tif88170, or bidentate or tridentate forms thereof.

[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 antigen-bound immunoglobulin. The C1 complex consists of a tetramer of C1q and proteases (C1r and C1s). C1q mediates complement binding to IgG or IgM. Following the binding event, proteases are activated, which cleave C4, initiating the rest of the pathway, which ends with opsonization. Overactivity of this pathway can lead to many inflammatory pathologies, including allograft rejection, neuromyelitis optica, generalized myasthenia gravis, and cold agglutinin disease. Degradation of C1q can alleviate symptoms associated with these inflammatory diseases.

[0491] The Protein Data Bank website provides the crystal structure 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). The PDB website also provides a structure of the complement C1q complex with its ligand bound, searchable by 6Z67 (Laursen, N. et al. Front. Immunol., 2020, (11), 1504).

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

[0493] In certain embodiments, the linker has an amino acid sequence, such as SEQ ID NO: 231 [ka] It is attached via the C-terminus of

[0494] In certain embodiments, the linker is, for example, SEQ ID NO: 231 [ka] is bound to the N-terminus of

[0495] Non-limiting examples of complement C1q degrading compounds include: [ka] Examples include:

[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 cytokine important in inflammatory responses. IL-17 is secreted by a distinct class 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 has been implicated as a key factor in psoriasis as well as other autoimmune diseases. Other diseases that may benefit from IL-17 therapy include, but are not limited to, asthma, rheumatoid arthritis, psoriatic arthritis, Crohn's disease, and inflammatory bowel disease. IL-17-induced inflammation has been shown to impede recovery after stroke.

[0497] The Protein Data Bank website lists the following: 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. (2009) Nat Immunol 10: 1245-1251), 5N9B (unpublished), and 2VXS (Gerhardt, S. et al. (2009) J Mol Biol 394: 905) provide searchable crystal structures of IL-17.

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

[0499] Additional binding ligands include: IVVTAPADLWDWIRA of SEQ ID NO: 340 (Liu et al. 2016, Scientific Reports 6:26071), ITVTMPADLWDWIRA of sequence number 341 (Liu et al. 2016, Scientific Reports 6:26071), IVVTIPADLWDWIRA of SEQ ID NO: 342 (Liu et al. 2016, Scientific Reports 6:26071), IVVTLPADLWDWIRA of SEQ ID NO: 343 (Liu et al. 2016, Scientific Reports 6:26071), SEQ ID NO: 344 IVVTVPADLWDWIRA (Liu et al. 2016, Scientific Reports 6:26071), IVVTMPADLWDWIMA of SEQ ID NO: 345 (Liu et al. 2016, Scientific Reports 6:26071), IVVTMPADLWDWINA of SEQ ID NO: 346 (Liu et al. 2016, Scientific Reports 6:26071), SEQ ID NO: 347 IVVTMPADLWDWIQA (Liu et al. 2016, Scientific Reports 6:26071), IHVTIPADLWDWINK of SEQ ID NO: 348 (Liu et al. 2016, Scientific Reports 6:26071), IHVTIPADLWDWIN of SEQ ID NO: 349 (Liu et al. 2016, Scientific Reports 6:26071), [ka] TIFF2024517812000283.tif214170TIFF2024517812000284.tif169170TIFF2024517812000285.tif197170TIFF2024517812000286.tif86170 are listed. 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0500] In certain embodiments, [ka] (In the formula, The IL-17 targeting ligand is any IL-17 ligand described in WO 2020 / 146194, WO 2020 / 163554, WO 2020 / 127685, and WO 2021 / 055376 (each of which is incorporated herein by reference), or a pharmaceutically acceptable salt thereof.

[0501] In certain embodiments, the IL-17 targeting ligand has 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 is -H or -CH2OCH3).

[0502] In certain embodiments, the IL-17 targeting ligand has the formula: [ka] (In the formula, R E1 is 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 is alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, fused cycloalkylaryl, substituted fused cycloalkylaryl, heteroaryl, substituted heteroaryl, or a D pocket substituent; Each R E3 are independently hydrogen, (C1-C7) alkyl, substituted (C1-C7) alkyl, or -OR E32 and m E is 0, 1, or 2, Each R E4 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 are independently -N- or -CR E11 - but X E1 , X E2 , X E3 , and X E4 Two or fewer of these are nitrogen, Each R E5 are independently hydrogen, (C1-C7) alkyl, substituted (C1-C7) alkyl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, heterocycle alkyl, substituted heterocycle alkyl, -NR E12 R E13 , -NR E14 C(O)R E15 , -NHSO2R E31 , OH, or B pocket substituents; R E6 is hydrogen or alkyl, R E7 is a heterocycle, a substituted heterocycle, -(CHR E16 ) o R E17 , or -(CHR E18 ) p R E19 or R E6 and R E7 together with the nitrogen atom to which they are attached form a piperazine, a substituted piperazine, a heterocycle, or a substituted heterocycle; [ka] or forming an A pocket substituent, R E8 is (C1-C7) alkyl, substituted (C1-C7) alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each R E11 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 are independently hydrogen, (C1-C7) alkyl, or substituted (C1-C7) alkyl; R E17 teeth, [ka] and Each R E18 are independently hydrogen, (C1-C7) alkyl, or substituted (C1-C7) alkyl; R E19 is -NR E27 R E28 and R E27 and R E28 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 is independently selected at each occurrence from hydrogen, alkyl, substituted alkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or alternatively, independently selected from RE9 and R E10 , R E21 and R E22 , and R E24 and R E25 together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl ring, or substituted cycloheteroalkyl ring; R E28 is hydrogen or alkyl, The A pocket substituents are [ka] is selected from the group consisting of The B pocket substituents are [ka] is selected from the group consisting of The D pocket substituents are [ka] is selected from the group consisting of The F pocket substituents are [ka] is selected from the group consisting of wherein each optional substituent for 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 carbocycles and 3- to 10-membered heterocycles, wherein C 3~10Carbocyclic rings and 3- to 10-membered heterocyclic rings are preferably halogen, -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 —CN), each optionally substituted with one or more substituents selected from

