Targeted bifunctional degraders

Abstract

In one aspect, the present invention provides bifunctional compounds that can be used to promote or enhance the degradation of a particular circulating protein. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance the degradation of a particular autoantibody. In certain embodiments, the treatment or management of a disease and / or disorder requires the degradation, removal, or reduction in the concentration of a circulating protein or autoantibody in a subject. Thus, in certain embodiments, administration of a compound of the present invention to a subject removes or reduces the circulating concentration of a circulating protein or autoantibody, thereby treating, ameliorating, or preventing the disease and / or disorder. In certain embodiments, the circulating protein is TNF. TIFF2025509732000564.tif110153

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 17 / 654,990, filed March 15, 2022, which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant GM067543 awarded by the National Institutes of Health and grant W81XWH-13-1-0062 awarded by the U.S. Army Medical Research Materiel Command. The government has certain rights in this invention.

[0003] Incorporation by reference of materials submitted as text files through the Patent Office Electronic Filing System The present disclosure contains one or more sequences in computer readable format in the attached text file entitled "047162-7250WO2_sequence_listing", which is 160.2 KB in size and created on March 14, 2023, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0004] Background to the disclosure One mechanism that controls the transport of molecules into cells is receptor-mediated endocytosis. In this process, a receptor on the cell surface binds to a specific ligand (or a molecule containing the specific ligand) present on the outside of the cell. This ligand can be a small molecule, metabolite, hormone, protein, or even a virus. This binding process triggers the inward budding (invagination) of the plasma membrane, forming a vesicle containing the receptor-ligand complex. The vesicle then becomes an endosome and subsequently fuses with a lysosome, where the receptor, along with its bound ligand cargo, is degraded, or the receptor is recycled to the cell surface for further collection of circulating ligand.

[0005] One such receptor is the asialoglycoprotein receptor (ASGPR). This receptor is a C-type lectin whose primary biological role is to bind to glycoproteins containing terminal galactose or N-acetylgalactosamine residues (asialoglycoproteins), internalize them, and subsequently remove them from the circulation. ASGPR removes target glycoproteins from the circulation through endocytosis and subsequent lysosomal degradation. ASGPR is highly expressed on the surface of hepatocytes, several human cancer cell lines, and hepatomas, and is less expressed by glandular cells in the gallbladder and stomach. These receptors are known to be involved in the clearance of IgG subtypes and other antibody isotypes from the circulation, the removal of apoptotic cells, the clearance of low-density lipoproteins (LDL) and chylomicron remnants, and the disposal of cellular fibronectin.

[0006] Tumor necrosis factor (TNF, also known as tumor necrosis factor alpha or TNFα) is a cell signaling protein (cytokine) involved in acute-phase systemic inflammatory responses. TNF is primarily produced by activated macrophages, but can also be produced by other cell types, such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons. The primary role of TNF is in regulating immune cells. TNF is an endogenous pyrogen and can induce fever, apoptotic cell death, cachexia, and inflammation, while also inhibiting tumor development and viral replication and responding to sepsis through IL1- and IL6-producing cells. Dysregulation of TNF production is implicated in diseases such as, but not limited to, Alzheimer's disease, cancer, major depression, psoriasis, and inflammatory bowel disease (IBD).

[0007] Autoantibodies are antibodies produced by the immune system that react with one or more of the subject's own proteins. Sometimes the immune system stops recognizing one or more normal components of the body as "self," resulting in the production of pathological (or disease-related) autoantibodies. These autoantibodies then attack the body's own healthy cells, tissues, or organs, causing inflammation and damage. Many autoimmune diseases, such as lupus erythematosus, are caused by these autoantibodies.

[0008] Pathological autoantibodies can target specific organs or be systemic in nature. Autoantibodies contribute to the development and perpetuation of many diseases, including but not limited to Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, atypical hemolytic uremic syndrome (HUS), fulminant antiphospholipid syndrome (CAPS), systemic lupus erythematosus (SLE), chronic inflammatory demyelinating polyneuropathy (CIDP), pediatric autoimmune streptococcal infection-associated neuropsychiatric disorders, and Sydenham's chorea.

[0009] Removal of disease-associated autoantibodies has been shown to reduce symptoms and improve clinical outcomes. Currently, strategies for reducing antibody titers include plasma exchange, in which a patient's plasma is separated extracorporeally from whole blood by centrifugation / filtration and replaced with plasma from healthy donors or albumin; and intravenous immunoglobulin therapy (IVIG), in which antibodies are pooled from human plasma from donors and injected intravenously into the patient. These approaches have limitations and drawbacks. Challenges with plasma exchange include high cost, inconvenience, and significant health risks and complications (e.g., stroke, hypotension, infection, and hypocalcemia). Similarly, IVIG has several drawbacks, including cost, long response time, and side effects (e.g., allergies).

[0010] There is a need in the art for new compounds and methods that allow for the inhibition, removal, and / or degradation of TNF to treat, ameliorate, and / or prevent certain diseases and / or disorders in a subject.There is a need in the art for new compounds and methods that allow for the inhibition, removal, and / or degradation of specific extracellular proteins to treat, ameliorate, and / or prevent certain diseases and / or disorders in a subject.There is a need in the art for new compounds and methods that allow for the inhibition, removal, and / or degradation of specific autoantibodies that mediate certain diseases and / or disorders in a subject.The present disclosure addresses these needs. Summary of the Invention

[0011] A brief summary of the disclosure The present disclosure provides compounds comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Protein binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) where the protein binder, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0012] The present disclosure further provides a compound comprising formula (II), or a salt, geometric isomer, stereoisomer, or solvate thereof: [TNF binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (II) where TNF binder, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0013] The present disclosure further provides a compound comprising formula (III), or a salt, geometric isomer, stereoisomer, or solvate thereof: [AATM] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (III) where AATM, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0014] The present disclosure further provides pharmaceutical compositions comprising at least one compound contemplated herein and at least one pharmaceutically acceptable excipient.

[0015] The present disclosure further provides a method of treating a disease or disorder in a subject, comprising administering a therapeutically effective amount of at least one compound contemplated herein. [Brief explanation of the drawings]

[0016] The drawings illustrate generally, by way of example, but not by way of limitation, various aspects of the present application.

[0017] As used herein, the term "REAG" refers to any reagent comprising -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM. In certain embodiments, a REAG reacts with a TNF binder group to incorporate the TNF binder into a compound of the present disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof. In certain embodiments, a REAG reacts with a protein binder group to incorporate the protein binder into a compound of the present disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof. In certain embodiments, a REAG reacts with an AATM group to incorporate the AATM into a compound of the present disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof. In certain embodiments, the symbol TIFF2025509732000002.tif2128 shows non-limiting positions to which REAG and / or protein binders and / or AATM may be covalently attached.

[0018] [Figure 1] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include folate receptor binders. [Figure 2] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 3] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 4] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 5] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 6] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 7] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 8]1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 9] 1 illustrates a non-limiting preparation of polymeric compounds containing mannose-6-phosphate receptor binders. [Figure 10] Non-limiting examples of R1 and / or R3 groups in ASGPRBM are shown below. [Figure 11] Non-limiting examples of R2 groups in ASGPRBM are shown below. [Figure 12] 1 provides non-limiting syntheses of compounds of the present disclosure. [Figure 13] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 14] 1 provides non-limiting syntheses of compounds of the present disclosure. [Figure 15] 1 provides non-limiting syntheses of compounds of the present disclosure. [Figure 16] 1 provides non-limiting syntheses of compounds of the present disclosure. [Figure 17] 1 provides non-limiting syntheses of compounds of the present disclosure. [Figure 18] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 19] Non-limiting syntheses of intermediates useful for preparing certain compounds of the present disclosure, such as, but not limited to, formula (2a), are provided. [Figure 20] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 21] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 22] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 23] 1 shows a non-limiting synthesis of a TNF binder contemplated within the scope of the present disclosure and its coupling with REAG to produce a compound of the present disclosure. [Figure 24A] 24A-24B show a non-limiting synthesis of the ASGPRBM group. [Figure 24B] See legend to Figure 24A. [Figure 25A] Figures 25A-25D show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 25B] See legend to Figure 25A. [Figure 25C] See legend to Figure 25A. [Figure 25D] See legend to Figure 25A. [Figure 26A] Figures 26A-26L show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 26B] See legend to Figure 26A. [Figure 26C] See legend to Figure 26A. [Figure 26D] See legend to Figure 26A. [Figure 26E] See legend to Figure 26A. [Figure 26F] See legend to Figure 26A. [Figure 26G] See legend to Figure 26A. [Figure 26H] See legend to Figure 26A. [Figure 26I] See legend to Figure 26A. [Figure 26J] See legend to Figure 26A. [Figure 26K]See legend to Figure 26A. [Figure 26L] See legend to Figure 26A. [Figure 27A] Figures 27A-27O show non-limiting syntheses of specific ASGPRBM groups. While this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 27B] See legend to Figure 27A. [Figure 27C] See legend to Figure 27A. [Figure 27D] See legend to Figure 27A. [Figure 27E] See legend to Figure 27A. [Figure 27F] See legend to Figure 27A. [Figure 27G] See legend to Figure 27A. [Figure 27H] See legend to Figure 27A. [Figure 27I] See legend to Figure 27A. [Figure 27J] See legend to Figure 27A. [Figure 27K] See legend to Figure 27A. [Figure 27L] See legend to Figure 27A. [Figure 27M] See legend to Figure 27A. [Figure 27N] See legend to Figure 27A. [Figure 27O] See legend to Figure 27A. [Figure 28A] 28A-28B show non-limiting compounds of the present disclosure, including PCSK9 binders, and their preparation. [Figure 28B] See legend to Figure 28A. [Figure 29] 1 illustrates non-limiting compounds of the present disclosure, including PCSK9 binders, and their preparation. [Figure 30]1 illustrates non-limiting compounds of the present disclosure, including PCSK9 binders, and their preparation. [Figure 31] 1 illustrates non-limiting compounds of the present disclosure, including PCSK9 binders, and their preparation. [Figure 32] 1 illustrates non-limiting compounds of the present disclosure, including VEGF binders, and their preparation. [Figure 33] 1 illustrates non-limiting compounds of the present disclosure, including VEGF binders, and their preparation. [Figure 34] 1 illustrates non-limiting compounds of the present disclosure, including TGF-β binders, and their preparation. [Figure 35] 1 illustrates non-limiting compounds of the present disclosure, including TGF-β binders, and their preparation. [Figure 36] 1 illustrates non-limiting compounds of the present disclosure, including TSP-1 binders, and their preparation. [Figure 37A] 37A-38B show non-limiting compounds of the present disclosure, including soluble uPAR binders, and their preparation. [Figure 37B] See legend to Figure 37A. [Figure 38A] 38A-38B show non-limiting compounds of the present disclosure, including PSMA binders, and their preparation. [Figure 38B] See legend to Figure 38A. [Figure 39A] 39A-39B show non-limiting compounds of the present disclosure, including IL-2 binders, and their preparation. [Figure 39B] See legend to Figure 39A. [Figure 40A] 40A-B show non-limiting compounds of the present disclosure, including GP120 binders, and their preparation. [Figure 40B] See legend to Figure 40A. [Figure 41] 1 illustrates non-limiting compounds of the present disclosure, including GP120 binders, and their preparation. [Figure 42] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 43]1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 44] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 45] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 46] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 47] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 48] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 49] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 50] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include MIF binders. [Figure 51A] Figures 51A-B show non-limiting PCSK9 ligands and their exemplary synthesis. [Figure 51B] See legend to Figure 51A. [Figure 52A] Figures 52A-B show non-limiting PCSK9 ligands and their exemplary synthesis. [Figure 52B] See legend to Figure 52A. [Figure 53] Figures 53A-B show non-limiting PCSK9 ligands and their exemplary synthesis. [Figure 54] 1 shows non-limiting PCSK9 ligands and their exemplary synthesis. [Figure 55A] Figures 55A-55N show non-limiting syntheses of specific ASGPRBM groups and / or compounds of the disclosure using MIF binder as a non-limiting protein binder. Any protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 55B] See legend to Figure 55A. [Figure 55C] See legend to Figure 55A. [Figure 55D] See legend to Figure 55A. [Figure 55E] See legend to Figure 55A. [Figure 55F] See legend to Figure 55A. [Figure 55G] See legend to Figure 55A. [Figure 55H] See legend to Figure 55A. [Figure 55I] See legend to Figure 55A. [Figure 55J] See legend to Figure 55A. [Figure 55K] See legend to Figure 55A. [Figure 55L] See legend to Figure 55A. [Figure 55M] See legend to Figure 55A. [Figure 55N] See legend to Figure 55A. [Figure 56A] Figures 56A-56O show non-limiting syntheses of specific ASGPRBM groups and / or compounds of the disclosure using MIF binder as a non-limiting protein binder. Any protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 56B] See legend to Figure 56A. [Figure 56C] See legend to Figure 56A. [Figure 56D] See legend to Figure 56A. [Figure 56E] See legend to Figure 56A. [Figure 56F] See legend to Figure 56A. [Figure 56G] See legend to Figure 56A. [Figure 56H] See legend to Figure 56A. [Figure 56I] See legend to Figure 56A. [Figure 56J] See legend to Figure 56A. [Figure 56K] See legend to Figure 56A. [Figure 56L]See legend to Figure 56A. [Figure 56M] See legend to Figure 56A. [Figure 56N] See legend to Figure 56A. [Figure 56O] See legend to Figure 56A. [Figure 57A] Figures 57A-M show non-limiting syntheses of TNF binders contemplated within the scope of the present disclosure and their coupling with REAG to produce compounds of the present disclosure, such as, but not limited to, formula (2b). [Figure 57B] See legend to Figure 57A. [Figure 57C] See legend to Figure 57A. [Figure 57D] See legend to Figure 57A. [Figure 57E] See legend to Figure 57A. [Figure 57F] See legend to Figure 57A. [Figure 57G] See legend to Figure 57A. [Figure 57H] See legend to Figure 57A. [Figure 57I] See legend to Figure 57A. [Figure 57J] See legend to Figure 57A. [Figure 57K] See legend to Figure 57A. [Figure 57L] See legend to Figure 57A. [Figure 57M] See legend to Figure 57A. [Figure 58] In a non-limiting embodiment, certain compounds of formula (2b) are depicted wherein R represents R3b. [Figure 59] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 60] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 61] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 62] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 63] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 64] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 65] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 66] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 67] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 68] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 69] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2b) is provided below. [Figure 70A] Figures 70A-70C show non-limiting syntheses of certain intermediates that can be used to prepare compounds of formula (2b) (showing R3) or compounds of formula (2c) (showing R2). [Figure 70B] See legend to Figure 70A. [Figure 70C] See legend to Figure 70A. [Figure 71] Non-limiting syntheses of certain compounds of the present disclosure are provided, including but not limited to formula (2c). [Figure 72] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2c) is provided below. [Figure 73] A non-limiting synthesis of intermediates that can be used to prepare compounds of formula (2c) is provided below. [Figure 74] A non-limiting synthesis of a compound of formula (2c) is shown below. [Figure 75] The structure of GalNAc-NH2 is shown. [Figure 76]