[0503] In certain embodiments, the I-17 targeting ligand has the formula: [ka] It is a ligand of

[0504] In certain embodiments, the IL-17 targeting ligand has the formula: [ka] (In the formula, [ka] is an arbitrarily substituted C 3~12 and optionally substituted 3- to 12-membered heterocycles, wherein the substituents on rings AF are independently, at each occurrence, selected from: 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 Alkenyl, C 2~10 Alkynyl (each of which 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 and optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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 Carbocycles and 3- to 12-membered heterocycles (each of which may contain 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 , -NO2, -CN, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more substituents independently selected from haloalkyl; is selected from [ka] is an arbitrarily substituted C 3~10 and each substituent on Ring B is independently, at each occurrence, selected from: 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 Alkenyl, C 2~10 Alkynyl (each of which 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 and optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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), each optionally substituted with one or more substituents selected from -CN, is selected from R F4 teeth, -C(O)N(R F23 )(R F24 ) and C(O) heterocycles (wherein the heterocycle is substituted with 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), and C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl (each of which 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 and optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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 ), each optionally substituted with one or more substituents selected from -CN, is selected from L F is a bond or is 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 alkyl, wherein C 1~6 Alkyl is halogen, OR F14 , -N(R F14 )2, -C(O)R F14 , 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 alkyl, wherein C 1~6 Alkyl is halogen, OR F15 , -N(R F15 )2, -C(O)R F15 , NO, =O, and -CN; A or R B At least one of the is not hydrogen, R F ' and R F'' are independently hydrogen, halogen, -OR F16 , and C 1~6 alkyl, wherein C 1~6 Alkyl is halogen, -OR F16 , -N(R F16 )2, -C(O)R F16 , -NO2, =O, and -CN; R F1 -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 ) and Each R F2 and R F3 are independently hydrogen, halogen, -OR F17 , C 1~6 Alkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl and C 3~6 Cycloalkyl is halogen, -OR F17 , -N(R F17 )2, -C(O) RF17 , -NO2, =O, and -CN, or R attached 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 -NO, =O, and -CN 3~6 forming a cycloalkyl, R F21independently in each occurrence, hydrogen, as well as halogen, -OR F17 , -N(R F17 )2, -C(O)R F17 , —NO2, ═O, and —CN; R F22 teeth, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl (each of which 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 and optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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 ), each optionally substituted with one or more substituents selected from -CN, and C 3~12 carbocyclic rings and 3- to 12-membered heterocyclic rings; Selected from C 3~12 Each of the carbocyclic ring and the 3- to 12-membered heterocyclic ring 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 Alkenyl, C 2~10 Alkynyl (each of which 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 and optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are preferably substituted with halogen, -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 ), each optionally substituted with one or more substituents selected from -CN, and optionally substituted with one or more substituents independently selected from R F23 teeth, Halogen, -OR F19 , -SR F19 , -N(R F19 )2, -NO2, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 Alkyl (where C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are preferably halogen, -OR F19 , -N(R F19 )2, each optionally substituted with one or more substituents selected from ═O, C1-C6 alkyl, C1-C6 haloalkyl, and —CN), and C 3~12 Carbocycles and 3- to 10-membered heterocycles (each of which may contain halogen, -OR F19 , -N(R F19 )2, optionally substituted with one or more substituents independently selected from: ═O, C1-C6 alkyl, C1-C6 haloalkyl, and —CN; is selected from R F24 represents hydrogen, as well as halogens, -OR F19 , -SR F19 , -N(R F19 )2, -NO2, -CN, C 3~6 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1~6 alkyl, R F11 , R F12 , R F13 , R F14 , R F15 , R F16 , R F17 , R F18 , and R F19are, independently, in each case, Hydrogen, and Halogen, -OH, -O-C1~C6 alkyl, -O-C1~C6 haloalkyl-NH2, -NO2, =O, -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 Alkyl (where C 3~10 The carbocycle and the 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl-NH2, —NO2, ═O, and —CN), and C 3~12 carbocyclic rings and 3- to 12-membered heterocyclic rings; Selected from C 3~12 Each of the carbocyclic ring and the 3- to 12-membered heterocyclic ring is Halogen, -OH, -O-C1-C6 alkyl, -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, and optionally substituted with one or more substituents independently selected from n F is selected from 0 and 1, and m F is a ligand of