[0033] Figure 1 shows a non-limiting synthesis of indole-GN3, a bifunctional molecule targeted at the degradation of human IgG / IgE / IgM. [Figure 77] 1 shows a non-limiting synthesis of AMD-GN3, a bifunctional molecule targeted at the selective degradation of human IgG. [Figure 78] 1 shows a non-limiting synthesis of FcIII-GN3, a bifunctional molecule aimed at the selective degradation of human IgG. [Figure 79] Figures 79A-79B show in vivo data demonstrating DNP-GN3-mediated cleavage of anti-DNP IgG in mouse serum. Figure 79A: Mouse experiment showing that the bifunctional molecule DNP-GN3 can induce degradation of injected anti-DNP IgG antibody in mouse serum, while the negative control molecule or vehicle control did not show this effect. Purple arrow: Mice were intraperitoneally injected with anti-DNP IgG antibody; green arrow: Mice were intraperitoneally injected with PBS (vehicle), DNP-(OH)3 (negative control), or DNP-GN3. Figure 79B: Structure of DNP-GN3. [Figure 80] 1 provides non-limiting syntheses of certain bifunctional compounds of the present disclosure. [Figure 81] 1 provides non-limiting syntheses of certain bifunctional compounds of the present disclosure. [Figure 82] 1 provides non-limiting syntheses of certain bifunctional compounds of the present disclosure. [Figure 83] 1 provides non-limiting syntheses of certain bifunctional compounds of the present disclosure. [Figure 84] 1 provides non-limiting syntheses of certain bifunctional compounds of the present disclosure. [Figure 85] The synthesis of DNP-OH3 is shown. [Figure 86]Figures 86A-C show that DNP-GN3 mediates ternary complex formation. Figure 86A: DNP-GN3 mediates ternary complex formation between hepatocytes and α-DNP antibody. Figure 86B: DNP-GN3-mediated ternary complex formation is inhibited by competitive binders of ASGPR or α-DNP antibody. Figure 86C: DNP-GN3-mediated ternary complex formation is inhibited by the previously reported ASGPR-binding proteins asialofetuin and asialoorosomucoid. [Figure 87] Figures 87A-87B show that endocytosis of α-DNP antibody depends on the concentration of both α-DNP antibody and DNP-GN3. Figure 87A: Endocytosis of α-DNP antibody after 6 hours. Figure 87B: Endocytosis of α-DNP antibody after 12 hours. [Figure 88] Figure 1 shows that DNP-GN3-mediated endocytosis is reduced by competitive binders of ASGPR or α-DNP antibodies. Controls are shown in gray, compounds predicted to inhibit the proposed mode of action of DNP-GN3 are shown in blue, and compounds predicted not to inhibit are shown in red. Data are shown as the mean ± SD of nine replicates across four experiments. Statistical significance was determined by Kruskall-Wallace test and post-hoc comparisons between each inhibitor group and the no-inhibitor group (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, "ns" P>0.9999). [Figure 89] Figure 8 shows that clathrin-dependent endocytosis inhibitors reduce DNP-GN3-mediated uptake of α-DNP antibody. Data are shown as the mean ± SD of nine replicates across four experiments. Statistics were performed as outlined in Figure 88. [Figure 90] 1 shows that the accumulation of α-DNP antibody-derived fluorescence in cells depends on the presence of α-DNP antibody and DNP-GN3. [Figure 91]Figures 91A-91B show that endocytosed α-DNP antibody is transported to lysosomes after 12 hours. Figure 91A: Endocytosed α-DNP antibody does not colocalize with the early endosome marker EEA1. Figure 91B: Endocytosed α-DNP antibody does not colocalize with the late endosome and lysosomal protein LAMP2 in cells. [Figure 92] Figures 92A and 92B show accumulation tests of protein fragments derived from the α-DNP antibody. Figure 92A: Protein fragments derived from the α-DNP antibody accumulate in the cell lysate over time. Figure 92B: Cell supernatant does not accumulate α-DNP antibody fragments over time. [Figure 93] Figures 93A-93C show that DNP-GN3 and DNP-OH3 exhibit no toxicity to mice at all tested concentrations. Figure 93A: Body weight of mice after treatment with DNP-GN3 or DNP-OH3. Statistical significance was analyzed by T-test. Figure 93B: Levels of aspartate transaminase (AST) in treated mice. The dashed line represents the normal range. Figure 93C: Levels of alanine transaminase (ALT) in treated mice. The dashed line represents the normal range. [Figure 94] This shows that serum levels of α-DNP antibodies decrease more rapidly after repeated treatment with DNP-GN3. Serum antibody levels were measured using an ELISA assay. Each experimental group contained three mice. Statistical significance in experiments involving in vivo depletion of α-DNP antibodies was assessed by repeated measures two-way analysis of variance and Tukey's test for post-hoc comparison of simple effects between each treatment group and the PBS group. [Figure 95] A significant decrease in serum levels of α-DNP antibodies was observed after treatment with DNP-GN3 but not with DNP-OH3. Each experimental group contained at least 5 mice. [Figure 96]This shows that a single dose of DNP-GN3 mediates a decrease in serum levels of α-DNP antibodies. Each experimental group contained at least eight mice. Statistical significance was assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparison of simple effects between each treatment group and the PBS group. [Figure 97] 1 shows that treatment with DNP-GN3 promotes the depletion of polyclonal α-DNP antibodies from serum. The PBS-treated group contained two mice, while the DNP-GN3 group contained three mice. [Figure 98] Figure 1 shows that the binding of α-DNP antibody to HepG2 cells is dependent on the concentration of DNP-AF3. Error bars represent the SD of three biological replicates. [Figure 99] Figure 1 shows that DNP-AF3-mediated antibody binding to HepG2 cells is inhibited by increasing concentrations of the α-DNP antibody-binding control DNP-OH3. Error bars represent the standard deviation of three biological replicates. [Figure 100] Figure 1 shows that DNP-AF3-mediated binding of α-DNP antibody to HepG2 cells is inhibited by increasing concentrations of the ASGPR-binding control monosaccharide AF. Error bars represent the standard deviation of three biological replicates. [Figure 101] Figure 1 shows that DNP-AF3-mediated binding of α-DNP antibody to HepG2 cells is inhibited by increasing concentrations of the ASGPR-binding protein ASOR, but not by ORM. Error bars represent the standard deviation of three biological replicates. [Figure 102] Figure 1 shows that DNP-AF3-mediated binding of α-DNP antibody to HepG2 cells is not inhibited by increasing concentrations of the ASGPR-binding protein ASF or the protein fetuin. Data points represent a single flow cytometry experiment at each concentration. Data are expressed as the mean fluorescence intensity of the cell population, as internal controls for 100% and 0% ternary complex formation were not included in this assay. [Figure 103A]Figures 103A-C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentration of both α-DNP antibody and DNP-AF3. Each data point represents an individual biological experiment. Figure 103A: DNP-AF3-mediated endocytosis of α-DNP antibody after 6 hours. [Figure 103B] Figures 103A-C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentration of both α-DNP antibody and DNP-AF3. Each data point represents an individual biological experiment. Figure 103B: DNP-AF3-mediated endocytosis of α-DNP antibody after 12 hours. [Figure 103C] Figures 103A-C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentration of both α-DNP antibody and DNP-AF3. Each data point represents an individual biological experiment. Figure 103C: DNP-AF3-mediated endocytosis of α-DNP antibody after 24 hours. [Figure 104] Figure 1 shows the increase in intracellular fluorescence over time resulting from DNP-AF3-mediated endocytosis of α-DNP antibody. α-DNP antibody was present at a concentration of 100 nM. Each data point represents an individual biological experiment. [Figure 105] Figure 1 shows that DNP-AF3-mediated endocytosis of antibodies by HepG2 cells is inhibited by both competitive binders, ASGPR and α-DNP antibodies. Antibodies were present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM. Error bars represent the standard deviation of three biological replicates. Significance was analyzed using one-way ANOVA with multiple comparisons versus no-additive controls. P values ​​are as follows: ASOR p=0.0040 (**); ORM p=0.8879 (ns); ASF p=0.0032 (**); fetuin p=0.7709 (ns); DNP-OH3 p=0.0073 (**); GalNAc p=0.0054 (**); AF p=0.0069 (**). [Figure 106]Figure 1 shows that DNP-AF3-mediated endocytosis of antibodies by HepG2 cells is inhibited by clathrin-mediated endocytosis inhibitors and global endocytosis inhibitors. The antibodies were present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM. Each data point represents an individual biological experiment. Black bars represent control conditions; red bars represent metabolic toxins; green bars represent inhibitors of phagocytosis and macropinocytosis; blue bars represent caveolin-dependent endocytosis inhibitors; and gray bars represent clathrin-dependent endocytosis inhibitors. Significance was analyzed using one-way ANOVA with multiple comparisons against the no-additive control. P values ​​are as follows: NaN3 / DOG p=0.0001(****); CytD p=0.0710(ns); EIPA p=0.9994(ns); amiloride p=0.4812(ns); nystatin p=0.9997(ns); indomethacin p=0.6682(ns); genistein p=0.8406(ns); NH4Cl p=0.0001(****); monensin p=0.0001(****); primaquine p=0.0001(****); chloroquine p=0.0001(****); bafilomycin p=0.0001(****) [Figure 107] Endocytosed α-DNP antibody accumulates in puncta within HepG2 cells over time. The antibody was present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM. The number and darkness of the puncta increase over time. [Figure 108] We demonstrate that both DNP-AF3 and α-DNP antibody are required for the observation of fluorophore-containing puncta in HepG2 cells. In the absence of DNP-AF3 or α-DNP antibody, no puncta are observed. [Figure 109] 1 shows that the fluorescent signal generated by endocytosed α-DNP antibody does not colocalize with the early endosomal protein EEA1. [Figure 110] 1 shows that the fluorescent signal generated by endocytosed α-DNP antibody colocalizes with the late endosomal and lysosomal protein LAMP2. [Figure 111] 1 shows direct fluorescent visualization of α-DNP antibody protein fragments in samples collected from cell culture supernatants. α-DNP antibody was present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM. [Figure 112] Direct fluorescence visualization of α-DNP antibody in samples collected from cell culture lysates is shown. Low accumulation of α-DNP antibody in cell lysates was observed in samples not treated with DNP-AF3. In contrast, DNP-AF3-treated cells showed a time-dependent increase in Alexa 488 signal derived from α-DNP antibody. [Figure 113] Ratiometric visualization of the intensity of fluorescence produced by the α-DNP antibody fragment. Densitometry was performed using Photoshop image analysis. [Figure 114] The time course of fluorescence intensity generated by proteins of different molecular weights in cell lysates is shown. Error bars represent the SD of three biological replicates. [Figure 115] Ratiometric representation of the accumulation of relatively low molecular weight Alexa 488-modified protein fragments in cell culture media. At 12 hours, the 25 kDa band becomes brighter than the 50 kDa band. Error bars represent the SD of three biological replicates. [Figure 116] Figure 1 shows the effect of different protease inhibitors on the degradation of endocytosed α-DNP antibody. Lower ratios indicate more degradation, while higher ratios indicate less degradation. Data points represent one biological replicate. [Figure 117] Figure 1 shows the effect of protease inhibitors on the degradation of endocytosed α-DNP antibody in HepG2 cells. Lower ratios indicate greater degradation. Error bars represent SD of three biological replicates. [Figure 118]Figure 1 shows the effect of selected protease inhibitors on the degradation of endocytosed α-DNP antibody in HepG2 cells. Lower ratios indicate greater degradation. Error bars represent SD of three biological replicates. Significance was analyzed using one-way ANOVA with multiple comparisons against the no protease inhibitor control. P values ​​are as follows: leupeptin p=.0504 (ns); E64 p=.0461 (*); pepstatin p=.9419 (ns); antipain p=.0252 (*); ALLN 100 p=.0418 (*); ALLN 10 p=.0267 (*). [Figure 119A] Figures 119A-B show the synthesis of the bifunctional molecule MIF-GN3. [Figure 119B] See legend to Figure 119A. [Figure 120] 1 shows the synthesis of MIF inhibitor 3w. [Figure 121] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-PEG2-GN3. [Figure 122] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-PEG4-GN3. [Figure 123] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-NVS-PEG3. [Figure 124] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-AF1. [Figure 125] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-AF2. [Figure 126] 1 shows the synthesis of the MIF-binding bifunctional molecule MIF-AF3. [Figure 127] 1 shows the structures of small molecules analyzed for inhibition of the enzymatic activity of mouse MIF. [Figure 128] Figures 128A-B show MIF depletion assays from cell culture supernatants. Figure 128A: Bifunctional MIF binding molecules mediate depletion of human MIF from cell culture supernatants. Figure 128B: MIF inhibitor 3w does not mediate depletion of MIF from cell culture supernatants. [Figure 129]Figure 1 shows that bifunctional MIF-binding molecules with an optimized ASGPR-binding motif deplete MIF from cell culture supernatants. Error bars represent the standard deviation of nine biological replicates. Human MIF protein was present at a concentration of 100 nM. [Figure 130] Figure 1 shows that MIF-GN3 mediates the endocytosis of fluorescently labeled human MIF protein. Each data point represents the mean of three biological replicates. Error bars represent the standard deviation. [Figure 131] Figure 1 shows that MIF-GN3 mediates uptake of fluorescently labeled MIF protein over a wide range of target protein concentrations. Each value represents one biological replicate. [Figure 132] Figure 1 shows that MIF-GN3-mediated MIF endocytosis by HepG2 cells is inhibited by clathrin-mediated inhibitors. The antibody was present at a concentration of 100 nM, and MIF-GN3 was present at a concentration of 200 nM. Each data point represents an individual biological experiment. Black bars represent control conditions, red represents metabolic toxins, green represents inhibitors of phagocytosis and macropinocytosis, blue represents caveolin-dependent endocytosis inhibitors, and gray represents clathrin-dependent endocytosis inhibitors. Values ​​represent the mean of three biological replicates. Error bars represent standard deviations. Statistical significance was determined by the Kruskall-Wallace test and post-hoc comparisons between each inhibitor group and the inhibitor-free group (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, "ns" P>0.9999). [Figure 133] Figure 1 shows that cells treated with MIF-GN3 and exogenous MIF accumulate MIF puncta in the cells. The MIF signal strongly colocalizes with LAMP2 but not with EEA1. MIF was present at a concentration of 100 nM, and MIF-GN3 was present at a concentration of 200 nM. [Figure 134] This shows that cells treated with MIF-GN3 showed more rapid clearance of human MIF from the circulation in mice 4 hours after treatment. Each data point represents the mean and SD of three mice in each group. T-test analysis at 4 hours showed no significant difference (p=0.1525). [Figure 135] This shows that cells treated with MIF-GN3 exhibited more rapid clearance of human MIF from the circulation in mice. Each data point represents the average of two (MIF intraperitoneal PBS group) or three (all other groups) serum sample readings. [Figure 136] This shows that mice treated with MIF-GN3 exhibit rapid clearance of human MIF from the circulation at early time points. Each data point represents the mean concentration of MIF in serum collected from four or five mice. Statistical significance was assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparison of simple effects between each treatment group and the PBS group. [Figure 137] 1 shows that treatment of mice with MIF-GN3 did not decrease serum levels of mouse MIF. Each point represents the mean value of 10 serum samples, and error bars are SD. Immediately after the 0-hour time point, animals received a single dose of MIF-GN3. [Figure 138] Administration of MIF-GN3 and α-MIF antibodies slowed the growth of PC3 human prostate cancer cells in mice. Each group consisted of five mice (except for the DNP-GN3 group, which had four mice). [Figure 139] This shows that administration of MIF-GN3 and α-MIF antibodies reduces circulating human MIF protein levels in mice injected with PC3 prostate cancer cells. Each group consisted of five mice (except for the DNP-GN3 group, which had four mice). [Figure 140] We show that administration of MIF-GN3 and α-MIF antibodies increases the survival rate of mice injected with human prostate cancer PC3 cells. Each group consisted of five mice (except for the DNP-GN3 group, which had four mice). [Figure 141] 1 shows the synthesis of the bifunctional molecule FcIII-BCN-GN3. [Figure 142]Figure 1 shows that FcIII-GN3 mediates endocytosis of human IgG across a range of concentrations. Fluorescence from a population of cells treated with human IgG but not compound is subtracted from these samples to reveal cellular autofluorescence and non-small molecule-mediated endocytosis. Each data point represents the mean of three biological replicates. Error bars represent standard deviation. [Figure 143] 1 shows that FcIII-BCN-GN3 mediates endocytosis of IgG over a range of concentrations over time. Each data point represents one biological replicate. [Figure 144] This shows that intracellular human IgG-derived fluorescence increases in the presence of FcIII-GN3. IgG was present at a concentration of 100 nM, and FcIII-GN3 was present at a concentration of 200 nM. [Figure 145] Figure 1 shows that FcIII-GN3 mediates lysosomal transport of human IgG. IgG was present at a concentration of 100 nM, and FcIII-GN3 was present at a concentration of 200 nM. The blue channel represents Hoechst nuclear staining. [Figure 146A] Figures 146A-B show fragments of bifunctional molecules that bind to TNF. Figure 146A: TNF binder. Figure 146B: Synthesis of the -[CON]h-[linker]i-[CON]h'-[CRBM]j' fragment of the molecule of formula (II). [Figure 146B] See legend to Figure 146A. [Figure 147A] Figures 147A-B show the characterization of the TNF binder of Figure 159A. Figure 147A: Mass spectrum of the TNF binder. Figure 147B: HPLC purification of the TNF binder. [Figure 147B] See legend to Figure 147A. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description of Disclosure In one aspect, the present disclosure provides bifunctional compounds that can be used to promote and / or enhance the degradation of extracellular proteins (or "proteins," which, in non-limiting examples, can be circulating proteins and / or cell surface proteins that can be bound to or embedded in a cell membrane) in a subject. In certain embodiments, treatment or management of a disease and / or disorder contemplated in this disclosure requires the degradation, removal, and / or reduction in the concentration of the extracellular protein in the subject. Thus, in certain embodiments, administration of a compound of the present disclosure to a subject removes the extracellular protein and / or reduces the circulating concentration of the extracellular protein, thereby treating, ameliorating, and / or preventing the disease and / or disorder in the subject. In some embodiments, the extracellular protein includes TNF. In some embodiments, the extracellular protein is TNF.

[0020] In certain embodiments, the compounds of the present disclosure include a group that binds to an extracellular protein. In other embodiments, the compounds of the present disclosure further include another group (such as, but not limited to, a small molecule) that binds to a cellular receptor, whereby binding results in endocytosis of the compound (and / or the extracellular protein-compound complex). The receptor binder and the extracellular protein binder can be linked by a linker, such as polyethylene glycol (PEG), any other linker described herein with a tunable length, or other linkers described herein and including one or more connector molecules, herein referred to as CON. When the extracellular protein-compound complex undergoes endocytosis, the extracellular protein is eventually degraded, and the compound can be degraded or recycled outside the cell. In some embodiments, the extracellular protein is TNF, and the compound of the present disclosure is a TNF binder.

[0021] In another aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of a specific autoantibody of interest. In certain embodiments, the autoantibody mediates a disease and / or disorder in a subject, and treatment or management of the disease and / or disorder requires the degradation, removal, or reduction of the concentration of the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the present disclosure to a subject removes the autoantibody and / or reduces the circulating concentration of the autoantibody, thereby treating, ameliorating, or preventing the disease and / or disorder in the subject.

[0022] In certain embodiments, the compounds of the present disclosure include another group (such as, but not limited to, a small molecule) that binds to a cellular receptor, thereby resulting in endocytosis of the compound (and / or the extracellular protein-compound complex). Furthermore, in certain embodiments, the compounds of the present disclosure include an autoantibody targeting moiety (AATM), such as, but not limited to, an autoantibody ligand, such as, but not limited to, a small molecule, peptide, and / or nucleic acid aptamer, that can bind to an autoantibody of interest. The receptor binder and AATM can be linked by a linker, such as polyethylene glycol (PEG), any other linker described herein with a tunable length, or other linkers described herein and including one or more connector molecules, referred to herein as CON. When the autoantibody-compound complex undergoes endocytosis, the autoantibody is eventually degraded, and the compound can be degraded or recycled to the outside of the cell.

[0023] While not wishing to be bound by theory, the bifunctional compounds of the present disclosure, which can be used to promote or enhance the degradation of specific autoantibodies of interest, offer clear advantages over existing methods for removing autoantibodies from a subject. AATM confers specificity to the bifunctional compounds. ATM can be used to target specific populations of autoantibodies. As shown elsewhere herein, compounds of the present disclosure, including anti-DNP IgG as a model autoantibody, successfully induced the degradation of anti-DNP IgG injected into mice.

[0024] The present disclosure provides a molecular approach to achieve similar goals as plasma exchange therapy in autoantibody-driven diseases. Unlike plasma exchange therapy, this technology can be easily performed by a variety of medical professionals (not limited to transfusion medicine specialists). Because this approach is based on small molecules derived from synthetic approaches, the present disclosure avoids the need for expensive equipment and materials and complex manufacturing practices. Compared to plasma exchange therapy and IVIG, this approach is cost-effective, safe, and accessible to patients.

[0025] Furthermore, the present disclosure provides a less invasive and safer route of administration compared to extracorporeal procedures, which may introduce additional complications. The compounds described herein are modular and versatile. The targeting motifs (CRBM and AATM) on either end of the linker can be modified to bind with high specificity to various autoantibodies of interest. Furthermore, the defined composition of the compounds allows for simpler and more consistent manufacturing practices and reduces batch-to-batch variability. The fact that AATM binds to autoantibodies predictably allows for prediction of treatment outcomes, drug-drug interactions, and possible side effects.

[0026] In certain embodiments, the receptor is the hepatocyte asialoglycoprotein receptor (ASGPR). In that case, the binding moiety is referred to herein as an ASGPR binding moiety or ASGPRBM. The present disclosure is not limited to this receptor, but rather contemplates the use of other receptors described herein or any other endocytic receptor known in the art.

[0027] Furthermore, the present disclosure is not limited to degradation that takes place in hepatocytes, rather, the present disclosure contemplates that non-hepatic cells in the body present specific degradation receptors, which are contemplated as being within the scope of the present disclosure.

[0028] In one aspect, the compounds of the present disclosure bind to extracellular proteins and / or autoantibodies and remove them from the internal circulation (and the body) through the liver. In some embodiments, the extracellular protein is extracellular TNF. Thus, the compounds of the present disclosure utilize the body's own mechanisms to degrade proteins and / or autoantibodies. Without wishing to be limited by theory, the compounds of the present disclosure bind to specific receptors located on specific cells, such as, but not limited to, hepatocytes, such as, but not limited to, ASGPR. This binding induces degradation of the protein target by intralysosomal proteolysis. As a result of this mechanism, the circulating levels of the extracellular protein target and / or extracellular autoantibody are reduced. In some embodiments, the extracellular protein target is TNF. As a result, the corresponding disease symptoms are attenuated in the subject to whom the compound is administered and / or disappear from the patient.

[0029] ASPGR functions to eliminate desialylated glycoproteins with exposed non-reducing D-galactose (Gal) or N-acetylgalactosamine (GalNac) terminal groups. ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is minimally present elsewhere in the body. ASGPR-mediated internalization of target glycoproteins exhibits a half-life of approximately 3 minutes. The bifunctional compounds disclosed herein selectively bind to extracellular proteins through the extracellular protein binder portion of the compound, thereby forming a protein complex. When this protein complex reaches the liver, the asialoglycoprotein receptor-binding portion (ASGPRBM) of the molecule engages the intralysosomal pathway in hepatocytes via ASGPR. Endosome-bound ASPGR releases extracellular protein ligands at pH 5.4, which are then removed from the circulation by hepatocytes. However, ASPGR remains available for recycling and buds into recycling endosomes, escaping lysosomal degradation. Indeed, depending on the cell line, ASPGR can recycle up to approximately 200 times with a recirculation rate of approximately 15-20 min. ASPGR exhibits very rough ligand size requirements, possibly reaching a diameter of approximately 70 nm. In contrast, IgM pentamers are approximately 20 nm in diameter and therefore fit the ligand size requirements of ASPGR.

[0030] The disclosures of International Patent Application No. PCT / US2019 / 026260, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199634), and International Patent Application No. PCT / US2019 / 026239, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199621), are incorporated herein by reference in their entireties.

[0031] In accordance with the present disclosure there may be employed conventional methods of chemical synthesis and pharmaceutical formulation, as well as techniques of pharmacology, molecular biology, microbiology, and recombinant DNA within the skill of the art, which techniques are well known and are explained fully elsewhere in the literature.

[0032] Reference will now be made in detail to certain aspects of the disclosed subject matter, some examples of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in conjunction with numbered claims, it will be understood that such subject matter as illustrated is not intended to limit the scope of the claims to the disclosed subject matter.

[0033] Throughout this document, values ​​expressed in range form should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly recited. For example, a range such as "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the term "about X to Y" has the same meaning as "about X to about Y." Similarly, unless otherwise indicated, the term "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z."

[0034] In the methods described herein, acts may be performed in any order unless a chronological or operational order is explicitly recited. Furthermore, certain acts may be performed simultaneously unless the express language of the claim requires that they be performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in a single operation, and the resulting process is within the literal scope of the claimed process.

[0035] definition As used herein, the term "about" allows for a variability of a value or range, for example, within 10%, within 5%, or within 1% of a stated value or stated range limit, and includes the exact value or range stated.

[0036] In this document, the terms "a," "an," or "the" are used to include one or more unless the context clearly dictates otherwise. The term "or" is used to mean a non-exclusive "or" unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." Furthermore, words or terms used herein and not defined elsewhere should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading and comprehension of this document and should not be construed as limiting. Information associated with a section heading may occur within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0037] The term "abnormal" when used in the context of an organism, tissue, cell, or component thereof means an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected) respective characteristic. A characteristic that is normal or expected in one cell or tissue type may be abnormal in a different cell or tissue type.

[0038] The term "acyl," as used herein, refers to a group containing a carbonyl moiety bonded through the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom, which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain a double bond or a triple bond within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may contain a heteroatom within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0039] As used herein, the term "alkyl" refers to straight-chain and branched alkyl groups and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0040] As used herein, the term "alkenyl" refers to straight-chain, branched-chain, and cyclic alkyl groups, as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0041] The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group can contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further contain double or triple bonds and heteroatoms. For example, an allyloxy group or a methoxyethoxy group is an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced thereby.

[0042] The term "alkynyl," as used herein, refers to straight- and branched-chain alkyl groups, as defined herein, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CHCH), and -CHC≡C(CHCH), among others.

[0043] The term "amine" as used herein refers to primary, secondary, and tertiary amines, e.g., having the formula N(group)3, where each group can independently be H or a non-H group, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, e.g., alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected, e.g., dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and RN, where each R is independently selected, e.g., trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" as used herein also includes ammonium ions.

[0044] The term "amino acid sequence variant" refers to a polypeptide having an amino acid sequence that differs to some extent from a native sequence polypeptide. Typically, amino acid sequence variants exhibit at least about 70% homology, at least about 80% homology, at least about 90% homology, or at least about 95% homology to the native polypeptide. Amino acid sequence variants exhibit substitutions, deletions, and / or insertions at specific positions within the amino acid sequence of the native amino acid sequence.

[0045] As used herein, the term "amino group" refers to any of the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and -NR3, which cannot be protonated. + "Amino" refers to the protonated form of each form except for the following: ##STR1## Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0046] The term "aminoalkyl" as used herein means an amine attached to an alkyl group, as defined herein. The amine group can occur at any suitable position within the alkyl chain, for example, at the end of the alkyl chain or anywhere within the alkyl chain.

[0047] As used herein, the term "aralkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. An aralkenyl group refers to an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0048] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains from about 6 to about 14 carbon atoms in the ring portion of the group. Aryl groups can be unsubstituted or substituted as defined herein. Representative substituted aryl groups can be mono- or multi-substituted, such as, but not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring.

[0049] As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to an antigen. An antibody can be an intact immunoglobulin derived from natural or recombinant sources, or an immunoreactive portion of an intact immunoglobulin. Typically, an antibody is a tetramer of an immunoglobulin molecule. Antibodies in this disclosure can exist in various forms, including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab, and F(ab)2, as well as single-chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

[0050] The term "antibody fragment" refers to a portion of an intact antibody, including the antigen-determining variable region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments, linear antibodies, scFv antibodies, single-domain antibodies such as sdAbs (VL or VH), e.g., camelid antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38), camelid VHH domains composed of a VL or VH domain that exhibits sufficient affinity for a target, and multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, as well as isolated complementarity-determining regions (CDRs) or other epitope-binding fragments of an antibody. Antigen-binding fragments may be incorporated into single-domain antibodies, maxi-antibodies, mini-antibodies, nano-antibodies, intrabodies, diabodies, triabodies, tetra-antibodies, v-NARs, and bis-scFvs (see, e.g., Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments may also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (U.S. Patent No. 6,703,199, which describes fibronectin polypeptide mini-antibodies). Antibody fragments also include human or humanized antibodies, or portions of human or humanized antibodies.

[0051] As used herein, the term "antigen" or "Ag" is defined as a molecule that elicits an immune response. This immune response may involve antibody production, activation of specific immunocompetent cells, or both. Those skilled in the art will understand that any macromolecule, including virtually any protein or peptide, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. Those skilled in the art will understand that any DNA containing a nucleotide sequence or partial nucleotide sequence encoding a protein that elicits an immune response, therefore, encodes an "antigen," as the term is used herein. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded solely by the full-length nucleotide sequence of a gene. It is understood that the present disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and that these nucleotide sequences may be configured in various combinations to elicit a desired immune response. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded by a "gene." It is understood that an antigen may be synthetically produced or derived from a biological sample, including, but not limited to, a tissue sample, a tumor sample, cells, or biological fluid.

[0052] As used herein, the term "aptamer" refers to a small molecule capable of specifically binding to another molecule. Aptamers are typically polynucleotide- or peptide-based molecules. Polynucleotide aptamers are DNA or RNA molecules, typically containing several nucleic acid strands that adopt highly specific three-dimensional conformations designed to exhibit appropriate binding affinity and specificity for specific target molecules, such as peptides, proteins, drugs, and vitamins, both organic and inorganic. These polynucleotide aptamers can be selected from large populations of random sequences through in vitro evolution. Peptide aptamers are typically loops of about 10 to about 20 amino acids attached to a protein scaffold that binds to a specific ligand. Peptide aptamers can be identified and isolated from combinatorial libraries using methods such as the yeast two-hybrid system.

[0053] As used herein, the term "asialoglycoprotein receptor binding moiety" or "ASGPRBM" refers to a group capable of binding to at least one hepatocyte asialoglycoprotein receptor on the surface of a cell, such as, but not limited to, a hepatocyte. When the ASGPRBM, and any additional moieties to which it is attached, bind to a receptor on the surface of the hepatocyte, the molecule comprising the ASGPRBM is taken up by the hepatocyte by the phagocytic machinery, where the molecule is at least partially degraded through lysosomal degradation.

[0054] As used herein, "C 6~10 -C 6~10 The term "biaryl" refers to a C 6~10 C covalently bound to the aryl moiety 6~10 C means an aryl moiety. 6~10 The aryl moiety can be any suitable aryl group described herein. 6~10 -C 6~10 Non-limiting examples of biaryl include biphenyl and binaphthyl.

[0055] The term "coding sequence" as used herein refers to a nucleic acid or its complementary sequence, or a portion thereof, that can be transcribed and / or translated to produce mRNA and / or a polypeptide or a fragment thereof. Coding sequences include exons in genomic DNA or premature primary RNA transcripts that are connected to each other by the cell's biochemical machinery to produce mature mRNA. The antisense strand is the complement of the nucleic acid, from which the coding sequence can be deduced. In contrast, the term "non-coding sequence" as used herein refers to a nucleic acid or its complementary sequence, or a portion thereof, that is not translated into amino acids in vivo, i.e., that does not interact with or attempt to arrange amino acids in the way that tRNA arranges amino acids. Non-coding sequences include both intron sequences in genomic DNA or premature primary RNA transcripts and gene-related sequences such as promoters, enhancers, and silencers.

[0056] As used herein, the terms "complementary" or "complementarity" are used in reference to polynucleotides (i.e., nucleotide sequences) related by base-pairing rules. For example, the sequence "AGT" is complementary to the sequence "TCA." Complementarity can be "partial," in which only some of the bases of a nucleic acid match according to the base-pairing rules. Alternatively, there can be "complete" or "total" complementarity between nucleic acids. The degree of complementarity between nucleic acid strands has a significant impact on the efficiency and strength of hybridization between nucleic acid strands. This is particularly important in amplification reactions and detection methods that rely on binding between nucleic acids.

[0057] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques for administering compounds in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0058] As used herein, the term " conservative variation " or " conservative substitution " refers to replacing amino acid residue with another biologically similar residue.Conservative variation or conservative substitution may not change the shape of peptide chain.Examples of conservative variation or conservative substitution include replacing one hydrophobic residue, such as isoleucine, valine, leucine or methionine, with another hydrophobic residue, or replacing one polar residue with another polar residue, such as replacing arginine with lysine, replacing glutamic acid with aspartic acid, or replacing glutamine with asparagine.

[0059] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Additionally, cycloalkyl groups include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight- or branched-chain alkyl groups, as defined herein. Representative substituted cycloalkyl groups can be mono- or more than twice substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or tri-substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0060] "Disease" refers to a state of health in an animal where the animal is unable to maintain homeostasis and where the animal's health continues to deteriorate unless the disease is remitted.

[0061] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health.

[0062] A disease or disorder is "in remission" when the severity of a symptom of the disease or disorder, the frequency with which the patient experiences the symptom, or both, is reduced.

[0063] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to produce a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be ascertained by one of ordinary skill in the art using routine experimentation.

[0064] As used herein, the term "efficacy" refers to the maximum effect (E) achieved within an assay. max ) means

[0065] "Encoding" refers to the inherent property of a particular sequence of nucleotides in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes and to have a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, and the resulting biological properties. Thus, a gene encodes a protein when the protein is produced in a cell or other biological system by transcription and translation of the mRNA corresponding to that gene. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is usually shown in a sequence listing, and the non-coding strand, which is used as a template for transcription of the gene or cDNA, can be said to encode the protein or other product of the gene or cDNA.

[0066] As used herein, the term "fragment," when applied to nucleic acids, refers to a subsequence of a larger nucleic acid. A "fragment" of a nucleic acid can be at least about 15 nucleotides in length; e.g., at least about 50 nucleotides to about 100 nucleotides; at least about 100 nucleotides to about 500 nucleotides; at least about 500 nucleotides to about 1000 nucleotides; at least about 1000 nucleotides to about 1500 nucleotides; about 1500 nucleotides to about 2500 nucleotides; or about 2500 nucleotides (and any integer value therebetween). As used herein, the term "fragment" as applied to a protein or peptide refers to a subsequence of a larger protein or peptide. A "fragment" of a protein or peptide can be at least about 20 amino acids in length; e.g., at least about 50 amino acids in length; at least about 100 amino acids in length; at least about 200 amino acids in length; at least about 300 amino acids in length; or at least about 400 amino acids in length (and any integer value therebetween).

[0067] As used herein, the term "GN3" refers to the following group: TIFF2025509732000003.tif73128

[0068] As used herein, the terms "halo," "halogen," or "halide" group by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0069] As used herein, the term "haloalkyl" includes monohaloalkyl groups, polyhaloalkyl groups in which all halo atoms may be the same or different, and perhaloalkyl groups in which all hydrogen atoms are replaced with halogen atoms such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0070] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. For example, heteroaryl rings can have from five to about 8-12 ring members. Heteroaryl groups refer to various heterocyclyl groups with aromatic electronic structures. A heteroaryl group referred to as a C2-heteroaryl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted or substituted with groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those enumerated herein.

[0071] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzyl, benzo ... hydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), ), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) nyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl zolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5 H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), but are not limited to these.

[0072] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0073] As used herein, "C 6~10 The term "5-6-membered heterobiaryl" refers to a C-membered heteroaryl moiety covalently linked through a single bond to a 5- or 6-membered heteroaryl moiety. 6~10 C means an aryl moiety. 6~10 The aryl and 5- to 6-membered heteroaryl moieties can be any suitable aryl and heteroaryl groups described herein. 6~10 Non-limiting examples of 5- to 6-membered heterobiaryls include: TIFF2025509732000004.tif19128 is an example. 6~10 When a 5- to 6-membered heterobiaryl is listed as a substituent (e.g., as an "R" group), C 6~10 -5-6 membered heterobiaryl is C 6~10 It is attached to the rest of the molecule through a moiety.

[0074] As used herein, "5-6 membered-C 6~10 The term "heterobiaryl" refers to a 5- to 6-membered -C 6~10 When heterobiaryl is recited as a substituent (e.g., as an "R" group), it is a 5- to 6-membered -C 6~10 C except that the heterobiaryl is attached to the rest of the molecule through a 5- or 6-membered heteroaryl moiety. 6~10 -The same as 5- to 6-membered heterobiaryl.

[0075] As used herein, the term "heterocyclyl" refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, heterocyclyl can be cycloheteroalkyl, heteroaryl, or any combination thereof, provided it is polycyclic. In some embodiments, heterocyclyl groups contain from three to about 20 ring members, while other similar groups have from three to about 15 ring members. A heterocyclyl group referred to as a C2-heterocyclyl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, etc. The number of carbon atoms and heteroatoms equals the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including species containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted or substituted as described herein.Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be groups such as, but not limited to, mono- or more than twice substituted piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with groups such as those enumerated herein.

[0076] As used herein, the term "heterocyclylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0077] As used herein, the term "independently selected from" means that the groups referenced are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, based on this definition, "X 1 , X 2 , and X 3 The phrase "independently selected from the noble gases" is intended to include, for example, X 1 , X 2 , and X3 scenario where all are the same, X 1 , X 2 , and X 3 scenario where all are different, X 1 and X 2 is the same but X 3 This would include scenarios where the .times. ...

[0078] As used herein, the term "immunoglobulin" or "Ig" is defined as a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes called BCRs (B cell receptors) or antigen receptors. Five members of this protein class are IgA, IgG, IgM, IgD, and IgE. IgA is the primary antibody present in bodily secretions, such as saliva, tears, breast milk, gastrointestinal secretions, and mucous secretions of the respiratory and genitourinary tracts. IgG is the most common circulating antibody. IgM is the major immunoglobulin produced in the primary immune response in most subjects. IgM is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses and is important in defense against bacteria and viruses. IgD is an immunoglobulin with no known antibody function but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0079] "Isolated" means changed or removed from its natural state. For example, a nucleic acid or polypeptide naturally present in a living animal is not "isolated," but the same nucleic acid or polypeptide partially or completely separated from the coexisting materials of its natural state is "isolated." An isolated nucleic acid or protein may exist in a substantially purified form or may exist in a non-native environment, such as a host cell.

[0080] As used herein, the term "modulate" means to mediate a detectable increase or decrease in the activity and / or level of an mRNA, polypeptide, or response in a subject compared to the activity and / or level of the mRNA, polypeptide, or response in a subject in the absence of treatment and compound, and / or compared to the activity and / or level of the mRNA, polypeptide, or response in an otherwise identical but untreated subject. This term encompasses activating, inhibiting, and / or otherwise affecting a natural signal or response to mediate a beneficial therapeutic response in a subject, preferably a human.

[0081] As used herein, the term "monovalent" means that the substituent is connected to the substituted molecule by a single bond. If the substituent is monovalent, e.g., F or Cl, then the substituent is attached to the atom it replaces by a single bond.

[0082] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur-containing groups such as alkylsulfide groups and arylsulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) hydrocarbyl, where R can be hydrogen (in instances containing other carbon atoms) or a carbon-based moiety, which may be substituted or unsubstituted.

[0083] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal, or cells thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting embodiments, the patient, subject, or individual is a human.

[0084] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing any undesired biological effects or deleterious interactions with any components of the composition contained therein.

[0085] As used herein, the phrase "pharmaceutically acceptable salts" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, as well as solvates, hydrates, or clathrates thereof.

[0086] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids, examples of which include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharinic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0087] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0088] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound described herein within or to a patient so that it can perform its intended function. Typically, these compounds are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound described herein and not harmful to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in the pharmaceutical compositions used in the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0089] As used herein, the term "polypeptide" refers to a polymer composed of amino acid residues, related natural structural variants, and synthetic, non-natural analogs thereof, linked through peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Generally, as used herein, the term "protein" refers to a large polypeptide. As used herein, the term "peptide" refers to a short polypeptide. Conventional notation is used herein to represent polypeptide sequences: the left-hand end of a polypeptide sequence is the amino-terminus, and the right-hand end of a polypeptide sequence is the carboxyl-terminus.

[0090] As used herein, the term "efficacy" refers to the half-maximal response (ED 50 ) means the dose required to produce

[0091] As used herein, the term "protein" refers to an extracellular protein of interest.

[0092] As used herein, the term "REAG" refers to any reagent comprising -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM. In certain embodiments, the REAG reacts with a TNF binder group to incorporate the TNF binder into a compound of the present disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof.

[0093] As used herein, the term "room temperature" means a temperature of about 15°C to 28°C.

[0094] The term "specifically binds" as used herein with respect to antibodies refers to an antibody that recognizes a specific antigen but does not substantially recognize or bind to other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. However, this cross-species reactivity, in and of itself, does not change the classification of the antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, this cross-reactivity, in and of itself, does not change the classification of the antibody as specific. In some cases, the terms "specific binding" or "specifically binds" can be used with respect to the interaction of an antibody, protein, or peptide with a second chemical species to mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species, e.g., the antibody recognizes and binds to a specific protein structure rather than proteins in general. If an antibody is specific for epitope "A," the presence of a molecule containing epitope A (or free, unlabeled A) in a reaction involving labeled "A" and the antibody reduces the amount of labeled A binding to the antibody.

[0095] As used herein, the term "solvent" means a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0096] As used herein, the terms "standard temperature" and "standard pressure" mean 20° C. and 101 kPa.

[0097] As used herein, the term "substantially" means "a majority of" or "mostly," similarly meaning at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term "substantially free" can mean completely free or having an insignificant amount, such that the amount of material present does not affect the material properties of the composition including the material, and such that the material is between about 0% and about 5%, or between about 0% and about 1%, or not more than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or not more than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or not more than about 0.001% by weight of the composition. The term "substantially free" can mean having an insignificant amount, such that a material is from about 0% to about 5%, or from about 0% to about 1%, or about 5% or less, or less than about 4.5%, equal to, or greater than about 4.5%, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% or less, or about 0% by weight of the composition.

[0098] The term "substituted" as used herein with respect to a molecule or organic group as defined herein means that one or more hydrogen atoms therein are replaced with one or more non-hydrogen atoms. As used herein, the term "functional group" or "substituent" refers to a group that can be substituted or is substituted on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxyl groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms in thiol groups, alkylsulfide groups and arylsulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxylamine, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be attached to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety, e.g., R can be hydrogen, (C1-C 100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with one or more of the nitrogen atoms to form a heterocyclyl.

[0099] As used herein, the term "synthetic antibody" refers to an antibody produced using recombinant DNA techniques, such as an antibody expressed by a bacteriophage as described herein. The term should also be taken to mean an antibody produced by synthesis of a DNA molecule encoding the antibody and expressing the antibody protein, or by synthesis of an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence is obtained using DNA and amino acid sequence synthesis techniques that are available and well known in the art.

[0100] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathological condition with the intent of reducing or eliminating those symptoms.

[0101] The term "thioalkyl" as used herein means a sulfur atom connected to an alkyl group, as defined herein. The alkyl group in a thioalkyl can be straight-chained or branched. Examples of straight-chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched alkoxy groups include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, isothiohexyl, and the like. The sulfur atom can occur at any suitable position within the alkyl chain, for example, at the terminal end of the alkyl chain or anywhere within the alkyl chain.

[0102] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0103] As used herein, the term "wild-type" refers to a gene or gene product isolated from a natural source. A wild-type gene is a gene that is most frequently observed in a population and is therefore arbitrarily intended to be the "normal" or "wild-type" form of the gene. In contrast, the term "modified" or "mutant" refers to a gene or gene product that exhibits modified sequence and / or functional properties (i.e., altered characteristics) compared to a wild-type gene or gene product. Note that naturally occurring mutants can be isolated. Naturally occurring mutants are identified by the fact that they exhibit altered characteristics (including altered nucleic acid sequences) compared to a wild-type gene or gene product.