[0505] In certain embodiments, the IL-17 targeting ligand has the formula: [ka] It is a ligand of

[0506] In certain embodiments, the IL-17 targeting ligand has the formula: [ka] (In the formula, R G1 is a 5- or 6-membered heteroaryl, a 9- or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl, a 4- to 6-membered heterocycloalkyl, and —NR GC R GD wherein the 5- or 6-membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl, and 4- to 6-membered heterocycloalkyl are selected from the group consisting of R GA and optionally substituted with one or more substituents independently selected from R GA is deuterium, halogen, hydroxy, -NR GC R GD , (C1-C6) alkyl, (C1-C6) alkylcarbonyl, (C3-C7) cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) alkylcarbonyl, (C3-C7) cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is selected from the group consisting of deuterium, halogen, hydroxy, cyano, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkoxy, —SO2—(C1-C4) alkyl, and —NR GC R GD and optionally substituted with one or more substituents independently selected from R G2 is selected from the group consisting of 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is selected from the group consisting of R GB wherein said 5- or 6-membered heteroaryl optionally contains —CO— as a ring member, and when said 5-membered heteroaryl contains nitrogen as a ring atom, said nitrogen is not RG8 and optionally substituted with a substituent selected from R GB is deuterium, halogen, cyano, hydroxy, -NR GC R GD , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-CO—O—(CH2) n or (C3-C7)cycloalkyl, where n is 1 to 4, and the (C1-C6)alkyl, (C1-C6)alkoxy, or (C3-C7)cycloalkyl is selected from the group consisting of deuterium, halogen, cyano, hydroxy, -NR GC R GD and (C1-C4)alkoxy; R GC and R GD are each independently selected from the group consisting of hydrogen and (C1-C6) alkyl, or R GC and R GD taken together form pyrrolidinyl or piperidinyl, wherein the (C1-C6) alkyl, pyrrolidinyl, or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and hydroxy; R G8 -L G -PO(OH)2 and -CHR GG O-(CO-A-NR GH )) 0又は1) -CO-A-NR GH R GI is selected from the group consisting of L G is a bond or -CHR GG O-, Here, each -CO-A-NR GH - independently represents an amino acid residue, which is selected from natural amino acids in either D or L form or a mixture of D and L forms, and which amino acid residues have a substituent R at the α-amino group. GH may be substituted with R GG , RGH , and R GI are independently selected from hydrogen and (C1-C6) alkyl; R G3 is selected from the group consisting of hydrogen, deuterium, hydroxy, and halogen; R G4 is selected from the group consisting of hydrogen, deuterium, and halogen; R G5 is -CHR G6 R G7 , (C3~C 10 ) cycloalkyl, and GG, wherein 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] and R G6 and R G7 are each independently hydrogen, phenyl, (C1-C6) alkyl, or (C3-C7) cycloalkyl, wherein the phenyl, (C1-C6) alkyl, or (C3-C7) cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, and (C1-C4) alkyl.

[0507] In certain embodiments, the IL-17 targeting ligand has the formula: [ka] It is a ligand of

[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 diverse biological functions. IL-6 is a potent inducer of the acute phase response and plays a key role in the terminal differentiation of B cells into Ig-secreting cells. IL-6 is also involved in lymphocyte and monocyte differentiation. IL-6 also acts on B cells, T cells, hepatocytes, hematopoietic progenitor cells, and cells of the CNS, and is required for the generation of T(H)17 cells. IL-6 has been implicated in a number of inflammatory diseases and cancers, including, but not limited to, Castleman's disease, metastatic castration-associated prostate cancer, renal cell carcinoma, large cell lung cancer, ovarian cancer, rheumatoid arthritis, and asthma.

[0509] The Protein Data Bank website provides not only the crystal structure of IL-6, which can be searched for 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 U S A., 2002, 99 15959-15964), but also the crystal structure of 4CNI (Shaw, S., et al., Mabs, 2014, 6: 773), and 4NI7 and 4NI9 (Gelinas et al., J Biol Chem. 2014, 289(12), 8720-8734), also provide crystal structures of IL-6 bound to various compounds. Furthermore, Gelinas et al. provide insights into the crystal structure of interleukin-6 complexed with a modified nucleic acid ligand (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: a novel form of receptor dimerization and its impact on signal transduction.

[0510] Non-limiting examples of direct or indirect inhibitors of IL-6 are shown in Figure 1. Additional direct or indirect inhibitors of IL-6 can be found, for example, in U.S. Patent Nos. 8,901,310, 10,189,796, and 9,694,015 (each of which is incorporated herein by reference). In another embodiment, the extracellular targeting ligand of IL-6 is Avimar C326 or a binding fragment thereof, 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 pathogen-derived molecules 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 has been implicated in 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's 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, IL-6 is produced in large amounts during exercise. In contrast to its role in stimulating the immune system, IL-6 is anti-inflammatory during exercise.