[0104] The term "autoimmune disease" refers to a disease or illness that occurs when the body's tissues are attacked by its own immune system. Examples of autoimmune diseases include, for example, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among others.

[0105] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of the present disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, and the like. septicemia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, steatohepatitis, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty's syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, related Rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barrow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II Oshtoran syndrome, Pediatric autoimmune streptococcal neuropsychiatric disorder (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff-person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease,Particularly including eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, and pyoderma gangrenosum.

[0106] Throughout this specification, the terms "cancer" or "neoplasia" are used to refer to a pathological process resulting in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cell proliferation, often more rapidly than normal tissues, and continue to grow even after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues; most infiltrate surrounding tissues, metastasize to several sites, likely recur after attempted removal, and likely cause patient death if not treated appropriately. As used herein, the term neoplasia is used to describe all cancerous conditions and encompasses or includes the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Neoplasia includes, but is not limited to, morphological irregularities in cells in the tissues of a subject or host, and a pathological proliferation of cells in the tissues of a subject relative to normal proliferation in the same type of tissue. Furthermore, neoplasia includes benign and malignant tumors, both invasive and non-invasive (e.g., colon tumors). Malignant neoplasms (cancers) are distinguished from benign neoplasms in that the former exhibit a greater degree of anaplasia, or loss of cellular differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoplasias from which target cells of the present disclosure may be derived include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder, intestinal, breast, cervical, colon, esophageal, head, kidney, liver, lung, neck, ovarian, pancreatic, prostate, and gastric cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma); Germline tumors (e.g., intestinal, breast, prostate, cervical, uterine, lung, ovarian, testicular, thyroid, astrocytoma, esophageal, pancreatic, gastric, liver, colon, and melanoma); mixed neoplasias, particularly carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratocarcinoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17). th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms are treatable using the compounds of the present disclosure.

[0107] Representative common cancers that may be treated with the compounds of the present disclosure include, for example, prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, and lymphoma, among others, which may be treated with one or more compounds of the present disclosure. Because of the activity of the compounds, the present disclosure is generally applicable to treating virtually any cancer in any tissue, and therefore the compounds, compositions, and methods of the disclosure are generally applicable to the treatment of cancer and to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0108] In certain aspects of the present disclosure, the cancer to be treated is metastatic cancer, recurrent cancer, or drug-resistant cancer, and particularly includes drug-resistant cancer.Apart from this, metastatic cancer can be found in virtually any tissue of cancer patients in the late stage of the disease, and typically metastatic cancer is found in virtually any tissue, including lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor).Therefore, the present disclosure is generally applicable to and can be used to treat any cancer in any tissue, regardless of etiology.

[0109] The term "anticancer agent" or "additional anticancer agent" refers to a compound other than the chimeric compounds of the present disclosure that can be used in combination with the compounds of the present disclosure to treat cancer. Exemplary anticancer agents that can be co-administered in combination with one or more chimeric compounds of the present disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., taxol), among others. Exemplary anti-cancer compounds for use in the present disclosure include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY 317615, neuradiab, vitespan, Rta744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estrogen Stradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-j-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 O i4 -(C2H4O2) X, where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine , chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levofloxacin Mysole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine,Marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and erbitux, cremophor-free paclitaxel, epothilone B B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony stimulating factor Stimulatory factors, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,Androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, PEG-1 receptor antagonists ... Filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib may be mentioned in particular, and immunotherapeutic agents, for example IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) such as indoximod (NLG-8187), navoximod (GDC-0919), and NLG802, PDL1 inhibitors (programmed death-ligand 1 inhibitors) including, for example, nivolumab, durvalumab, and atezolizumab, PD1 inhibitors such as pembrolizumab (Merck), and CTLA-4 inhibitors (cytotoxic T-lymphocyte-associated protein 4 / cluster of differentiation 152 inhibitors) including ipilimumab and tremelimumab, among others.

[0110] In addition to anticancer drugs, some other agents can be co-administered with the chimeric compounds of the present disclosure in the treatment of cancer.These include active substances, minerals, vitamins and nutritional supplements that have shown some effectiveness in inhibiting cancer tissue or its growth, or are otherwise useful in the treatment of cancer.For example, to treat cancer, one or more of dietary selenium, vitamin E, lycopene, soybean food, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids and phytoestrogens, including β-sitosterol, can be used in combination with the present compounds.

[0111] The term "inflammatory disease" is used to describe diseases or conditions that involve acute, but often chronic, inflammation as a primary symptom of the disease or condition. Inflammatory diseases include neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias); immune response disorders that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis, combating damaging inflammation); chronic inflammatory diseases including, for example, inflammatory bowel disease, including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren's disease; hyperglycemic disorders; and lipid metabolism disorders. Diabetes mellitus (types I and II) affecting the function and / or structure of pancreatic islets, pancreatic beta cell death, and associated hyperglycemic disorders, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, leprechaunism, and lipoatrophic diabetes), and dyslipidemia (e.g., hyperlipidemia, high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), high triglycerides, and metabolic syndrome, which occur in obese subjects). These conditions include, inter alia, autoimmune diseases, liver disease, kidney disease (apoptosis in plaques, glomerular disease), cardiovascular disease (particularly including infarction, ischemia, stroke, pressure overload, and complications during reperfusion), muscle degeneration and muscle atrophy, mild inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological manifestations (both central and peripheral) including stroke, age-related dementia, and sporadic Alzheimer's disease, as well as psychiatric conditions including depression, stroke and spinal cord injury, and arteriosclerosis. These conditions and / or conditions respond to treatment using the compounds and / or pharmaceutical compositions of the present disclosure, as elevated MIF levels are often observed in these diseases. It should be noted that there is some overlap between certain autoimmune and inflammatory diseases described herein.

[0112] Throughout this disclosure, various aspects of the present disclosure may be presented in the form of ranges. It should be understood that the description in range form is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the like, as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0113] compound In one aspect, the disclosure provides a compound comprising Formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Protein binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I)

[0114] In certain embodiments, the compound comprises Formula (Ia), or a salt, geometric isomer, stereoisomer, or solvate thereof. [Protein binder]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] (Ia)

[0115] In (I) and / or (Ia), the protein binder is a molecule, such as, but not limited to, a small molecule and / or a peptide, that binds to an extracellular protein ("protein") of interest. In certain embodiments, the treatment or management of a disease and / or disorder requires the degradation, removal, and / or reduction in the concentration of the extracellular protein in a subject. In certain embodiments, the extracellular protein binder in (I) and / or (Ia) is capable of binding to a circulating extracellular protein in the plasma of a subject with the same affinity or substantially similar affinity as the extracellular protein binder itself.

[0116] In (I) and / or (Ia), the CRBM is a cellular receptor binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradative cells in a subject, whereby binding of (I) or (Ia) results in endocytosis and degradation of (I) and / or (Ia) and / or extracellular proteins. In certain embodiments, the CRBM is an ASGPRBM, which is a cellular receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of hepatocytes or other degradative cells in a subject.

[0117] In (I) and / or (Ia), each CON is independently a bond or a group that covalently links the protein binder to the CRBM, the protein binder to the linker, and / or the linker to the CRBM.

[0118] In (I) and / or (Ia), the linker is a group having a valency ranging from 1 to 15. In certain embodiments, the linker has a valency of 1 to 10. In certain embodiments, the linker has a valency of 1 to 5. In certain embodiments, the linker has a valency of 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or protein binder groups, optionally through CON, where the linker itself optionally comprises one or more CON groups.

[0119] In certain embodiments, k' is an integer ranging from 1 to 15. In certain embodiments, k' is an integer ranging from 1 to 10. In certain embodiments, k' is an integer ranging from 1 to 5. In certain embodiments, k' is an integer ranging from 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0120] In certain embodiments, j is an integer ranging from 1 to 15. In certain embodiments, j is an integer ranging from 1 to 10. In certain embodiments, j is an integer ranging from 1 to 5. In certain embodiments, j is an integer ranging from 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0121] In certain embodiments, h is an integer ranging from 0 to 15. In certain embodiments, h is an integer ranging from 1 to 15. In certain embodiments, h is an integer ranging from 1 to 10. In certain embodiments, h is an integer ranging from 1 to 5. In certain embodiments, h is an integer ranging from 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0122] In certain embodiments, h' is an integer ranging from 0 to 15. In certain embodiments, h' is an integer ranging from 1 to 15. In certain embodiments, h' is an integer ranging from 1 to 10. In certain embodiments, h' is an integer ranging from 1 to 5. In certain embodiments, h' is an integer ranging from 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0123] In certain embodiments, i is an integer ranging from 0 to 15. In certain embodiments, i is an integer ranging from 1 to 15. In certain embodiments, i is an integer ranging from 1 to 10. In certain embodiments, i is an integer ranging from 1 to 5. In certain embodiments, i is an integer ranging from 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0124] In certain embodiments, at least one of h, h', and i is at least one.

[0125] In certain embodiments, k', j', h, h', and i are each independently 1, 2, or 3.

[0126] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0127] In another aspect, the disclosure provides a compound comprising Formula (II), or a salt, geometric isomer, stereoisomer, or solvate thereof: [TNF binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (II)

[0128] In certain embodiments, the compound comprises Formula (IIa), or a salt, geometric isomer, stereoisomer, or solvate thereof. [TNF Binder]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (IIa)

[0129] In (II) and / or (IIa), the TNF binder is a molecule, such as, but not limited to, a small molecule and / or a peptide, that binds to TNF. In certain embodiments, the treatment or management of a disease and / or disorder requires the degradation, removal, and / or reduction of the concentration of TNF in a subject. In certain embodiments, the TNF binder in (II) and / or (IIa) is capable of binding to circulating TNF in the plasma of a subject with the same affinity or substantially similar affinity as the TNF binder itself.

[0130] In (II) and / or (IIa), the CRBM is a cellular receptor binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradative cells in a subject, whereby binding of (II) and / or (IIa) results in endocytosis and degradation of (II) and / or (IIa) and / or TNF. In certain embodiments, the CRBM is an ASGPRBM, which is a cellular receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of hepatocytes or other degradative cells in a subject.

[0131] In (II) and / or (IIa), each CON is independently a bond or a group that covalently links the TNF binder to the CRBM, the TNF binder to the linker, and / or the linker to the CRBM.

[0132] In (II) and / or (IIa), the linker is a group having a valence ranging from 1 to 15. In certain embodiments, the linker has a valence of 1 to 10. In certain embodiments, the linker has a valence of 1 to 5. In certain embodiments, the linker has a valence of 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or TNF binder groups, optionally through CON, where the linker itself optionally comprises one or more CON groups.

[0133] In certain embodiments, k' is an integer ranging from 1 to 15. In certain embodiments, k' is an integer ranging from 1 to 10. In certain embodiments, k' is an integer ranging from 1 to 5. In certain embodiments, k' is an integer ranging from 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0134] In certain embodiments, j is an integer ranging from 1 to 15. In certain embodiments, j is an integer ranging from 1 to 10. In certain embodiments, j is an integer ranging from 1 to 5. In certain embodiments, j is an integer ranging from 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0135] In certain embodiments, h is an integer ranging from 0 to 15. In certain embodiments, h is an integer ranging from 1 to 15. In certain embodiments, h is an integer ranging from 1 to 10. In certain embodiments, h is an integer ranging from 1 to 5. In certain embodiments, h is an integer ranging from 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0136] In certain embodiments, h' is an integer ranging from 0 to 15. In certain embodiments, h' is an integer ranging from 1 to 15. In certain embodiments, h' is an integer ranging from 1 to 10. In certain embodiments, h' is an integer ranging from 1 to 5. In certain embodiments, h' is an integer ranging from 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0137] In certain embodiments, i is an integer ranging from 0 to 15. In certain embodiments, i is an integer ranging from 1 to 15. In certain embodiments, i is an integer ranging from 1 to 10. In certain embodiments, i is an integer ranging from 1 to 5. In certain embodiments, i is an integer ranging from 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0138] In certain embodiments, at least one of h, h', and i is at least one.

[0139] In certain embodiments, k', j', h, h', and i are each independently 1, 2, or 3.

[0140] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0141] In yet another aspect, the present disclosure provides a compound comprising Formula (III), or a salt, geometric isomer, stereoisomer, or solvate thereof: [AATM] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (III)

[0142] In certain embodiments, the compound comprises Formula (IIIa), or a salt, geometric isomer, stereoisomer, or solvate thereof. [AATM]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (IIIa)

[0143] In (III) or (IIIa), the AATM is a ligand of an autoantibody. The ligand can be, for example, a small molecule, a peptide, and / or a nucleic acid aptamer. In certain embodiments, the autoantibody mediates a disease and / or disorder in a subject, and treatment or management of the disease and / or disorder requires degradation, removal, or reduction in the concentration of the autoantibody in the subject. In certain embodiments, the AATM in (III) or (IIIa) is capable of binding to an autoantibody in the plasma of a subject with the same affinity or substantially similar affinity as the AATM itself.

[0144] In (III) or (IIIa), the CRBM is a cellular receptor binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradative cells in a subject, whereby binding results in endocytosis and degradation of (III) and / or (IIIa) and / or the autoantibody. In certain embodiments, the CRBM is an ASGPRBM, which is a cellular receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of hepatocytes or other degradative cells in a subject.

[0145] In (III) or (IIIa), each CON is independently a bond or a group that covalently links the AATM to the CRBM, the AATM to the linker, and / or the linker to the CRBM.

[0146] In (III) or (IIIa), the linker is a group having a valence ranging from 1 to 15. In certain embodiments, the linker has a valence of 1 to 10. In certain embodiments, the linker has a valence of 1 to 5. In certain embodiments, the linker has a valence of 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or AATM groups, optionally through CON, where the linker itself optionally comprises one or more CON groups.

[0147] In certain embodiments, k' is an integer ranging from 1 to 15. In certain embodiments, k' is an integer ranging from 1 to 10. In certain embodiments, k' is an integer ranging from 1 to 5. In certain embodiments, k' is an integer ranging from 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0148] In certain embodiments, j is an integer ranging from 1 to 15. In certain embodiments, j is an integer ranging from 1 to 10. In certain embodiments, j is an integer ranging from 1 to 5. In certain embodiments, j is an integer ranging from 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0149] In certain embodiments, h is an integer ranging from 0 to 15. In certain embodiments, h is an integer ranging from 1 to 15. In certain embodiments, h is an integer ranging from 1 to 10. In certain embodiments, h is an integer ranging from 1 to 5. In certain embodiments, h is an integer ranging from 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0150] In certain embodiments, h' is an integer ranging from 0 to 15. In certain embodiments, h' is an integer ranging from 1 to 15. In certain embodiments, h' is an integer ranging from 1 to 10. In certain embodiments, h' is an integer ranging from 1 to 5. In certain embodiments, h' is an integer ranging from 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0151] In certain embodiments, i is an integer ranging from 0 to 15. In certain embodiments, i is an integer ranging from 1 to 15. In certain embodiments, i is an integer ranging from 1 to 10. In certain embodiments, i is an integer ranging from 1 to 5. In certain embodiments, i is an integer ranging from 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0152] In certain embodiments, at least one of h, h', and i is at least one.

[0153] In certain embodiments, k', j', h, h', and i are each independently 1, 2, or 3.

[0154] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0155] CRBM folate receptor In certain embodiments, the CRBM is folic acid or any fragment or derivative thereof capable of binding to a folate receptor. Folate receptors bind to folic acid and reduced folate derivatives and mediate the delivery of tetrahydrofolate to the inside of cells, which is then converted from monoglutamic acid to polyglutamic acid (e.g., 5-methyltetrahydrofolate) since only the monoglutamic acid form can be transported across the cell membrane. Human proteins from this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor γ.

[0156] In certain embodiments, the folate CRBM is methotrexate or a biologically active fragment thereof: Includes TIFF2025509732000005.tif27128.

[0157] In certain embodiments, the folate CRBM is pemetrexed or a biologically active fragment thereof: Includes TIFF2025509732000006.tif25128.

[0158] In certain embodiments, a folate CRBM may be incorporated into a compound of the present disclosure through one of its carboxylic acids, as shown in Figure 1. In other embodiments, a folate CRBM may be incorporated into a compound of the present disclosure using N-hydroxysuccinamidyl (NHS)-activated folic acid, as shown in Figure 1 for folic acid (similar chemistry applies to methotrexate and pemetrexed). TIFF2025509732000007.tif70128

[0159] mannose receptor In certain embodiments, the CRBM is a group that binds to the mannose receptor. In certain embodiments, the CRBM comprises the following group: TIFF2025509732000008.tif18128

[0160] In certain embodiments, the mannose receptor CRBM can be prepared by reacting the following reagent (which may be protected with an appropriate protecting group): TIFF2025509732000009.tif17128 may be used to bind to a compound of the disclosure (such as, but not limited to, REAG); wherein X is S or O and R is TIFF2025509732000010.tif18137, and each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0161] In certain embodiments, the mannose receptor CRBM is part of a polymer molecule. The molecule can include one or more independently selected mannose receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM can be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein.

[0162] Mannose-6-phosphate (M6P) receptor In certain embodiments, the CRBM is a group that binds to the mannose-6-phosphate (M6P) receptor. In certain embodiments, the CRBM comprises the following group: TIFF2025509732000011.tif17128In the formula, X is O or S, and R 1 is selected from the group consisting of: TIFF2025509732000012.tif48128

[0163] In certain embodiments, the CRBM can be prepared by reacting the following reagents (which may be protected with suitable protecting groups): TIFF2025509732000013.tif17128 may be used to bind to a compound of the disclosure (such as, but not limited to, REAG); In the formula, X and R 1is as defined elsewhere herein, and R 2 teeth, TIFF2025509732000014.tif38137, and each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0164] In certain embodiments, the M6P receptor CRBM is part of a polymer molecule. The molecule can include one or more independently selected M6P receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM can be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein. Figures 2-9 show exemplary mannose receptor binders and their preparation.

[0165] In certain embodiments, the M6P receptor CRBM is one of the following (Yamaguchi, et al., 2016, J. Am. Chem. Soc. 138(38):12472-12485): TIFF2025509732000015.tif107128

[0166] In certain embodiments, the M6P receptor CRBM is one of the following (US 2011 / 0110960 to Platenburg): TIFF2025509732000016.tif102144

[0167] Low-density lipoprotein receptor-related protein 1 (LRP1) receptor In certain embodiments, the CRBM is an LRP1 (low density lipoprotein receptor-related protein 1; also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or cluster of differentiation 91 (CD91)) binding group comprising one of the following amino acid sequences: TIFF2025509732000017.tif117144

[0168] Low-density lipoprotein receptor (LDLR) In certain embodiments, the CRBM is an LDLR (low density lipoprotein receptor) binding group comprising one of the following amino acid sequences: TIFF2025509732000018.tif211140TIFF2025509732000019.tif131139

[0169] FcγRI receptor In certain embodiments, the CRBM is an FcγRI binding group comprising one of the following amino acid sequences: TIFF2025509732000020.tif225140

[0170] Transferrin receptor In certain embodiments, the CRBM is a transferrin receptor binding group comprising one of the following amino acid sequences: TIFF2025509732000021.tif104141

[0171] Macrophage scavenger receptor In certain embodiments, the CRBM is a macrophage scavenger receptor binding portion comprising one of the following amino acid sequences: TIFF2025509732000022.tif77145

[0172] As used herein, Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, Sar is sarcosine, Pip is pipecolic acid, Nleu is norleucine, and NMeLeu is N-methylleucine.

[0173] G protein-coupled receptors In certain embodiments, the CRBM is a G protein-coupled receptor (GPCR) binding moiety. In certain embodiments, the binding moiety binds to a GPCR and induces internalization of the receptor. In certain embodiments, the receptor is CXCR7 (see, e.g., Nalawansha, et al., 2019, ACS Cent. Sci. 5(6):1079-1084). In certain embodiments, the binding moiety is TIFF2025509732000023.tif34128, wherein each occurrence of R is independently H or C1-C6 alkyl. In certain embodiments, the CRBM can be prepared by reacting the following reagents (optionally protected with a suitable protecting group): TIFF2025509732000024.tif34128 may be used to bind to a compound of the disclosure (such as, but not limited to, REAG); wherein at least one occurrence of R is REAG, and the remaining occurrences of R are independently H or C1-C6 alkyl.