[0514] The Protein Data Bank website provides the crystal structure 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), 1IL6 (Xu, GY et al. Solution structure of recombinant human interleukin-6 (1997) J Mol Biol 268: 468-481), and the structure of IL-6 bound in an 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. Pat. No. 10,633,423, U.S. Pat. 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] SEQ ID NO: 350 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWEKIGlaKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SEQ ID NO: 351 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG30L)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SEQ ID NO: 352 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG20Br)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SEQ ID NO: 353 QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaK(PEG40Br)INDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SEQ ID NO: 354 FDhLDCIHRLLEAFLDPNLTEQQRWEKIDKINDECE (Ranganath, S. et al. PLoS ONE 10(11):e0141330) QSDChaDCIHRLLEAF(4-F)LDPNLTEEQRWERIGlaKINDECE of SEQ ID NO: 355 (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SWQSDChaDCIHRLLEAFLDK-AcNLTEEQRWERIDKINDECE of SEQ ID NO: 356 (Ranganath, S. et al. PLoS ONE 10(11):e0141330) SWQSDChaDCIHRLLEAFLDK-PEG40BrNLTEEQRWERIDKINDECE of SEQ ID NO: 357 (Ranganath, S. et al. PLoS ONE 10(11):e0141330)

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

[0518] SEQ ID NO: 358 EEX3X4AWX7EIHX 11 LPNLX 16 X17 X 18 QX 20 X 21 AFIX 25 X 26 LX 28 X 29 (U.S. Patent No. 10,633,423) (where, 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 is selected from A, I, K, L, M, N, R, S, T, and V; X 16 is selected from N and T; X 17 is selected from A, I, T, and V; X 18 is selected from D, E, G, H, K, N, Q, R, S, and T; X 20 is selected from I, L, M, R, T, and V; X 21 is selected from A, S, T, and V; X 25 is selected from I, M, Q, S, T, V, and W; X 26 is selected from K and S; X 28 is selected from F, L, M, and Y, and X 29 is selected from D and R).

[0519] SEQ ID NO: 359 EEX3X4AWX7EIHX 11 LPNLX 16 X 17 X 18 QX 20 X 21 AFIX 25 X 26 LX 28 X 29(U.S. Patent No. 10,669,314) (where, 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 is selected from A, I, K, L, M, N, R, S, T, and V; X 16 is selected from N and T; X 17 is selected from A, I, T, and V; X 18 is selected from D, E, G, H, K, N, Q, R, S, and T; X 20 is selected from I, L, M, R, T, and V; X 21 is selected from A, S, T, and V; X 25 is selected from I, M, Q, S, T, V, and W; X 26 is selected from K and S; X 28 is selected from F, L, M, and Y, and X 29 is selected from D and R).

[0520] In certain embodiments, the targeting ligand for treating an IL-6-mediated disease 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; 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 certain embodiments, the gp130 targeting ligand is [ka] is selected from.

[0522] Immunoglobulin A1 (IgA1) Immunoglobulin A is a class of antibody typically found in secretions but also present in serum. IgA contains four heavy chains and four light chains in a dimeric form. IgA exists in two isotypes, IgA1 and IgA2. IgA1 contains more repeats in the hinge region and is the predominant form found in serum. IgA production maintains strong mucosal immunity and defense against pathogens, but it can be toxic. IgA nephropathy, also known as Buerger's disease, is the pathological accumulation of IgA antibodies that impairs kidney function. The etiology of this disease remains unclear, but glycosylation patterns in the hinge region have been suggested to play a role. 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, and representative examples include 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] Direct or indirect IgA1 binding molecules include jacalin and SEQ ID NO: 360 YYALSDAKEEEPRYKALRGENQDLREKERKYQDKIKKLEEKEKNLEKKS.

[0525] Linker Embodiments In a non-limiting embodiment, the linker A and linker B is, 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 are independently, in each occurrence, a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO2—, —S(O)—, —C(S)—, or —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 )-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, -CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -, -[-(CH2)2-O-] n -, -[O-(CH2)2] n -, -[O-CH(CH3)C(O)] n -, -[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -, -[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated monocarboxylic or dicarboxylic acid, each of which is selected from the group consisting of R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21is independently, in each occurrence, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 , haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycle; and The remaining variables are selected from:

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

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

[0528] In one embodiment, the divalent residue of an amino acid is [ka] wherein the amino acids may be oriented in either direction and the amino acids may be in the L- or D-form.

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

[0530] Non-limiting examples of divalent residues of dicarboxylic acids produced from nucleophilic addition reactions include: [ka] Examples include:

[0531] As 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] As 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 a dicarboxylic acid is reacted with a condensation reaction: [ka] is generated from

[0534] Non-limiting examples of divalent residues of dicarboxylic acids produced from the condensation include: [ka] Examples include:

[0535] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: [ka] Examples include:

[0536] Non-limiting examples of divalent residues of saturated dicarboxylic acids include: [ka] Examples include:

[0537] Non-limiting examples of divalent residues 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-), lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 CH2-).

[0538] Non-limiting embodiments of divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paulic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid: [ka] Examples include:

[0539] Non-limiting examples of divalent residues of fatty acids include linoleic acid (-C(O)(CH)(CH)CH(CH)(CH)CH-), docosahexaenoic acid (-C(O)(CH)(CHCHCH)CH-), eicosapentaenoic acid (-C(O)(CH)(CHCHCH)CH-), α-linolenic acid (-C(O)(CH)(CHCHCH)CH-), stearidonic acid (-C(O)(CH)(CHCHCH)CH-), γ-linolenic acid (-C(O)(CH)(CHCHCH)CH-), α ... -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-), paulinic 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-).

[0540] In certain embodiments, the linker C teeth, [ka] (In the formula, R 22 is independently, at each occurrence, alkyl, —C(O)N—, —NC(O)—, —N—, —C(R 21)-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 ) N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 and The remaining variables are selected from:

[0541] In certain embodiments, the linker D teeth, [ka] (In the formula, R 32 is independently, in each occurrence, alkyl, N + X - , -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from X - is an anionic group, e.g., Br - or Cr - and All other variables are as defined herein).

[0542] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0543] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0544] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0545] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0546] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0547] In certain embodiments, the linker A teeth, [ka] each optionally substituted with 1, 2, 3, or 4 optional substituents as defined herein.

[0548] In certain embodiments, the linker A teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0549] In certain embodiments, the linker A teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0550] In certain embodiments, the linker A teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0551] In certain embodiments, the linker B teeth, [ka] is selected from.

[0552] In certain embodiments, the linker B teeth, [ka] is selected from.

[0553] In certain embodiments, the linker B , linker C , or a linker D teeth, [ka] wherein tt is independently selected from 1, 2, or 3, and ss is 3-tt.

[0554] In certain embodiments, the linker B , linker C , or a linker D teeth, [ka] wherein tt and ss are as defined herein.

[0555] In certain embodiments, the linker B , linker C , or a linker D teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, and tt and ss are as defined herein.

[0556] In certain embodiments, the linkerB , linker C , or a linker D teeth, [ka] TIFF2024517812000339.tif191170, wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, and tt and ss are as defined herein.

[0557] In certain embodiments, the linker B , linker C , or a linker D teeth, [ka] wherein each heteroaryl and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, and tt and ss are as defined herein.

[0558] In certain embodiments, the linker A teeth, [ka] is selected from.

[0559] In certain embodiments, the linker A teeth, [ka] is selected from.

[0560] In certain embodiments, the linker A teeth, [ka] is selected from.

[0561] In certain embodiments, the linker A teeth, [ka] is selected from.

[0562] In certain embodiments, the linker B teeth, [ka] is selected from.

[0563] In certain embodiments, the linker B teeth, [ka] is selected from.

[0564] In certain embodiments, the linker B teeth, [ka] is selected from.

[0565] In certain embodiments, the linker B teeth, [ka] is selected from.

[0566] In certain embodiments, the linker C teeth, [ka] is selected from.

[0567] In certain embodiments, the linker C teeth, [ka] is selected from.

[0568] In certain embodiments, the linker C teeth, [ka] is selected from.

[0569] In certain embodiments, the linker C teeth, [ka] is selected from.

[0570] In certain embodiments, the linker C teeth, [ka] is selected from.

[0571] In certain embodiments, the linker C teeth, [ka] is selected from.

[0572] In certain embodiments, the linker C teeth, [ka] is selected from.

[0573] In certain embodiments, the linker C teeth, [ka] is selected from.

[0574] In certain embodiments, the linker D teeth, [ka] is selected from.

[0575] In certain embodiments, the linker D teeth, [ka] is selected from.

[0576] In certain embodiments, the linker D teeth, [ka] is selected from.

[0577] In certain embodiments, the linker D teeth, [ka] is selected from.

[0578] In certain embodiments, the linker D teeth, [ka] is selected from.

[0579] In certain embodiments, the linker D teeth, [ka] is selected from.

[0580] In certain embodiments, the linker D teeth, [ka] is selected from.

[0581] In certain embodiments, the linker A teeth, [ka] is selected from.

[0582] In certain embodiments, the linker A teeth, [ka] is selected from.

[0583] In certain embodiments, the linker A teeth, [ka] is selected from.

[0584] In certain embodiments, the linker A teeth, [ka] wherein each is selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0585] In certain embodiments, the linker A teeth, [ka] is selected from.

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

[0587] In certain embodiments, the linker A teeth, [ka] is selected from.

[0588] In certain embodiments, the linker A teeth, [ka] is selected from.

[0589] In certain embodiments, the linker A teeth, [ka] is selected from.

[0590] In certain embodiments, the linker A teeth, [ka] is selected from.

[0591] In certain embodiments, the linker A teeth, [ka] is selected from.

[0592] In certain embodiments, the linker A teeth, [ka] is selected from.