[0174] Asialoglycoprotein receptor (ASGPR) The present disclosure contemplates the use of ASGPR binding moieties (ASGPRBM).

[0175] In certain embodiments, the ASGPRBM group is any group described in Huang, et al., 2017, Bioconjugate Chem. 28:283-295, which is incorporated herein by reference in its entirety.

[0176] In certain embodiments, the ASGPRBM group has the structure: TIFF2025509732000025.tif22128, where X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X is O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker 3 or 4 atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) groups.

[0177] In certain embodiments, R N1 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0178] In certain embodiments, when X is two atoms in length, X in the ASGPRBM is -OC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[0179] In certain embodiments, when X is 3 atoms in length, X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1)-S-, -OC(R N1 )(R N1 )-N(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-, -N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )-, -N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )

[0180] In certain embodiments, when X is four atoms in length, X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1)-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, or -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[0181] In certain embodiments, X is OCH2 and R N1 is H.

[0182] In certain embodiments, X is CHO and RN1 is H.

[0183] In certain embodiments, the ASGPRBM has the following structure: Includes TIFF2025509732000026.tif18128.

[0184] In certain embodiments, the ASGPRBM has the following structure: Includes TIFF2025509732000027.tif19128.

[0185] In certain embodiments, R 1 is the group shown in Figure 10. In certain embodiments, R 3 is the group shown in Figure 10. In certain embodiments, R 1 and R 3 are each independently a group shown in FIG.

[0186] In certain embodiments, R 1 and R 3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (alkynyl), -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens.

[0187] In certain embodiments, R 1 and R 3 are each independently Ph(CH2) K-, which is optionally substituted with 1 to 3 independently selected halogens; C1 to C4 alkyl optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0188] In certain embodiments, R 1 and R 3 are each independently represented by the following structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 where R 7 is a C1-C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxy groups; —NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2.

[0189] In certain embodiments, K is 0. In certain embodiments, K is 1. In certain embodiments, K is 2. In certain embodiments, K is 3. In certain embodiments, K is 4.

[0190] In certain embodiments, K' is 1. In certain embodiments, K' is 2. In certain embodiments, K' is 3. In certain embodiments, K' is 4.

[0191] In certain embodiments, R N3 Each occurrence of R is independently H or C1-C3 alkyl. N3 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0192] In certain embodiments, each R N4each occurrence is independently H, C1-C3 alkyl, or Ph-(CH2) K In certain embodiments, R N4 each occurrence independently represents H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2) K -It is.

[0193] In certain embodiments, R 1 and R 3 are each independently selected from the group consisting of: TIFF2025509732000028.tif24128wherein CYC represents a group consisting of: Selected from TIFF2025509732000029.tif102143, wherein: The bond shown in TIFF2025509732000030.tif2128 is -(CH2) K indicates the site on CYC to which it is connected.

[0194] In certain embodiments, L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON. 1 is a bond. In certain embodiments, L 1 is a linker. In certain embodiments, L 1 is a -CON- linker. In certain embodiments, L 1 is -CON-linker-CON.

[0195] In certain embodiments, R C is absent, H, C1-C4 alkyl optionally substituted with 1 to 3 optionally substituted halogens and / or 1 to 2 hydroxyl groups, or a group having the following structure: TIFF2025509732000031.tif21128, wherein R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH2)K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens, C1-C3 alkoxy optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens.

[0196] In certain embodiments, R N2 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0197] In certain embodiments, R C teeth The file is TIFF2025509732000032.tif23141.

[0198] In certain embodiments, R 1 and R 3 are each independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocycle is -L 1 and -R C is further substituted with

[0199] In certain embodiments, R N Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0200] In certain embodiments, R 2 is the group shown in FIG.

[0201] In certain embodiments, R 2 Ha-(CH2) K -N(R N1 )-C(=O)R AM is.

[0202] In certain embodiments, R AM is H, C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) K -NR N3 R N4 is.

[0203] In certain embodiments, R 2 teeth TIFF2025509732000033.tif15128, wherein: R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, —(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R TA is C3~C10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, each of which may be CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) optionally substituted with 1 to 3 independently selected halogens. K C(=O)-(C1-C4 alkyl), or R TA teeth TIFF2025509732000034.tif44128, which is optionally substituted with 1 to 3 C1-C3 alkyl groups, each of which is optionally substituted with 1 to 3 independently selected halogens; or R TA teeth TIFF2025509732000035.tif26128, wherein each -(CH2) K The group is optionally substituted with 1 to 4 C1 to C3 alkyl groups which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups.

[0204] In certain embodiments, the ASGPRBM group has the structure: TIFF2025509732000036.tif46148 included, During the ceremony, R Ais C1-C3 alkyl optionally substituted with 1 to 5 independently selected halogens; Z A Ha-(CH2) IM -, -O-(CH2) IM -, -S-(CH2) IM -, -NR M -(CH2) IM -, -C(=O)-(CH2) IM -, a PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH2) IM NR M - and; Z B is absent, -(CH2) IM -, -C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M - and; R M is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups; Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0205] In certain embodiments, R A is methyl or ethyl, either of which may be substituted with 1 to 3 fluorines.

[0206] In certain embodiments, Z A is a PEG group containing 1 to 4 ethylene glycol residues.

[0207] In certain embodiments, the ASGPRBM group comprises one of the following (Mamidyala, et al., 2012, J. Am. Chem. Soc. 134:1978-1981): TIFF2025509732000037.tif35128TIFF2025509732000038.tif199150TIFF2025509732000039.tif197141TIFF2025509732000040.tif58146

[0208] In certain embodiments, the ASGPRBM group comprises one of the following (Sanhueza, et al., 2017, J. Am. Chem. Soc. 139:3528-3536): TIFF2025509732000041.tif113142

[0209] Linker and CON In certain embodiments, the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

[0210] In certain embodiments, the linker has the structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together to form a pyrrolidine group or a hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15.

[0211] In certain embodiments, the linker has the structure —[N(R ' -(CH2) 1~15—C(═O)]—, where R′ is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1-100.

[0212] In certain embodiments, the linker has the structure: -ZD-Z'- Including, During the ceremony, Z and Z' each independently represent a bond; TIFF2025509732000042.tif23159; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); In certain embodiments, each i is independently 0 to 100; in certain embodiments, 0 to 75; in certain embodiments, 1 to 60; in certain embodiments, 1 to 55; in certain embodiments, 1 to 50; in certain embodiments, 1 to 45; in certain embodiments, 1 to 40; in certain embodiments, 2 to 35; in certain embodiments, 3 to 30; in certain embodiments, 1 to 15; in certain embodiments, 1 to 10; in certain embodiments, 1 to 8; in certain embodiments, 1 to 6; in certain embodiments, 0, 1, 2, 3, 4, or 5; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; m' is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; n is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; and in certain embodiments, from 1, 2, 3, 4, or 5.

[0213] In certain embodiments, the linker has the structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2-, or -(CH2CH2CH2O) n - Including, In the formula, n and n' are each independently an integer ranging from 1 to 25; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 12; in certain embodiments, from 2 to 11; in certain embodiments, from 2 to 10; in certain embodiments, from 2 to 8; in certain embodiments, from 2 to 6; in certain embodiments, from 2 to 5; in certain embodiments, from 2 to 4; in certain embodiments, from 2 or 3; and in certain embodiments, from 1, 2, 3, 4, 5, 6, 7, or 8.

[0214] In certain embodiments, the linker has the structure: -PEG-CON-PEG- Including, wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The file is TIFF2025509732000043.tif13128.

[0215] In certain embodiments, CON has the structure: TIFF2025509732000044.tif77128, wherein R′ and R″ are each independently H, methyl, or a bond.

[0216] In certain embodiments, CON has the following diamide structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- Including, In the formula, each R 1 is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, and in certain embodiments 1 to 7, and in certain embodiments 1, 2, 3, 4, 5, or 6.

[0217] In certain embodiments, CON has the structure: TIFF2025509732000045.tif13128 included, During the ceremony, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O)M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2) M1 -C(O)NR 4 - but R 1a , R 2a , and R 3a and H are not simultaneously; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be 0 at the same time.

[0218] In certain embodiments, CON has the structure: Includes TIFF2025509732000046.tif42128.

[0219] protein binders Any protein binder that binds to a protein of interest (which in certain embodiments is a circulating protein) is useful within Formula (I) and Formula (Ia) of the present disclosure. In certain non-limiting embodiments, the binder is a small molecule. In certain non-limiting embodiments, the binder is a peptide and / or polypeptide.

[0220] The protein binder can be incorporated into the compound of formula (I) and / or formula (Ia) using any method known in the art and / or any technique described or exemplified herein.For example, the protein binder can be bound to the linker and / or CON using amide coupling, ester coupling, nucleophilic substitution, electrophilic substitution, radical coupling, or any other synthetic method known in the art.The binding position of the protein binder should be a position in formula (I) or formula (Ia) where the bound protein binder can still bind to the protein of interest.It is within the scope of standard experimental methods that are planned and / or known to those skilled in the art to envision the binding mode of the protein binder to the protein of interest, identify potential binding sites on the protein binder, and / or bind the protein binder to CON and / or linker and determine whether this binding interferes with the binding of the protein binder to the protein of interest.

[0221] In certain embodiments, the protein binder is an antibody, such as, but not limited to, a monoclonal antibody. The antibody of interest can be incorporated into the compound of Formula (I) or Formula (Ia) using any method known in the art and / or any technique described or exemplified herein. For example, the antibody can be attached to the linker and / or CON through carboxylic acid groups on the surface of the antibody, for example, using amide- or ester-forming chemical reactions. For example, the antibody can be attached to the linker and / or CON through amine groups on the surface of the antibody, for example, using amide-forming chemical reactions. For example, the antibody can be attached to the linker and / or CON through thiol groups on the surface of the antibody, for example, using nucleophilic substitution chemical reactions. In this case, the surface cysteine ​​residues may be present in the wild-type antibody and / or may be introduced by mutation, for example, using site-directed mutagenesis. Linkers and / or CONs useful within the scope of the present disclosure may be any linkers known in the art, as long as the presence of the linker does not significantly interfere with the ability of the antibody to bind to the protein of interest.

[0222] In certain embodiments, the protein binder is a polypeptide.Any method known in the art and / or any technique described or exemplified herein can be used to incorporate a polypeptide of interest into the compound of formula (I) or formula (Ia).For example, the polypeptide can be linked to a linker and / or CON through its C-terminus and / or its N-terminus, for example, using amide or ester-forming chemical reaction.For example, the polypeptide can be linked to a linker and / or CON through any intermediate residue, for example, using amide or ester-forming chemical reaction and / or nucleophilic substitution chemical reaction (for example, when the polypeptide has a thiol residue).The polypeptide can be synthesized by standard Fmoc-SPPS.After introducing a linker at the N-terminus or C-terminus, a functional handle (N3, alkyne, etc.) can be introduced, allowing for simple linkage to a targeting domain.

[0223] Protein-based protein binders, such as antibodies, polypeptides, etc., can be synthesized by various methods well known in the art, such as expression of binders in E. coli (E. coli) that do not require post-translational modifications (PTMs), or expression of binders that do not require PTMs in mammalian cultures. These binding proteins can be made bifunctional by introducing unnatural amino acid tags (N3, alkynes, etc.) for linkage, followed by reaction with the corresponding targeting domain, or by many other well-known bioorthogonal reactions for specific tagging of proteins.

[0224] As will be understood by those skilled in the art, any protein binder that can recognize and specifically bind to protein of interest is useful in the present disclosure.The present disclosure should not be interpreted as being limited to any one protein binder that is known or previously unknown, provided that the protein binder can specifically bind to protein of interest and prevent or minimize the biological activity of protein of interest.

[0225] In certain embodiments, the protein of interest is CD40L. In certain embodiments, protein binders that bind to CD40L include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000047.tif74128

[0226] In certain embodiments, the protein of interest is PCSK9. In certain embodiments, protein binders that bind to PCSK9 include the following (wherein the peptide C-terminus may be amidated and the wavy line indicates a potential, non-limiting point of attachment to REAG within contemplated compounds of the present disclosure): TIFF2025509732000048.tif100128 (where X = OH or NH2).

[0227] In certain embodiments, the protein of interest is PCSK9. In certain embodiments, the protein binder that binds to PCSK9 includes any of the binders described in WO2018 / 057409. In certain embodiments, the protein binder includes any of the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000049.tif201134TIFF2025509732000050.tif76141

[0228] In certain embodiments, the protein of interest is VEGF. In certain embodiments, protein binders that bind to VEGF include the following (wherein the peptide C-terminus may be amidated and the wavy line indicates a potential, non-limiting point of attachment to REAG within contemplated compounds of the present disclosure): TIFF2025509732000051.tif4128 (where X = OH or NH2), TIFF2025509732000052.tif47128.

[0229] In certain embodiments, the protein of interest is TGF-β. In certain embodiments, protein binders that bind to TGF-β include the following (wherein the peptide C-terminus may be amidated and the wavy line indicates a potential, non-limiting point of attachment to REAG within contemplated compounds of the present disclosure): TIFF2025509732000053.tif4128 (where X = OH or NH2), TIFF2025509732000054.tif66128.

[0230] In certain embodiments, the protein of interest is TSP-1. In certain embodiments, protein binders that bind to TSP-1 include the following (wherein the peptide C-terminus may be amidated and the wavy line indicates a potential, non-limiting point of attachment to REAG within contemplated compounds of the present disclosure): TIFF2025509732000055.tif4128 (where X = OH or NH2).

[0231] In certain embodiments, the protein of interest is soluble uPAR. In certain embodiments, protein binders that bind to uPAR include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000056.tif82128

[0232] In certain embodiments, the protein of interest is soluble PSMA. In certain embodiments, protein binders that bind to PSMA include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000057.tif35128

[0233] In certain embodiments, the protein of interest is IL-2. In certain embodiments, protein binders that bind to IL-2 include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000058.tif34128

[0234] In certain embodiments, the protein of interest is GP120. In certain embodiments, protein binders that bind to GP120 include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000059.tif170128

[0235] In certain embodiments, the protein of interest is MIF. In certain embodiments, protein binders that bind to MIF include the following (where the wavy line indicates a potential, non-limiting point of attachment for REAG within contemplated compounds of the present disclosure): TIFF2025509732000060.tif67128

[0236] In certain embodiments, the protein of interest is IgA, as known in the art or described elsewhere herein. In certain embodiments, protein binders that bind to MIF include any peptide described in Hatanaka, et al., 2012, J. Biol. Chem. 287:43126-43136, including, but not limited to: TIFF2025509732000061.tif23181

[0237] These peptides may be acyclic (as free thiols) or cyclized as oxidized thiols (disulfide bonds). Additionally, the present disclosure contemplates incorporating these peptides into the compounds of the present disclosure through N- and / or C-terminal conjugation.

[0238] In certain embodiments, the protein binder that binds to IgA is any Fc-α receptor peptidomimetic described in Heineke, et al., 2017, Eur. J. Immunol. 47:1835-1845, including but not limited to: Linear peptides: TIFF2025509732000062.tif17128 Cyclic peptide: CLIPS TIFF2025509732000063.tif44128 Cyclic peptides: oxidation TIFF2025509732000064.tif24128

[0239] These peptides may be acyclic (as free thiols) or cyclized as oxidized thiols (disulfide bonds). Additionally, the present disclosure contemplates incorporating these peptides into the compounds of the present disclosure through N- and / or C-terminal conjugation.

[0240] CLIPS refers to the cyclization of linear peptides by reaction of the thiol functional group of cysteine ​​with a small, rigid entity. This anchor reacts only with the thiol and is covalently attached to the peptide. Non-limiting examples of CLIPS crosslinkers contemplated in this disclosure include: TIFF2025509732000065.tif87128

[0241] TNF binder Any TNF binder that binds to TNF is useful within Formula (II) and Formula (IIa) of the present disclosure. In certain non-limiting embodiments, the binder is a small molecule. In certain non-limiting embodiments, the binder is a peptide and / or polypeptide.

[0242] The TNF binder can be incorporated into the compounds of formula (II) and formula (IIa) using any method known in the art and / or any technique described or exemplified herein. For example, the TNF binder can be bound to the linker and / or CON using amide coupling, ester coupling, nucleophilic substitution, electrophilic substitution, radical coupling, or any other synthetic method known in the art. The binding position of the TNF binder should be a position in formula (II) and formula (IIa) where the bound TNF binder can still bind to TNF. It is within the scope of standard experimental methods that are planned and / or known to those skilled in the art to envision the binding mode of the TNF binder to TNF, identify potential binding sites on the TNF binder, and / or bind the TNF binder to CON and / or linker and determine whether this binding interferes with the binding of the TNF binder to TNF.

[0243] In certain embodiments, the TNF binder is an antibody, such as, but not limited to, a monoclonal antibody. The antibody of interest can be incorporated into the compounds of Formula (II) and Formula (IIa) using any method known in the art and / or any technique described or exemplified herein. For example, the antibody can be attached to the linker and / or CON through a carboxylic acid group on the surface of the antibody, for example, using amide- or ester-forming chemical reactions. For example, the antibody can be attached to the linker and / or CON through an amine group on the surface of the antibody, for example, using amide-forming chemical reactions. For example, the antibody can be attached to the linker and / or CON through a thiol group on the surface of the antibody, for example, using nucleophilic substitution chemical reactions. In this case, the surface cysteine ​​residue may be present in the wild-type antibody and / or may be introduced by mutation, for example, using site-directed mutagenesis. The linker and / or CON useful within the scope of the present disclosure can be any linker known in the art, as long as the presence of the linker does not significantly interfere with the ability of the antibody to bind to TNF.

[0244] In certain embodiments, the TNF binder is a polypeptide. The polypeptide of interest can be incorporated into the compounds of formula (II) and formula (IIa) using any method known in the art and / or any technique described or exemplified herein. For example, the polypeptide can be linked to the linker and / or CON through its C-terminus and / or its N-terminus, for example, using amide or ester-forming chemical reactions. For example, the polypeptide can be linked to the linker and / or CON through any intermediate residue, for example, using amide or ester-forming chemical reactions and / or nucleophilic substitution chemical reactions (e.g., when the polypeptide has a thiol residue). The polypeptide can be synthesized by standard Fmoc-SPPS. In certain embodiments, the C-terminus of the peptide is amidated. After introducing the linker at the N-terminus or C-terminus, a functional handle (N3, alkyne, etc.) can be introduced, allowing for simple linkage to the ASGPR targeting domain. Non-limiting examples include: The file is TIFF2025509732000066.tif27138.

[0245] Protein-based TNF binders, such as antibodies, polypeptides, etc., can be synthesized by various methods well known in the art, such as expression in E. coli of binders that do not require post-translational modifications, or expression in mammalian cultures of binders that do not require PTMs. These binding proteins can be converted into bifunctional proteins that target TNF-ASGPR by introducing unnatural amino acid tags (N3, alkynes, etc.) for linkage and then reacting with the corresponding ASGPR targeting domain, or by many other well-known bioorthogonal reactions for specific tagging of proteins.

[0246] As will be appreciated by those skilled in the art, any TNF binder capable of recognizing and specifically binding to TNF is useful in the present disclosure, and the present disclosure should not be construed as limited to any one TNF binder, known or previously unknown, provided that the TNF binder is capable of specifically binding to TNF and preventing or minimizing the biological activity of TNF.

[0247] In a particular embodiment, the TNF binder comprises the polypeptide STPTRYS (SEQ ID NO:120) (Guangdong Yixue 2008, 29(1):55-57).

[0248] In a particular embodiment, the TNF binder comprises the polypeptide CALWHWWHC (SEQ ID NO:121) or C(T / S)WLHWWAC (SEQ ID NO:122) (Diyi Daxue Xuebao 2002, 22(7):597-599).

[0249] In certain embodiments, the TNF binder comprises any Tbab protein described in Zhu, et al., 2016, Protein Sci. 25:2066-2075.

[0250] In certain embodiments, the TNF binder comprises the polypeptide (L / M)HEL(Y / F)(L / M)X(W / Y / F) (SEQ ID NO:123) described in Zhang, et al., 2003, Biochem. Biophys. Res. Commun. 310:1181-1187.

[0251] In certain embodiments, the TNF binder comprises one of the following polypeptides: TIFF2025509732000067.tif11128(Yang, et al., 2019, FEBS Lett. 593:1292-1302).

[0252] In certain embodiments, the TNF binder comprises TNFR1 or TNFR2 (Yang & Yang, 2013, Fenxi Huaxue / Chinese J. Anal. Chem. 41:664-669).

[0253] In certain embodiments, the TNF binder comprises anti-cachexin C1 and / or C2 (Lian, et al., 2013, J. Am. Chem. Soc. 135:11990-11995). TIFF2025509732000068.tif59128

[0254] In certain embodiments, the TNF binder comprises adalimumab, infliximab, etanercept, golimumab, and / or certolizumab.

[0255] In certain embodiments, the TNF binder comprises the 29.2 kDa scFv identified in Safarpour, et al., 2018, Iran. J. Pharm. Res. 17:743-752.

[0256] In certain embodiments, the TNF binder is TIFF2025509732000069.tif4128 (a non-limiting example can be a sulfur-linked tris-bromomethylmesitylene core; Luzi, et al., 2015, Protein Eng. Des. Sel. 28:45-52).

[0257] In certain embodiments, the TNF binder comprises any of the affibodies (approximately 60 amino acids) identified in Lofdahl, et al., 2009, N. Biotechnol. 26:251-259.

[0258] In certain embodiments, the TNF binder comprises any of the affibodies identified in Kronqvist, et al., 2008, Protein Eng. Des. Sel. 21:247-255.

[0259] In certain embodiments, the TNF binder comprises any of the affibodies identified in Jonsson, et al., 2009, Biotechnol. Appl. Biochem. 54:93-103.

[0260] In certain embodiments, the TNF binder comprises the bispecific albumin / TNF binding polypeptide identified in Nilvebrant, et al., 2011, PLoS One 6.

[0261] In certain embodiments, the TNF binder comprises the ubiquitin-based artificial binding protein identified in Hoffmann, et al., 2012, PLoS One 7:2-11.

[0262] In certain embodiments, the TNF binder comprises the HIHDDLLRYYGW linear peptide (SEQ ID NO:127) or the four-branched peptide (SEQ ID NO:128) identified in Brunetti, et al., 2014, Molecules 19:7255-7268.

[0263] In certain embodiments, the TNF binder comprises any of the TNF-α binding peptides (P51 and P52) identified in Alizadeh, et al., 2017, Eur. J. Pharm. Sci. 96:490-498. TIFF2025509732000070.tif67138

[0264] In certain embodiments, the TNF binder comprises the scFv antibody identified in Alizadeh, et al., 2015, Adv. Pharm. Bull. 5:661-666.

[0265] In certain embodiments, the TNF binder comprises any of the TNF-binding peptides described in WO 2006 / 053568, which is incorporated herein by reference in its entirety, such as, but not limited to, KRWSRYF (SEQ ID NO:129), which may be multivalent in certain embodiments.

[0266] In certain embodiments, the TNF binder comprises any of the TNF-binding peptides described in WO 2015 / 055597, which is incorporated herein by reference in its entirety (such as, but not limited to, HIHDDLLRYYGW (SEQ ID NO:127), which may be multivalent in certain embodiments).

[0267] In certain embodiments, the TNF binder comprises YCWSQYLCY (SEQ ID NO:130) identified in Arthritis & Rheumatism 2007, 56(4):1164-74.

[0268] In certain embodiments, the TNF binder comprises DFLPHYKNTSLGHRP (SEQ ID NO:131) identified in Chirinos-Rojas, et al., 1998, J. Immunol. 161:5621-5626.

[0269] In certain embodiments, the TNF binder comprises YCLYQSWCY (SEQ ID NO:132). In certain embodiments, the TNF binder is in a reduced form (i.e., has internal disulfide bonds). In certain embodiments, the TNF binder is in an oxidized form (i.e., does not have internal disulfide bonds). See Figure 12 for a non-limiting example.

[0270] In certain embodiments, the TNF binder comprises one of the following: TIFF2025509732000071.tif111145(Zaka, et al., 2019, J. Biomol. Struct. Dyn. 37:2464-2476).

[0271] In certain embodiments, the TNF binder comprises one of the following: TIFF2025509732000072.tif87142 (Shen, et al., 2014, Eur. J. Med. Chem. 85:119-126). For non-limiting examples, see Figures 13 and 14.

[0272] In certain embodiments, the TNF binder comprises: TIFF2025509732000073.tif50128See Figure 15 for a non-limiting example.

[0273] In certain embodiments, the TNF binder comprises: TIFF2025509732000074.tif46128See Figure 16 for a non-limiting example.

[0274] In certain embodiments, the TNF binder comprises: TIFF2025509732000075.tif47128See Figure 17 for a non-limiting example.

[0275] In certain embodiments, the TNF binder comprises one of the following (Saddala & Huang, 2019, J. Transl. Med. 17:1-16): TIFF2025509732000076.tif123137

[0276] In certain embodiments, TNF binders include SPD-304 and analogs thereof (He, et al., 2005, Science 310:1022-1025; Papaneophytou, et al., 2015, Medchemcomm 6:1196-1209). TIFF2025509732000077.tif206109

[0277] Non-limiting chemical schemes for preparing and derivatizing these compounds are provided herein. TIFF2025509732000078.tif89132 Scheme 2. Reagents and Conditions. Route A: A1) NaBH(OAc)3 / MeOH or DCE, with or without pH adjustment with AcOH, and A2) TMOF, NaBH3CN, or NaBH4; Route B: B1) CDI / THF and B2) i. (COCl)2, DMF / THF, ii. pyridine or Et3N / THF. TIFF2025509732000079.tif160154Structures of the 55 compounds tested (SPD304; compound 1 and 54 SPD304 analogs; compounds 2a–17). (Mettou, et al., 2018, SLAS Discov.23:84-93). See Figure 18 for a non-limiting example.

[0278] In certain embodiments, the TNF binder comprises a compound of formula (2a): TIFF2025509732000080.tif20128 formula, A 1 and A 2 are independently substituted or unsubstituted phenyl groups, where the substituents include F, Cl, Br, I, OH, C1-C4 alkyl, C1-C4 alkyl substituted with at least one OH, C1-C4 fluoroalkyl (such as but not limited to CF3), C1-C4 alkoxy, C1-C4 haloalkoxy, benzyloxy, and at least one of the following heterocycles optionally substituted with at least one of F, Cl, Br, I, OH, C1-C4 alkyl, C1-C4 alkyl substituted with at least one OH, C1-C4 fluoroalkyl (such as but not limited to CF3), C1-C4 alkoxy, and C1-C4 haloalkoxy (the dotted line indicates the point of attachment): TIFF2025509732000081.tif65128; Each R 5 are independently hydrogen or optionally substituted C1-C4 alkyl; R 1 and R 2are independently hydrogen or optionally substituted C1-C4 alkyl; X 1 and X 2 are independently carbonyl or CH2; n is 2, 3, or 4; R 3 and R 4 are independently hydrogen or optionally substituted C1-C4 alkyl, or R 3 and R 4 may be taken together to form a heterocyclyl ring. See Figure 19 for a non-limiting example.

[0279] For example, A 1 and A 2 are 1-(3-(trifluoromethyl)phenyl)-1H-indole and 6,7-dimethyl-4H-chromen-4-one, respectively, and X 1 and X 2 If both are CH2, R 3 and R 4 forms a heterocyclyl ring, such as, but not limited to, a piperazinyl ring.

[0280] In certain embodiments, the TNF binder comprises the small molecule IA-14069.

[0281] In certain embodiments, the TNF binder is TIFF2025509732000082.tif27128 (Mouhsine, et al., 2017, Sci. Rep. 7:1-10 (2017). In certain embodiments, the linker and / or Con can be attached to the sulfonamidophenyl ring. See Figure 20 for a non-limiting example.

[0282] In certain embodiments, the TNF binder comprises one of the following: TIFF2025509732000083.tif23128(Melagraki, et al., 2017, PLoS Comput. Biol. 13:1-27).

[0283] In certain embodiments, the TNF binder comprises one of the following: TIFF2025509732000084.tif73128(Melagraki, et al., 2018, Front. Pharmacol. 9:1-12).

[0284] In certain embodiments, the TNF binder is TIFF2025509732000085.tif32128 (Ma, et al., 2014, J. Biol. Chem. 289:12457-12466). In certain embodiments, the linker and / or CON can be attached to the phenyl group indicated by the arrow. See Figure 21 for a non-limiting example.

[0285] In certain embodiments, the TNF binder comprises one of the following: TIFF2025509732000086.tif22128 where R represents a non-limiting derivatization site (Kumar, et al., 2011, Chem. Commun. 47:5010-5012). See Figure 22 for a non-limiting example.

[0286] In certain embodiments, the TNF binder is TIFF2025509732000087.tif18128 (Jiajiu & Shaw, 2013, Cancer Chemother Pharmacol 72:1-7 (2013)).

[0287] In certain embodiments, the TNF binder comprises any dihydro-benzo[cd]indole-6-sulfonamide or analogue shown herein (non-limiting points of attachment to the REAG include naphthyl-containing R1 or hydrophobic R groups on the right-hand side of the molecule). TIFF2025509732000088.tif56140TIFF2025509732000089.tif182128

[0288] In certain embodiments, the TNF binder comprises any of the following: TIFF2025509732000090.tif148128(Shiu-Hin Chan, 2010, Angew Chem Int Ed Engl. 49:2860-4).

[0289] In certain embodiments, the TNF binder comprises any of the following: TIFF2025509732000091.tif121138

[0290] In certain embodiments, the TNF binder comprises any of the following: TIFF2025509732000092.tif64135(Chen, et al., 2017, J. Chem. Inf. Model. 57:1101-1111).

[0291] In certain embodiments, the TNF binder comprises any of the compounds disclosed in US Pat. No. 10,266,532, which is incorporated herein by reference in its entirety.

[0292] In certain embodiments, the TNF binder comprises any of the compounds disclosed in US Pat. No. 9,879,016, which is incorporated herein by reference in its entirety.

[0293] In certain embodiments, the TNF binder comprises any compound disclosed in WO 2008 / 142623, which is incorporated herein by reference in its entirety.

[0294] In certain embodiments, the TNF binder comprises: In certain embodiments, the linker and / or CON can be attached to the compound through a piperidinyl group (Blevitt, et al., 2017, J. Med. Chem. 60:3511-3517). See Figure 23 for a non-limiting example.

[0295] In certain embodiments, the TNF binder comprises a compound of formula (2b), or a pharmaceutically acceptable salt, tautomer, geometric isomer, or stereoisomer thereof: TIFF2025509732000094.tif25128 formula, R 1 is H, OH, F, or optionally substituted (C1-C3) alkyl; R 2 is optionally substituted aryl, optionally substituted (C3-C8)cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or R 1 and R 2 may be taken together to form an optionally substituted saturated or partially saturated carbocyclic ring, or an optionally substituted saturated or partially saturated heterocyclic ring; A 1 , A 2 , and A 3 At most two of them are N, and the rest are independently C(R A2 ) and; X is N and Y is C, where Z 1 -C(R z )2- and Z 2 -C(R z )2-, -N(R z1 ) - or -O-; or Z 1 is -CH2- and Z 2 Ha-Z 2a -Z 2b - and Here Z 2a is Z 1 binds to Z 2b is C(R 1 )(R 2 ) bond; Z 2a and Z 2b are independently -C(R z )2-, -C(R z )2C(R z )2-, -O-, or -N(R z1 )-, except for Z2a and Z 2b One of them is -C(R z )2- or -C(R z )2C(R z )2-; or -Z 2a -Z 2b -is-N(R z1 )C(O)- or -C(O)N(R z1 )-form; or, X is C and Y is N, except that R 1 is neither -OH nor -F, where Z 1 -C(R z )2- and Z 2 -C(R z )2-; or Z 1 -C(R z )2- and Z 2 Ha-Z 2a -Z 2b - and Here Z 2a is Z 1 binds to Z 2b is C(R 1 )(R 2 ) and Z 2a -C(R z )2-, -C(R z )2C(R z )2-, -O-, or -N(R z1 ) and Z 2b -C(R z )2- or -Z 2a -Z 2b -is-N(R z1 )C(O)- or -C(O)N(R z1 )-formed; R 3 Ha-R 3a -R 3b where R 3a is optionally substituted aryl, optionally substituted saturated or partially saturated heterocyclyl, or optionally substituted heteroaryl; R 3bare H, -CF3, -CN, -C(O)OH, -N(R a )(R b ), -C(O)N(R a )(R b ), —C(O)-optionally substituted heterocyclyl, —O(R a ), -S(O)2(C1-C3) alkyl, -S(O)2N(R c )(R d ), -S-(C1-C3) alkyl, -S(O)2-R c Optionally substituted (C1-C5) alkyl, -(CH2) p -Optionally substituted (C3-C6)cycloalkyl, -(CH2) p -optionally substituted heteroaryl, or -(CH2) p - optionally substituted saturated, unsaturated, or partially saturated heterocyclyl; provided that R 2 When R is an optionally substituted phenyl, 3b is neither H nor methoxy; R a and R b are independently H, optionally substituted (C1-C5) alkyl, -C(O)- optionally substituted (C1-C5) alkyl, optionally substituted -(CH2) p -(C3-C6)cycloalkyl, and -(CH2) p - optionally substituted heterocyclyl; R c and R d are independently H, optionally substituted (C1-C5) alkyl, or optionally substituted -(CH2) p -(C3-C6)cycloalkyl, and -(CH2) p - optionally substituted heterocyclyl; R A2 are independently H, CF, halo, or (C-C) alkyl; R z are independently H, F, CF3, —OH, or (C1-C3) alkyl; R z1 are independently H or (C1-C3) alkyl; p is independently 0, 1, or 2.

[0296] In certain embodiments, R 2 is not a phenyl substituted with -OCHF2.

[0297] In certain embodiments, the compounds are 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; [5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]methanol; tert-butyl The compound is not 4-[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazine-1-carboxylate; (1R or S)-7-[6-chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-[(6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; and (1R or S)-1-phenyl-7-[6-(piperazin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0298] In certain embodiments, the compounds are 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; [5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]methanol; tert-butyl 4-[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazine-1-carboxylate; (1R or S)-7-[6-chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-[(6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; or (1R or S)-1-phenyl-7-[6-(piperazin-1-yl)pyridin-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0299] In certain embodiments, the compound of formula (2a) comprises one of the following: TIFF2025509732000095.tif47128 formula, A 2 is CH or N; A 3 is CH or N; B 1 is CH2 or O; B 2 is CH2 or O; X is C or N; Y is C or N; Z 1 is CH2 or O; Z 2 is CH2 or O.

[0300] In certain embodiments, R 3ais selected from the group consisting of: TIFF2025509732000096.tif16128

[0301] In certain embodiments, R 3b is selected from the group consisting of: TIFF2025509732000097.tif239137 In certain embodiments, R 3a or R 3b The TNF linker can be attached to the compounds of the present disclosure using the R 3a Or R 3b This can be done, for example, using any hydroxyl, amino, amide, thiyl, or carboxylic acid group present in or that can be introduced into R. In any of these cases, as known to those skilled in the art, 3a or R 3b The hydroxyl groups in R can be used to form ester bonds, for example. 3a or R 3b The carboxylic acid group in R can be used, for example, to form an ester or amide bond; 3a or R 3b The amino groups in R can be used, for example, to form amide and imine groups, and the like. 3a or R 3b The amino, amide, or thiyl groups therein can be used, for example, to form chemical bonds through alkylation or nucleophilic substitution.

[0302] In certain embodiments, R 1 is selected from the group consisting of H, methyl, and hydroxyl.

[0303] In certain embodiments, R 1 and R 2 together form one of the following: TIFF2025509732000098.tif22128

[0304] In certain embodiments, R 4 is selected from the group consisting of: TIFF2025509732000099.tif63128