[0593] In certain embodiments, the linker A teeth, [ka] is selected from.

[0594] In certain embodiments, the linker A teeth, [ka] is selected from.

[0595] In certain embodiments, the linker A teeth, [ka] is selected from.

[0596] In certain embodiments, the linker A teeth, [ka] is selected from.

[0597] In certain embodiments, the linker A teeth, [ka] is selected from.

[0598] In certain embodiments, the linker B teeth, [ka] is selected from.

[0599] In certain embodiments, the linker B teeth, [ka] is selected from.

[0600] In certain embodiments, the linker B teeth, [ka] wherein each is selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0601] In certain embodiments, the linker B teeth, [ka] is selected from.

[0602] In certain embodiments, the linker B teeth, [ka] is selected from.

[0603] In certain embodiments, the linker B teeth, [ka] is selected from.

[0604] In certain embodiments, the linker B teeth, [ka] is selected from.

[0605] In certain embodiments, the linker B teeth, [ka] is selected from.

[0606] In certain embodiments, the linker B teeth, [ka] is selected from.

[0607] In certain embodiments, the linker B teeth, [ka] is selected from.

[0608] In certain embodiments, the linker B teeth, [ka] is selected from.

[0609] In certain embodiments, the linker B -Linker A teeth, [ka] is selected from.

[0610] In certain embodiments, the linker B -Linker A teeth, [ka] is selected from.

[0611] In certain embodiments, the linker C teeth, [ka] is selected from.

[0612] In certain embodiments, the linker C teeth, [ka] is selected from.

[0613] In certain embodiments, the linker C teeth, [ka] is selected from.

[0614] In certain embodiments, the linker C teeth, [ka] is selected from.

[0615] In certain embodiments, the linker C teeth, [ka] is selected from.

[0616] In certain embodiments, the linker C teeth, [ka] TIFF2024517812000400.tif235170, where each is R 21 and optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0617] In certain embodiments, the linker C teeth, [ka] is selected from.

[0618] In certain embodiments, the linker C teeth, [ka] is selected from.

[0619] In certain embodiments, the linker C teeth, [ka] is selected from.

[0620] In certain embodiments, the linker C teeth, [ka] is selected from.

[0621] In certain embodiments, the linker C teeth, [ka] is selected from.

[0622] In certain embodiments, the linker C teeth, [ka] is selected from.

[0623] In certain embodiments, the linker C teeth, [ka] is selected from.

[0624] In certain embodiments, the linker C -(linker A )2 is, [ka] is selected from.

[0625] In certain embodiments, the linker C -(linker A )2 is, [ka] is selected from.

[0626] In certain embodiments, the linker C -(linker A )2 is, [ka] is selected from.

[0627] In certain embodiments, the linker C -(linker A )2 is, [ka] is selected from.

[0628] In certain embodiments, the linker D teeth, [ka] is selected from.

[0629] In certain embodiments, the linker D teeth, [ka] is selected from.

[0630] In certain embodiments, the linker D teeth, [ka] wherein each is selected from R 21 and optionally substituted with 1, 2, 3, or 4 substituents selected from:

[0631] In certain embodiments, the linker B -(linker A )teeth, [ka] is selected from.

[0632] In certain embodiments, the linker C -(linker A )teeth, [ka] is selected from.

[0633] In certain embodiments, the linker D -(linker A )teeth, [ka] is selected from.

[0634] In certain embodiments, the linker B teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0635] In certain embodiments, the linker B teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0636] In certain embodiments, the linker B teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0637] In certain embodiments, the linker B , linker C , or a linker D teeth, [ka] wherein each heteroaryl, heterocycle, cycloalkyl, and aryl may be optionally substituted, where allowed by valence, with any combination of 1, 2, 3, or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl.

[0638] In certain embodiments, the linker A teeth, [ka] is selected from.

[0639] In certain embodiments, the linker A teeth, [ka] and each is substituted with one or two optional substituents.

[0640] In certain embodiments, the linker A is a bond.

[0641] In certain embodiments, the linker A The left side of is attached to the ASGPR-binding ligand, and the right side is the linker B , linker C , or a linker D is attached to the

[0642] In certain embodiments, the linker A The right side of is attached to the ASGPR-binding ligand, and the right side is the linker B , linker C , or a linker D is attached to the

[0643] In certain embodiments, the linker B teeth, [ka] is selected from.

[0644] In certain embodiments, the linker B teeth, [ka] is selected from.

[0645] In certain embodiments, the linker B The left side of the A is attached to the

[0646] In certain embodiments, the linker BThe right side of the molecule is attached to an extracellular targeting ligand, and the left side is a linker A is attached to the

[0647] In certain embodiments, the linker B is a bond.

[0648] In an alternative embodiment, the linker is as shown above, wherein: [ka] teeth, [ka] and is replaced with, for example, the linker B but, [ka] In this embodiment, the linker is [ka] is.

[0649] In an alternative embodiment, the linker is as shown above, wherein: [ka] teeth, [ka] and is replaced with, for example, the linker B but, [ka] In this embodiment, the linker is [ka] is.