[0305] In certain embodiments, the compound is selected from the group consisting of: 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 4-(3-fluorophenyl)-7-(2-morpholinopyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (R)-1-phenyl-7-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (S)-2-(2-morpholinopyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 2-(5-(1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(2-((1R,6S)-3,10-diazabicyclo[4.3.1]decan-10-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-amine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-cyclopenta[4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-(5-(8-phenyl-7,8-dihydro-6H-cyclopenta[4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-(5-(4-(2-methoxyphenyl)-3,4-dihydro-1H-pyran[3',4':4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2-(5-(8-(pyridin-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 2-(5-(1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-1,4-oxazepane; 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-4-methylpiperidin-4-ol; (4-fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; (4-fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)azepan-4-ol; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1-(5-(9-(3-fluorophenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(9-(3-fluorophenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-((R)-8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-((S)-4-(2-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(4-(3-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(4-(2-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 4-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)morpholine; (R)-7-(5-((R)-9-phenyl-8,9-dihydro-6H-pyrano[3',4':4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-7-(5-((R)-4-phenyl-3,4-dihydro-1H-pyrano[3',4':4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-1-(5-(9-(2-methoxyphenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(5-((S)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-1(5H)-one; (S)-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-2-one; (S)-2-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-3-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)oxetan-3-ol; (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)cyclobutanol; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)tetrahydro-2H-pyran-4-ol; (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2-(5-(4-(2,6-dichlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-2-(5-(4-(2-methoxyphenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)propan-2-ol; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(4-(2-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazin-4,1'-inden]-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (S)-2-hydroxy-1-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-1-ol; (R)-1-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; (S)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (R)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-4-(3-fluorophenyl)-7-(2-morpholinopyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one with ethane (1:1); 7-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)thiomorpholine 1,1-dioxide; -(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 3,3-difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-2-(5-(4-(2-(difluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 1-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one; 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 3,3-difluoro-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; 7-(4-(isopropylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; (S)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol; 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 4-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; 2-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide; 1-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(4-(ethylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (S)-7-(2-morpholinopyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-7-(2-(1,4-oxazepan-4-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine; 3,3-difluoro-1-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol; (1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-3-yl)methanol; 1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)azepan-4-ol; (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazine-1-sulfonamide; N-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzyl)methanesulfonamide; 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; 7-(4-(methylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(2-(1,4-oxazepan-4-yl)pyrimidin-5-yl)-4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide; (4-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)morpholin-2-yl)methanol; (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)thiomorpholine 1,1-dioxide; 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine; (R)-4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)morpholine; 2-(5-(1-(3-fluorophenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-(4-fluoro-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 4-(5-(9-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(2-(1'-methyl-[4,4'-bipiperidin]-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 7-(2-morpholinopyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(2-methylmorpholino)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)morpholine; Ethyl 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-2-yl]pyrimidin-2-yl]amino]acetate; (S)-7-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenyl)acetonitrile; 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one; 7-(2-cyclopropylpyrimidin-5-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-2-one; 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyridin-2-yl)oxy)acetic acid; 7-(6-(ethylsulfonyl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 4-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one; 10-(3-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperazin-2-one; (S)-6-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-6-azaspiro[3.4]octan-2-ol; N,N-dimethyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; N-ethyl-N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 7-(6-morpholinopyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)propan-2-ol; 2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-4-(2-hydroxyethyl)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-7-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-3-yl)acetic acid; 7-(5-methyl-6-morpholinopyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(2-methyl-1H-imidazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(1-cyclohexyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 2-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-(4-(methylsulfonyl)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 1-(1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)ethanol; (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-1,4-diazepan-2-one; 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenoxy)acetonitrile; (S)—N-(1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanesulfonamide; (S)-3-(1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)propanoic acid; 4-phenyl-7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)piperazin-2-one; 7-(5-fluoro-6-methoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; N,N-dimethyl-5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-amine; 7-(2-methylpyridin-4-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (4S)-4-phenyl-7-(2-(2-(trifluoromethyl)morpholino)pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-2,7-diazaspiro[4.4]nonan-1-one; N-Cyclopentyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine; 7-(2-(1H-pyrazol-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(2,6-dimethylmorpholino)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(6-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(5-ethoxypyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 2-(2-morpholinopyrimidin-5-yl)-9-(m-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 7-(6-(methylthio)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; Ethyl 2-((5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)acetate; (S)-3-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-1-yl)propan-1-ol; 9-(3-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 2-(2-morpholinopyrimidin-5-yl)-9-phenyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 4-(2,5-difluorophenyl)-7-(2-morpholinopyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-phenyl-7-(6-(piperazin-1-yl)pyridin-3-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 9-(2-Methoxyphenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; (S)-7-(2-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(1H-imidazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(furo[3,2-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(3-chlorophenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; N-ethyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenoxy)acetonitrile; 2-(2-morpholinopyrimidin-5-yl)-10-(m-tolyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 2-((5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)acetic acid; N-cyclopropyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 1-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)piperazin-1-yl)ethanone; 7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 9-(3-fluoro-2-methylphenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 8-Phenyl-2-(4-(pyrimidin-2-yl)piperazin-1-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 9-(4-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one; 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)acetic acid; 10-(4-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 9-(3-chlorophenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; N-cyclopropyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine; 9-(3-chloro-5-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; N,N-dimethyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine; 1-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid; 7-(6-Isopropoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(6-Isopropoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-(5-(6-phenyl-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-c]pyridin-3-yl)pyrimidin-2-yl)morpholine; 1-phenyl-7-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)picolinonitrile; 7-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(2-morpholinopyrimidin-5-yl)-9-(p-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-ol; 7-(6-(methylsulfonyl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; N-(2-methoxyethyl)-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 4-phenyl-7-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid; 7-(5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)thiophene-2-carboxylic acid; 7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-7-(2-(1'-methyl-[4,4'-bipiperidin]-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(2-Methoxypyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(3-chloro-5-fluorophenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 3-(2-hydroxyethyl)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidin-3-ol; 4-(5-(9-(2-methoxyphenyl)-6,7-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; 10-(4-Methoxyphenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 7-(5-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-Phenyl-7-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine; 2-(2-morpholinopyrimidin-5-yl)-10-(p-tolyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-carbonitrile; (R)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(2-((R)-3-(methylsulfonyl)pyrrolidin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-([1,2,5]oxadiazolo[3,4-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 2-(5-(6-phenyl-7,8-dihydro-6H-pyrrolo[1,2':1,2]imidazo[4,5-c]pyridin-3-yl)pyrimidin-2-yl)propan-2-ol; 7-(2-methylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-Phenyl-7-(pyrimidin-5-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(6-Methoxy-5-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(4-chlorophenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenyl)acetonitrile; N-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzyl)methanesulfonamide; 7-(6-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)propan-2-ol; (S)-7-(2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 4-phenyl-7-(6-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-8-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]decan-4-one; 7-(6-isopropoxy-5-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-H-benzo[d]pyrrolo[1,2-a]imidazole; N-methyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine; N-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)acetamide; N-ethyl-N-methyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2-amine; 7-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(3,5-dimethoxyphenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; N,N-dimethyl-3-((5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)oxy)propan-1-amine; (3R,4R)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidine-3,4-diol; N-(2-(dimethylamino)ethyl)-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 10-(3-Methoxyphenyl)-2-(2-morpholinopyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-ol; 7-(1,5-dimethyl-1H-pyrazol-4-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; N,N-dimethyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide; 7-(3-(methylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 4-phenyl-7-(pyrido[2,3-b]pyrazin-7-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-methyl-5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2(1H)-one; (3S,4S)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidine-3,4-diol; 4-phenyl-7-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 2-(2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-yl)phenol; 4-(5-(6-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:4,5-b']dipyridin-3-yl)pyrimidin-2-yl)piperazin-2-one; (S)-7-(2-(3-morpholinoazetidin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(methylsulfonyl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (R)-7-(2-morpholinopyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(2-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 1-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)azetidine-3-carboxylic acid; 7-(1-methyl-1H-pyrrol-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; or N-(2-morpholinoethyl)-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-amine.

[0306] In certain embodiments, the compound is selected from the group consisting of: 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 3,3-difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-2-(5-(4-(2-(difluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)propan-2-ol; (S)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 1-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one; 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 3,3-difluoro-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol; 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; 7-(4-(isopropylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine; 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)propan-2-ol; 2-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide; (S)-7-(2-morpholinopyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]nonan-2-ol; 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)propan-2-ol; (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)propan-2-ol; Ethyl 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-2-yl]pyrimidin-2-yl]amino]acetate; or 2-((5-(9-(2-Methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyridin-2-yl)oxy)acetic acid.

[0307] In certain embodiments, the compound is selected from the group consisting of: (8aR)-7-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol; 5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine; 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-3-ol; 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-morpholinopyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazin-4,1'-inden]-7-yl)pyrimidin-2-yl)piperidin-4-ol; (1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-3-yl)methanol; (8aS)-7-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2'-(2-(1,4-oxazepan-4-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 3,3-Difluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; 2-hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one; 2-Hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; (4-fluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 2'-(2-morpholinopyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)azepan-4-ol; (S)-2-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-ol; (R)-2-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-ol; (8aR)-7-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol; 5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine; 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-3-ol; 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-morpholinopyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazin-4,1'-inden]-7-yl)pyrimidin-2-yl)piperidin-4-ol; (1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-3-yl)methanol; (8aR)-7-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2'-(2-(1,4-oxazepan-4-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 3,3-Difluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; 2-hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one; 2-Hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; (4-fluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 2'-(2-morpholinopyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)azepan-4-ol; (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; (1r,4r)-4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol; (1s,4s)-4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol; 3-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclopentanol; 2'-(2-morpholinopyrimidin-5-yl)-6',7'-dihydrospiro[cyclohexane-1,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine]; 2'-(2-morpholinopyrimidin-5-yl)-6',7'-dihydrospiro[chroman-4,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine]; 2'-(2-(piperazin-1-yl)pyrimidin-5-yl)-6'H,8'H-spiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-Methoxypyrimidin-5-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-ethoxypyrimidin-5-yl)-6',8-dihydrospiro[chroman-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-(methylsulfonyl)pyrimidin-5-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-(1,4-diazepan-1-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)-N-isopropylpyrimidin-2-amine; 2'-(2-morpholinopyrimidin-5-yl)-6',8-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-ol; 2'-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 5-(6'H,8'H-spiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine; (8aR)-7-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-3-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)azetidin-3-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)pyrrolidin-3-ol; 3-((5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-3-methylazetidin-3-ol; 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(5,5-dimethyl-2,5-dihydro-1H-pyrrol-3-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2,5-Dihydro-1H-pyrrol-3-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-(piperazin-1-yl)pyrimidin-5-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-Methoxypyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2-(tert-butoxy)-1-((2S)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; 2-(tert-butoxy)-1-((3S)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-3-methylpiperazin-1-yl)ethanone; 2-(tert-butoxy)-1-((3R)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-3-methylpiperazin-1-yl)ethanone; 2-(tert-butoxy)-1-((2R)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; 1-((2S)-4-(5-(2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethan-1-one; 1-((3S)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-3-methylpiperazin-1-yl)-2-hydroxyethanone; 1-((3R)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-3-methylpiperazin-1-yl)-2-hydroxyethanone; 1-((2R)-4-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethanone; 2-(5-(2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-ol; 2'-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-3(2H)-one; 2'-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-6'-ol; 2'-(1-(pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 1-(4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)-5,6-dihydropyridin-1(2H)-yl)-3-methoxy-3-methylbutan-1-one; (S)-1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-7-(5-((S)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (1S,4r)-4-((4-((S)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol; 1-((S)-4-(5-((S)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethanone; 1-((R)-4-(5-((S)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethanone; 1-((R)-4-(5-((R)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethanone; 1-((S)-4-(5-((R)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethanone; 1-(5-(6',8'-dihydrospiro[isochroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; (8aR)-7-(5-(6',8'-dihydrospiro[isochroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 2'-(2-morpholinopyrimidin-5-yl)-6',8'-dihydrospiro[isochroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2-(5-(2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-amine; (S)-2-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)propan-2-amine; or 2'-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-3-ol.

[0308] In certain embodiments, the compound is selected from the group consisting of: ((R)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)pyrrolidin-2-yl)methanol; ((S)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)pyrrolidin-2-yl)methanol; (R)-1-(2-(methylsulfonyl)ethyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; (R)-1-(2-hydroxy-2-methylpropyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; 1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)ethanol; 2-cyclopropyl-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)ethanol; (5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol; 1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)ethanol; 1-cyclopropyl-2-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 1-((R)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; 1-((S)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; (1R,3R)-3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolidin-2-yl)pyridin-2-yl)oxy)cyclopentanecarbonitrile; (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; 2-(5-(8-(pyridin-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 1-((S)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; 2-hydroxy-1-((R)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; (R)-7-(5-((R)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-((R)-4-(5-((R)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; (R)-7-(5-((S)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-7-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (S)-7-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; (R)-1-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-hydroxy-1-((R)-4-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; (R)-7-(5-((S)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 1-((R)-4-(5-((R)-8-(3-(hydroxymethyl)phenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; 1-((R)-4-(5-((R)-8-(3-(hydroxymethyl)phenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)ethanone; (S)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl 2-amino-3-methylbutanoate; (R)-1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl phosphate dihydrogen salt·hydrochloride; (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclopentanol; (R)-4-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol; (R)-2-(2-(oxetan-3-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol; (R)-2-(2-(oxetan-3-ylmethoxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)ethanol; (R)-2-(2-(((S)-1-methylpyrrolidin-3-yl)oxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (1S,4s)-4-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol; (8R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-8-phenyl-2-(2-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(cyclopentyloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(cyclohexyloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-Methyl 4-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanecarboxylate; Methyl 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclopentanecarboxylate; (R)-2-(2-butoxypyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine; (1R,3R)-3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolidin-2-yl)pyridin-2-yl)oxy)cyclopentanecarbonitrile; (R)-8-phenyl-2-(2-((S)-pyrrolidin-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-8-phenyl-2-(2-(piperidin-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-8-phenyl-2-(2-((R)-pyrrolidin-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-2-(2-(6-azaspiro[3.4]octan-1-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(6-azaspiro[3.4]octan-2-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-2-(2-(6-azaspiro[3.5]nonan-1-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; (R)-1-(2-methoxyethyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one; (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2(1H)-one; 4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-(tetrahydrofuran-3-yl)pyridin-2(1H)-one; (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one; (R)-8-phenyl-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin]-2'-yl)pyridin-2-yl)oxy)cyclohexanol; (R)-1-(5-(3-fluoro-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-(2-morpholinopyrimidin-5-yl)-9-phenyl-7,9-dihydro-6H-pyran[4',3':4,5]imidazo[1,2-b]pyridazine; trans-4-((4-(4-(2-methoxyphenyl)-3,4-dihydro-2H-pyran[2',3':4,5]imidazo[1,2-a]pyridin-7-yl)pyridin-2-yl)oxy)cyclohexanol; (8aS)-7-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one; 3,3-difluoro-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-(2-(1,4-oxazepan-4-yl)pyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine; (1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-3-yl)methanol; (4-fluoro-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol; 2-hydroxy-1-(4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one; 2-Hydroxy-1-(4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-1-yl)ethanone; (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(2-methoxyethoxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-methyl-1-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)propan-2-ol; (R)-8-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (1S,4s)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexanol; (1R,4r)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[1':22',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexanol; ((1R,4r)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexyl)methanol; (R)-8-phenyl-2-(1-(pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; Methyl 2-(4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)cyclohex-3-en-1-yl)acetate; 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (R)-1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; (S)-2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (R)-2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-ol; (R)-2-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propan-2-amine; 2-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido-[3',2':4,5]imidazo[2,1-c][1,4]oxazine; or (1R,4R)-4-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol.

[0309] In certain embodiments, the compound is selected from the group consisting of: 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 9-Phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine; 4-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine; 1-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 1-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)propan-2-ol; 9-Phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine; 1-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol; 4-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine; 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)propan-2-ol; or 1-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol.

[0310] The disclosures of U.S. Patent Nos. 10,266,532 B2 and 9,856,253 B2 and U.S. Patent Application Publication Nos. 20160304517A1 and 2018 / 0179198 A1 are incorporated herein by reference in their entireties.

[0311] In certain embodiments, the TNF binder comprises a compound of formula (2c), or a pharmaceutically acceptable salt, tautomer, geometric isomer, or stereoisomer thereof: TIFF2025509732000100.tif28128In formula, X, Y, and Z are independent CR 4 or N; provided that Y and Z are not both N; A is -C(R z )2- and; E is CH2 or O and G is CH; or E is CH2 and G is CH or N; R 1 is optionally substituted aryl or optionally substituted heteroaryl; R 2 Ha-R 2a -R 2b where R 2a is an optionally substituted saturated, unsaturated, or partially saturated heterocyclyl, or an optionally substituted heteroaryl; R 2b -N(R a )(R b ), -O(R a ), optionally substituted (C1-C5) alkyl, optionally substituted (C3-C6) cycloalkyl, -(CH2) p -optionally substituted heteroaryl, or -(CH2) p -optionally substituted heterocyclyl; R a and R b are independently H, optionally substituted (C1-C5) alkyl, and —(CH2) n - optionally substituted heterocyclyl; R 4 are independently H, halo, CF, or (C-C) alkyl; R z are independently H, halo, CF, or (C-C) alkyl; n is 0 or 1; p is 0 or 1.

[0312] In certain embodiments, compounds of formula (2c) include: TIFF2025509732000101.tif27128 where G is N or CH; Z is CH or CF.

[0313] In certain embodiments of compounds of formula (2c), R 1 is selected from the group consisting of: TIFF2025509732000102.tif34128

[0314] In certain embodiments of compounds of formula (2c), R 2 is selected from the group consisting of: TIFF2025509732000103.tif61142

[0315] In certain embodiments, R 2 The TNF linker can be attached to the compounds of the present disclosure using the R 2 This can be done, for example, using any hydroxyl, amino, amide, thiyl, or carboxylic acid group present in or that can be introduced into R. In any of these cases, as known to those skilled in the art, 2 The hydroxyl groups in R can be used to form ester bonds, for example. 2 The carboxylic acid group in R can be used, for example, to form an ester or amide bond; 2 The amino groups in R can be used, for example, to form amide and imine groups, and the like. 2 The amino, amide, or thiyl groups therein can be used, for example, to form chemical bonds through alkylation or nucleophilic substitution.

[0316] In certain embodiments, the compound is selected from the group consisting of: 3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 1-(5-(3-(2-(difluoromethoxy)phenyl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-6-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 3-(2-(difluoromethoxy)phenyl)-6-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-6-(2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-6-(2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-morpholinopyrimidin-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazol-11(7H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazol-11(7H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-(1,1-dioxidothiomorpholino)pyrimidin-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazol-11(7H)-one; 3-(2-Methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 2-methyl-6-(6-(2-morpholinopyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-3-yl)benzonitrile; 6-(2-morpholinopyrimidin-5-yl)-3-phenyl-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 4-Methoxy-3-(6-(2-morpholinopyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-3-yl)benzonitrile; 2-Methoxy-3-(6-(2-morpholinopyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-3-yl)benzonitrile; 3-(1-Isopropyl-1H-pyrazol-5-yl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 2-methyl-6-(6-(2-morpholinopyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-3-yl)benzamide; rac-(1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; rac-(1R,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; rac-(1R,10bR)-1-(2-(difluoromethoxy)phenyl)-9-(2-morpholinopyrimidin-5-yl)-3,4-dihydro-1H-[1,4]oxazino[3,4-a]isoindol-6(10bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (1R)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)-4-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; (R)-6-(2-((R)-4-acetyl-2-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-6-(2-((R)-4-acetyl-3-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazol-9-one; (R)-6-(2-((R)-4-acetyl-3-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one; 9b-(2-Methoxyphenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one; or 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one.

[0317] AATM Any autoantibody targeting moiety (AATM) that binds to an autoantibody is useful within the scope of this disclosure. In certain non-limiting embodiments, the autoantibody is pathological. Any autoantibody known in the art is contemplated within the scope of this disclosure.

[0318] In certain embodiments, the AATM is any peptide and / or small molecule known in the art or described elsewhere herein that binds to FcRn.

[0319] In certain embodiments, the AATM comprises an FcRn antagonist, such as, but not limited to, rozanolixizumab (see, e.g., Kiessling, et al., 2017, Sci. Transl. Med. 9:eaan1208).

[0320] In certain embodiments, the AATM comprises an FcRn antagonist, such as, but not limited to, efgartigimod (see, e.g., Ulrichts, et al., 2018, J. Clin. Invest. 128(10):4372).

[0321] In certain embodiments, the AATM comprises 2,4-dinitrobenzene, or any derivative or analog thereof, optionally substituted on the phenyl ring. TIFF2025509732000104.tif18128

[0322] In certain embodiments, the AATM comprises the following cyclic peptide FcIII, or any reduced form thereof (e.g., any corresponding free thiol derivative thereof; see, e.g., Science 2000, 287:1279-1283): Chemical groups indicated with * are non-limiting attachment points for a linker or CON in compounds of the present disclosure. TIFF2025509732000105.tif88128, Also represented as TIFF2025509732000106.tif10128 (SEQ ID NO:139, C-terminally amidated internal cystine form).

[0323] In certain embodiments, the AATM comprises the following cyclic peptide FcIII-4C(amide), or any reduced form thereof (e.g., any corresponding free thiol derivative thereof; see, e.g., Bioconjugate Chem. 2016, 27:1569). Chemical groups indicated with * are non-limiting attachment points for a linker or CON in compounds of the present disclosure. TIFF2025509732000107.tif97128, Also represented as TIFF2025509732000108.tif13128 (SEQ ID NO:140, C-terminally amidated internal cystine form).

[0324] In certain embodiments, the AATM comprises a compound of formula (3a) or (3b): TIFF2025509732000109.tif26128In formula, R 1 each occurrence is independently F, Cl, Br, I, CN, NO2, R, OR, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, -N(R)2, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)2, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)N(R)2, -N(R)S(=O)2R, -N(R)C(=O)OR, -N(R)C(=O)R, and -N(R)C(=O)N(R)2, where each occurrence of R is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4; X 2 is a bond, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 2each occurrence is independently F, Cl, Br, I, CN, NO2, R, OR, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, -N(R)2, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)2, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)N(R)2, -N(R)S(=O)2R, -N(R)C(=O)OR, -N(R)C(=O)R, and -N(R)C(=O)N(R)2, where each occurrence of R is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; n is 0, 1, 2, 3, or 4; X 3 is a bond, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 3 is H, R, -OH, -NH2, -NHR, -C(=O)OH, or -SH, where each occurrence of R is C1-C6 alkyl or C3-C8 cycloalkyl; R 4 is cycloalkyl, including multicyclic cycloalkyl, which is optionally substituted with 1 to 4 groups independently substituted from the group consisting of F, Cl, Br, I, CN, NO, R, OR, C-C haloalkyl, C-C halocycloalkyl, C-C haloalkoxy, C-C halocycloalkoxy, -N(R), -SR, -S(=O)R, -S(=O)R, -S(=O)N(R), -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)N(R), -N(R)S(=O)R, -N(R)C(=O)OR, -N(R)C(=O)R, and -N(R)C(=O)N(R), where each occurrence of R is independently H, C-C alkyl, or C-C cycloalkyl; where AATM is R 3 through or at least one R 1 Or R 2 is linked to a linker or CON via

[0325] In certain embodiments, the AATM comprises one of the following compounds (see WO 2006 / 024175 A1): Each chemical group marked with an * indicates a non-limiting attachment position of a linker or CON in the compounds of the present disclosure. TIFF2025509732000110.tif141128

[0326] In certain embodiments, the AATM comprises the following compound: The chemical bonds shown in TIFF2025509732000111.tif2128 represent non-limiting attachment positions of the linker or CON in the compounds of the present disclosure (see Chemistry & Biology 18:1179-1188). TIFF2025509732000112.tif19128In formula, R 1 each occurrence is independently F, Cl, Br, I, CN, NO2, R, OR, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, -N(R)2, -SR, -S(=O)R, -S(=O)2R, -S(=O)2N(R)2, -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)N(R)2, -N(R)S(=O)2R, -N(R)C(=O)OR, -N(R)C(=O)R, and -N(R)C(=O)N(R)2, where each occurrence of R is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4; R 2 is independently H, F, Cl, Br, I, CN, NO, R, OR, C-C haloalkyl, C-C halocycloalkyl, C-C haloalkoxy, C-C halocycloalkoxy, -N(R), -SR, -S(=O)R, -S(=O)R, -S(=O)N(R), -C(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)N(R), -N(R)S(=O)R, -N(R)C(=O)OR, -N(R)C(=O)R, and -N(R)C(=O)N(R), where each occurrence of R is independently H, C-C alkyl, or C-C cycloalkyl.