[0650] In an alternative embodiment, the linker is as shown above, wherein: [ka] teeth, [ka] can be replaced with.

[0651] Embodiments of ASGPR-Binding Ligands In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0652] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0653] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker Ais replaced by a bond to

[0654] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0655] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0656] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0657] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0658] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0659] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0660] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 or R 1 is the linker A is replaced by a bond to

[0661] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, a linker A is attached to the nitrogen at the C5 position.

[0662] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, a linker A is attached to oxygen at the C5 position.

[0663] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, a linker A is attached to the nitrogen at the C5 position.

[0664] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, a linker A is attached to the nitrogen at the C5 position.

[0665] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0666] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0667] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0668] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0669] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0670] In certain embodiments, the extracellular proteolytic compound has the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0671] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5 is the linker A is replaced with a bond to R * teeth, [ka] is selected from.

[0672] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 5* is the linker A is replaced with a bond to R 5* is alkyl, C(O)R 3 , or hydrogen.

[0673] In certain embodiments, the ASGPR binding ligand has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein when the ASGPR-binding ligand is part of an extracellular proteolytic compound, R 1 or R 5 is the linker A is replaced by a bond to

[0674] In certain embodiments, R * teeth, [ka] is selected from.

[0675] R * Non-limiting examples of [ka] Examples include:

[0676] In certain embodiments, the ASGPR bind...

Claims

1. formula: 【Chemistry 1】 (In the formula, The ASGPR binding ligand is 【Chemistry 2】 (In the formula, R １ Or R ５ is the linker Ａ is replaced with a bond to R １ is the linker Ａ When replaced with a bond to ５ are independently hydrogen, heteroalkyl, C ０ ~C ６ Alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, 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-S(O)R ３ , C ０ ~C ６ Alkyl-C(S)R ３ , C ０ ~C ６ Alkyl-S(O) ２ R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-S(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(S)R ３ , C ０ ~C ６ Alkyl-N(R ８ ) -S(O) ２ R ３ , C ０ ~C ６ Alkyl-O-C(O)R ３ , C ０ ~C ６ Alkyl-O-S(O)R ３ , C ０ ~C ６ Alkyl-O-C(S)R ３ , -N=S(O)(R ３ ) ２ , C ０ ~C ６ Alkyl N ３ , and C ０ ~C ６ Alkyl-O-S(O) ２ R ３ each of which is optionally substituted with 1, 2, or 3 substituents; R ５ is the linker Ａ When replaced with a bond to １ are independently hydrogen, heteroalkyl, C ０ ~C ６ Alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, 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-S(O)R ３ , C ０ ~C ６ Alkyl-C(S)R ３ , C ０ ~C ６ Alkyl-S(O) ２ R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-S(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(S)R ３ , C ０ ~C ６ Alkyl-N(R ８ ) -S(O) ２ R ３ , C ０ ~C ６ Alkyl-O-C(O)R ３ , C ０ ~C ６ Alkyl-O-S(O)R ３ , C ０ ~C ６ Alkyl-O-C(S)R ３ , -N=S(O)(R ３ ) ２ , C ０ ~C ６ Alkyl N ３ , and C ０ ~C ６ Alkyl-O-S(O) ２ R ３ each of which is optionally substituted with 1, 2, or 3 substituents; R ３ is independently at each occurrence hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR ８ , and -NR ８ R ９ is selected from the group consisting of R ６ and R ７ is independently at each occurrence hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR ８ , -alkyl-NR ８ R ９ , C(O)R ３ , S(O)R ３ , C(S)R ３ , and S(O) ２ R ３ is selected from the group consisting of R ８ and R ９ is independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R １０ is hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, 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, heterocycle, 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-S(O)R ３ , C ０ ~C ６ Alkyl-C(S)R ３ , C ０ ~C ６ Alkyl-S(O) ２ R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-S(O)R ３ , C ０ ~C ６ Alkyl-N(R ８ )-C(S)R ３ , C ０ ~C ６ Alkyl-N(R ８ ) -S(O) ２ R ３ , C ０ ~C ６ Alkyl-O-C(O)R ３ , C ０ ~C ６ Alkyl-O-S(O)R ３ , C ０ ~C ６ Alkyl-O-C(S)R ３ , -N=S(O)(R ３ ) ２ , C ０ ~C ６ Alkyl N ３ , and C ０ ~C ６ Alkyl-O-S(O) ２ R ３ each optionally substituted with 1, 2, 3, or 4 substituents, or a pharma- ceutically acceptable salt thereof; the extracellular protein targeting ligand is a ligand that binds to the immunoglobulin G protein; Linker A and linker B are each independently 【Chemistry 3】 and The linker C is 【Chemistry 4】 and The linker D is 【Chemistry 5】 and R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are independently, at each occurrence, a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NR 6 —, —NR 6 C(O)—, —O—, —S—, —NR 6 —, —C(R 21 R 21 )—, —P(O)(R 3 )O—, —P(O)(R 3 )—, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, —CH 2 CH 2 -[O-(CH 2 ) 2 ] n -O-, -CH 2 CH 2 -[O-(CH 2 ) 2 ] n -NR 6 -, -CH 2 CH 2 -[O-(CH 2 ) 2 ] n -, -[-(CH 2 ) 2 -O-] n -, -[O-(CH 2 ) 2 ] n -, -[O-CH(CH 3 )C(O)] n -, -[C(O)-CH(CH 3 )-O] n -, -[O-CH 2 C(O)] n -, -[C(O)-CH 2 -O] n -, divalent residues of fatty acids and divalent residues of unsaturated or saturated mono- or dicarboxylic acids, each of which is selected from the group consisting of R 21 and optionally substituted with 1, 2, or 3 substituents independently selected from n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R 7 , -NR 8 SO 2 R 3 , -NR 8 S(O)R 3 , haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycle; R 22 is independently selected at each occurrence from the group consisting of alkyl, —C(O)N—, —NC(O)—, —N—, —C(R 21 )—, —P(O)O—, —P(O)—, —P(O)(NR 6 R 7 )N—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; R 32 is independently selected at each occurrence from the group consisting of alkyl, N + X − , —C—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; X − is Br − or Cl − , The optional substituents are each independently, when permitted by valence, alkyl, alkenyl, alkynyl, haloalkyl, -OR ６ , F, Cl, Br, I, -NR ６ R ７ , heteroalkyl, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azido, 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 , -SF ５ , 【Chemistry 6】 wherein said optional substituents are selected to result in a stable compound.

2. R ６５ , R ６６ , and R ６７ are independently hydrogen, C ０ ~C ６ The compound of claim 1, wherein the alkyl is selected from cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, and haloalkoxy.

3. R ６７ CF ３ 2. The compound of claim 1,

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

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

6. The ASGPR binding ligand is 【Chemistry 7】 2. The compound of claim 1,

7. The ASGPR binding ligand is 【Chemistry 8】 2. The compound of claim 1,

8. The ASGPR binding ligand is 【Chemistry 9】 2. The compound of claim 1,

9. R １ is the linker Ａ is not bonded to any of 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 10. The compound of claim 1, selected from:

10. R ５ is the linker Ａ is not bonded to any of 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 10. The compound of claim 1, selected from:

11. Linker Ａ teeth, 【Chemistry 10】 2. The compound of claim 1 , selected from:

12. Linker Ａ teeth, 【Chemistry 11】 10. The compound of claim 1, selected from:

13. Linker Ａ teeth, 【Chemistry 12】 2. The compound of claim 1 , selected from:

14. The compound has the formula: 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof.

15. The compound has the formula: 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof.

16. R ２２ is selected from the group consisting of alkyl, —C(O)N—, —NC(O)—, —N—, heterocycle, and heteroaryl, each of which is ２１ 16. The compound of claim 15, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

17. Linker Ｃ teeth, 【Chemistry 15】 16. The compound of claim 15, selected from:

18. The compound has the formula: 【Chemistry 16】 The compound of claim 1 ,

19. Linker Ｄ teeth, 【Chemistry 17】 20. The compound of claim 18, selected from:

20. The compound according to any one of claims 1 to 19, wherein the IgG targeted extracellular protein targeting ligand is Fc-BP-2.

21. The compound of any one of claims 1 to 19, wherein the IgG targeted extracellular protein targeting ligand is Fc-III.

22. The compound has the formula: 【Chemistry 18】 【change】 or a pharma- ceutically acceptable salt thereof.

23. The compound has the formula: 【Chemistry 19】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof.

24. 【Catalogue 20】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof.

25. The compound of claim 1 , wherein the extracellular protein targeting ligand binds to IgG4.

26. The compound of claim 1, wherein the extracellular protein targeting ligand binds to an IgG autoantibody.

27. The compound of claim 26, wherein the autoantibody binds to a TSH receptor.

28. The compound of claim 26, wherein the autoantibody binds to a citrullinated protein.

29. structure: 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof.

30. structure: 【Chemical 22】 or a pharma- ceutically acceptable salt thereof.

31. A pharmaceutical composition for treating a disorder mediated by immunoglobulin G, comprising a compound according to any one of claims 1 to 19 and 22 to 30, and a pharma- ceutically acceptable carrier.

32. The compound is 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof.

33. The compound is 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof.

34. The pharmaceutical composition of claim 31, wherein the disorder is rheumatoid arthritis.

35. The pharmaceutical composition of claim 31, wherein the disorder is an autoimmune thyroid disease.

36. The pharmaceutical composition described in claim 35, wherein the autoimmune thyroid disease is autoimmune thyroid eye disease.

37. The pharmaceutical composition of claim 31, wherein the IgG-mediated disorder is myasthenia gravis.

38. The pharmaceutical composition of claim 31, wherein the IgG-mediated disorder is dilated cardiomyopathy.

39. The pharmaceutical composition of claim 31, wherein the IgG-mediated disorder is lupus.

40. The pharmaceutical composition of claim 31, wherein the IgG-mediated disorder is multiple sclerosis.

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