[0327] The disclosures of U.S. Patent No. 9,879,016 B2 and U.S. Patent Application Publication No. 2016 / 0304526 A1 are incorporated herein by reference in their entireties.

[0328] Additional galactose- and talose-based ASGPR binding moieties In certain aspects, the present disclosure relates to compounds of the general chemical structure of Formula II that are useful for clearing circulating proteins associated with a disease state or condition in a patient or subject. TIFF2025509732000113.tif10128 Formula II

[0329] As used herein, the term "extracellular protein targeting ligand" is used interchangeably with the term CPBM (cellular protein binding moiety). As used herein, the term "ASGPR ligand" is used interchangeably with asialoglycoprotein receptor (ASGPR) binding moiety, as defined herein.

[0330] In compounds of Formula II, each [CON] is an optional connector chemical moiety, which, if present, is either directly connected to a [CPBM] or a [CRBM] or connects a [Linker-2] to a [CPBM] or a [CRBM].

[0331] In the compound of formula II, [Linker-2] is a chemical moiety having a valence of 1 to 15 that is covalently bonded to one or more [CRBM] and / or [CPBM] groups through a [CON] that optionally contains a [MULTICON] group, where the [Linker-2] itself optionally contains one or more [CON] or [MULTICON] groups; k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer of 0 to 15; i L is an integer between 0 and 15, However, h, h', and i L at least one of is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0332] A [MULTICON] group can connect one or more [CRBM]s or [CPBM]s to one or more [Linker-2]s. In various embodiments, [Linker-2] has a valence of 1-10. In various embodiments, [Linker-2] has a valence of 1-5. In various embodiments, [Linker-2] has a valence of 1, 2, or 3. In various embodiments, in compounds of Formula II, [Linker-2] can be one or more linkers as defined herein. A , linker B , linker C , linker D , and / or combinations thereof.

[0333] In compounds of Formula II, xx is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0334] In compounds of Formula II, yy is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0335] In compounds of Formula II, zz is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0336] In the compound of formula II, X 1 is O, S, N(R b ), and C(R 4 )(R 4 ) 1 to 5 adjacent atoms independently selected from 1If is one atom, then X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 If there are two atoms, then X 1 Not more than one atom of 6 ) and X 1 If X is 3, 4, or 5 atoms, 1 Up to two atoms of 6 ) and; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 More selected; R 4 independently at each occurrence, hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 More selected; R 6 and R 7 independently at each occurrence, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; R 8 and R 9is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0337] A. Galactose-Based ASGPR-Binding Cellular Receptor Binding Moieties of Formula II In certain embodiments, the compound of formula II is TIFF2025509732000114.tif65128TIFF2025509732000115.tif211114TIFF20255 09732000116.tif205113TIFF2025509732000117.tif198108TIFF2025509732000 118.tif204108TIFF2025509732000119.tif143128TIFF2025509732000120.tif2 14112TIFF2025509732000121.tif95128TIFF2025509732000122.tif132128TIFF2 Selected from 025509732000123.tif137128TIFF2025509732000124.tif150128TIFF2025509732000125.tif162129TIFF2025509732000126.tif148128TIFF2025509732000127.tif161132TIFF2025509732000128.tif196109TIFF2025509732000129.tif171128TIFF2025509732000130.tif169128TIFF2025509732000131.tif126128

[0338] In certain embodiments, the compound of formula II has the following structure: I have one of the following: TIFF2025509732000132.tif117128.

[0339] In various embodiments, the ASGPR ligand is degraded to form a C 1 or C 5 (R 1 or R 5In various embodiments, the ASGPR ligand is linked at the C 6 For example, the ASGPR ligand is TIFF2025509732000133.tif17128, non-limiting examples of ASGPR binding compounds of Formula II include TIFF2025509732000134.tif51128, or a di- or tri-substituted version thereof, or a pharmaceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives bound to the linker moiety.

[0340] In any of the embodiments herein in which an ASGPR ligand is selected for use in a degrading agent, the ASGPR ligand is typically linked to a C 5 is linked to an extracellular protein targeting ligand at position (e.g., the linker is 6 (This may refer to a carbon hydroxyl or other functional moiety that can be used for linking purposes.) The linker and the extracellular protein targeting ligand are C 1 When attached through a position, the carbon in question is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group.

[0341] In various embodiments, the ASGPR ligand is C 3 Also in C 4 In certain embodiments, ASGPR ligands useful for incorporation into compounds of Formula II are: TIFF2025509732000135.tif68128TIFF2025509732000136.tif134128TIFF2025509732000137.tif200122TI FF2025509732000138.tif217124TIFF2025509732000139.tif213127TIFF2025509732000140.tif154128TIFF Selected from 2025509732000141.tif181128TIFF2025509732000142.tif175128TIFF2025509732000143.tif146132TIFF2025509732000144.tif156128TIFF2025509732000145.tif158131TIFF2025509732000146.tif132128

[0342] In certain embodiments, the compound of formula II is Selected from TIFF2025509732000147.tif191130TIFF2025509732000148.tif91129TIFF2025509732000149.tif190128TIFF2025509732000150.tif122128

[0343] B. Talos-based ASGPR-binding cell receptor binding moieties of Formula II In certain embodiments, the compound of formula II is TIFF2025509732000151.tif68128TIFF2025509732000152.tif189128TIFF2025509732000153.tif170128TIFF2025509732000154.tif182128TIFF2025509732000155.tif183128TIFF2025509732000156.tif146128TIFF2025509732000157.tif185128TIFF2025509732000158.tif190128TIFF2025509732000159.tif215112TIFF2025509732000160.tif156128TIFF2025509732000161.tif202109TIFF2025509732000162.tif161128TIFF2025509732000163.tif99128TIFF2025509732000164.tif134129TIFF2025509732000165.tif137129TIFF2025509732000166.tif201136TIFF2025509732000167.tif101128TIFF2025509732000168.tif216133TIFF2025509732000169.tif213129TIFF2025509732000170.tif22695TIFF2025509732000171.tif209116TIFF2025509732000172.tif212139TIFF2025509732000173.tif182128TIFF2025509732000174.tif194125TIFF2025509732000175.tif177128TIFF2025509732000176.tif223119TIFF2025509732000177.tif128128TIFF2025509732000178.tif167128TIFF2025509732000179.tif168128TIFF2025509732000180.tif198105TIFF2025509732000181.tif210104TIFF2025509732000182.tif128128TIFF2025509732000183.Selected from tif157128TIFF2025509732000184.tif157128TIFF2025509732000185.tif169128TIFF2025509732000186.tif148128TIFF2025509732000187.tif146128TIFF2025509732000188.tif69128.

[0344] In certain embodiments, the compound of formula II is an extracellular proteolytic compound, wherein the ASGPR ligand is a ligand described herein. TIFF2025509732000189.tif51128

[0345] In certain embodiments, in the compound of formula II, the ASGPR ligand is at C1 or C5 (R 1 or R 5 In certain embodiments, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is TIFF2025509732000190.tif17128, non-limiting examples of ASGPR binding compounds of Formula II include TIFF2025509732000191.tif110128, or a di- or tri-substituted version thereof, or a pharmaceutically acceptable salt thereof, wherein di- or tri-substituted refers to the number of additional galactose derivatives attached to the linker moiety. In certain embodiments, the compound of Formula II is TIFF2025509732000192.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0346] In certain embodiments, the compound of formula II is TIFF2025509732000193.tif141128TIFF2025509732000194.tif147128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0347] In certain embodiments, the compound of formula II is TIFF2025509732000195.tif140128TIFF2025509732000196.tif147128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0348] In certain embodiments, the compound of formula II is TIFF2025509732000197.tif140128TIFF2025509732000198.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0349] In certain embodiments, the compound of formula II is TIFF2025509732000199.tif142128TIFF2025509732000200.tif147128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0350] In certain embodiments, the compound of formula II is TIFF2025509732000201.tif141128TIFF2025509732000202.tif148128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0351] In certain embodiments, the compound of formula II is TIFF2025509732000203.tif141128TIFF2025509732000204.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0352] In certain embodiments, the compound of formula II is TIFF2025509732000205.tif141128TIFF2025509732000206.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0353] In certain embodiments, the compound of formula II is TIFF2025509732000207.tif154128TIFF2025509732000208.tif147128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0354] In certain embodiments, the compound of formula II is TIFF2025509732000209.tif155128TIFF2025509732000210.tif146128TIFF2025509732000211.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0355] In certain embodiments, the compound of formula II is TIFF2025509732000212.tif154128TIFF2025509732000213.tif148128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0356] In certain embodiments, the compound of formula II is TIFF2025509732000214.tif154128TIFF2025509732000215.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0357] In certain embodiments, the compound of formula II is TIFF2025509732000216.tif154128TIFF2025509732000217.tif147128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0358] In certain embodiments, the compound of formula II is TIFF2025509732000218.tif153128TIFF2025509732000219.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), and R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0359] In certain embodiments, the compound of formula II is TIFF2025509732000220.tif154128TIFF2025509732000221.tif165128TIFF2025509732000222.tif 202128TIFF2025509732000223.tif202112TIFF2025509732000224.tif199128TIFF20255097320002 Selected from 25.tif165128TIFF2025509732000226.tif201113TIFF2025509732000227.tif202113TIFF2025509732000228.tif203113TIFF2025509732000229.tif196132TIFF2025509732000230.tif72128

[0360] In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are TIFF2025509732000231.tif62128TIFF2025509732000232.tif152128TIFF2025509732000233.tif114128TIFF202550 9732000234.tif158128TIFF2025509732000235.tif134128TIFF2025509732000236.tif163128TIFF202550973200023 Selected from 7.tif140129TIFF2025509732000238.tif192107TIFF2025509732000239.tif190130TIFF2025509732000240.tif217126TIFF2025509732000241.tif63128TIFF2025509732000242.tif156128TIFF2025509732000243.tif199126

[0361] C. ASGPR Ligand / Binding Moieties in Compounds of Formula II In certain embodiments, in the compound of formula II, R 1 is hydrogen.

[0362] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509732000244.tif6128.

[0363] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509732000245.tif6128.

[0364] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509732000246.tif5128.

[0365] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509732000247.tif6128.

[0366] In certain embodiments, in the compound of formula II, R 1 teeth TIFF2025509732000248.tif5128.

[0367] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509732000249.tif6128.

[0368] In certain embodiments, in the compound of formula II, R 1 is a C0-C6 alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.

[0369] In certain embodiments, in the compound of formula II, R 1 is alkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0370] In certain embodiments, in the compound of formula II, R 1 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in compounds of formula II, R 1 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in compounds of formula II, R 1 is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in compounds of formula II, R 1 is F.

[0371] In certain embodiments, in the compound of formula II, R 1 is Cl.

[0372] In certain embodiments, in the compound of formula II, R 1 is Br.

[0373] In certain embodiments, in the compound of formula II, R1 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0374] In certain embodiments, in the compound of formula II, R 1 is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0375] In certain embodiments, in the compound of formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0376] In certain embodiments, in the compound of formula II, R 1 is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0377] In certain embodiments, in the compound of formula II, R 1 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0378] In certain embodiments, in the compound of formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0379] In certain embodiments, in the compound of formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.

[0380] In certain embodiments, in the compound of formula II, R 1 -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6 , C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R3 , 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, or C0-C6 alkyl-OS(O)2R 3 each of which may be substituted with 1, 2, 3, or 4 substituents.

[0381] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0382] In certain embodiments, in the compound of formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0383] In certain embodiments, in the compound of formula II, R 2 is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, 3, or 4 substituents.

[0384] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000250.tif37128.

[0385] In certain embodiments, in the compound of formula II, R2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0386] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 -S(O)-R 3 is.

[0387] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 -C(S)-R 3 is.

[0388] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 -S(O)(NR 6 )-R 3 is.

[0389] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents -N=S(O)(R 3 )2.

[0390] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 C(O)NR 9 S(O)2R 3 is.

[0391] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 -S(O)2-R 10 is.

[0392] In certain embodiments, in the compound of formula II, R2 is optionally substituted with 1, 2, 3, or 4 substituents; 8 -C(NR 6 )-R 3 is.

[0393] In certain embodiments, in the compound of formula II, R 2 is hydrogen.

[0394] In certain embodiments, in the compound of formula II, R 2 is R 10 is.

[0395] In certain embodiments, in the compound of formula II, R 2 is alkyl-C(O)-R 3 is.

[0396] In certain embodiments, in the compound of formula II, R 2 -C(O)-R 3 is.

[0397] In certain embodiments, in the compound of formula II, R 2 is alkyl.

[0398] In certain embodiments, in the compound of formula II, R 2 is haloalkyl.

[0399] In certain embodiments, in the compound of formula II, R 2 Ha-OC(O)R 3 is.

[0400] In certain embodiments, in the compound of formula II, R 2 Ha-NR 8 -C(O)R 10 is.

[0401] In certain embodiments, in the compound of formula II, R 2 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0402] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0403] In certain embodiments, in the compound of formula II, R 2 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0404] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 6 -alkenyl.

[0405] In certain embodiments, in the compound of formula II, R 2 is -O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0406] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 6 -alkynyl.

[0407] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 6 -heteroaryl.

[0408] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with 1, 2, 3, or 4 substituents; 6 -aryl.

[0409] In certain embodiments, in the compound of formula II, R 2 is -O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0410] In certain embodiments, in the compound of formula II, R2 is -O-aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0411] In certain embodiments, in the compound of formula II, R 2 is -O-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0412] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000251.tif11128.

[0413] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000252.tif17128.

[0414] In certain embodiments, in the compound of formula II, R 2 teeth TIFF2025509732000253.tif99128, where R is an optional substituent as defined herein.

[0415] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000254.tif42128.

[0416] In certain embodiments, in the compound of formula II, R 2A teeth TIFF2025509732000255.tif100128, where R is an optional substituent as defined herein.

[0417] In certain embodiments, in the compound of formula II, R 2A teeth Selected from TIFF2025509732000256.tif42128.

[0418] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000257.tif140128.

[0419] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000258.tif134137.

[0420] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000259.tif8128.

[0421] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000260.tif8128.

[0422] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000261.tif37128.

[0423] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000262.tif39128.

[0424] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000263.tif19128.

[0425] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000264.tif14128.

[0426] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000265.tif42128.

[0427] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000266.tif42128.

[0428] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000267.tif11128.

[0429] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000268.tif12128.

[0430] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000269.tif39128.

[0431] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000270.tif36128.

[0432] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000271.tif59128.

[0433] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000272.tif58128.

[0434] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000273.tif32128.

[0435] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000274.tif33128.

[0436] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000275.tif70128.

[0437] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000276.tif69128.

[0438] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000277.tif22128.

[0439] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000278.tif22128.

[0440] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000279.tif22128.

[0441] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000280.tif23128.

[0442] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000281.tif19128.

[0443] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000282.tif18128.

[0444] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000283.tif20128.

[0445] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000284.tif20128.

[0446] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000285.tif91128.

[0447] In certain embodiments, in the compound of formula II, R 2 or R 2A teeth Selected from TIFF2025509732000286.tif95128.

[0448] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000287.tif26128.

[0449] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000288.tif26128.

[0450] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000289.tif9128.

[0451] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509732000290.tif9128.

[0452] In certain embodiments, in the compound of formula II, R 2 is selected from .

[0453] In certain embodiments, in the compound of formula II, R 2 is a spirocyclic heterocycle, e.g. TIFF2025509732000291.tif12128, but not limited to it.

[0454] In certain embodiments, in the compound of formula II, R 2 is a silicon-containing heterocycle, such as TIFF2025509732000292.tif13128, but not limited to it.

[0455] In certain embodiments, in the compound of formula II, R 2 is replaced by SF5, e.g. TIFF2025509732000293.tif21128, but not limited to it.

[0456] In certain embodiments, in the compound of formula II, R 2 is substituted with sulfoxime, e.g. TIFF2025509732000294.tif21128, but not limited to it.

[0457] In certain embodiments, in the compound of formula II, R 10 is selected from bicyclic heterocycles.

[0458] In certain embodiments, in the compound of formula II, R 10 is selected from spirocyclic heterocycles.

[0459] In certain embodiments, in the compound of formula II, R 10 Ha-NR 6 -heterocycles.

[0460] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509732000295.tif12128.

[0461] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509732000296.tif39128.

[0462] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509732000297.tif18128.

[0463] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509732000298.tif30128.

[0464] In certain embodiments, in compounds of formula II, the ring is Selected from TIFF2025509732000299.tif126128.

[0465] In certain embodiments, in the compound of formula II, R 30 teeth Selected from TIFF2025509732000300.tif31128.

[0466] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000301.tif13128.

[0467] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000302.tif11128.

[0468] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000303.tif14128.

[0469] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000304.tif11128.

[0470] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000305.tif14128.

[0471] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000306.tif14128.

[0472] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000307.tif13128.

[0473] In certain embodiments, in the compound of formula II, R 200 teeth TIFF2025509732000308.tif13128.

[0474] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000309.tif11128.

[0475] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000310.tif12128.

[0476] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000311.tif11128.

[0477] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509732000312.tif11128.

[0478] Linker In a non-limiting embodiment, in the compound of Formula II, the linker A and linker B is independent Selected from TIFF2025509732000313.tif10128, wherein: R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 independently at 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, and 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 R 21 optionally substituted with 1, 2, 3, or 4 further independently selected substituents; n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 independently at each occurrence, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R ...

Claims

1. Compounds selected from the following group, or their salts, geometric isomers, stereoisomers, or solvates: [Protein Binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, A protein binder is a molecule that binds to an extracellular protein or autoantibody; optionally, the extracellular protein is TNF; CRBM is a cell receptor-binding portion that binds to at least one receptor on the surface of a degradable cell in question, and the binding of (I) by it leads to endocytosis and degradation of extracellular proteins; Each CON is either independently linked or is a group that covalently links the protein binder to the CRBM, the protein binder to the linker, and / or the linker to the CRBM; A linker is a group having a valency in the range of 1 to 15; k' is an integer in the range of 1 to 15; h is an integer in the range of 0 to 15; i is an integer in the range of 0 to 15; h' is an integer in the range of 0 to 15; j is an integer in the range of 1 to 15; Here, the compound Selected from the group consisting of, in the formula, Extracellular protein targeting ligands are molecules that bind to extracellular proteins or autoantibodies; X 1 is one to five groups independently selected from O, S, N(R 6 ), and C(R 4 )(R 4 ), where when X 1 is one group, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ), and when X 1 is two groups, one or fewer groups of X 1 are O, S, or N(R 6 ), and when X 1 is three, four, or five groups, two or fewer groups of X 1 are O, S, or N(R 6 ); R 2 teeth (i) Heteroaryls comprising an aryl, a heterocyclic, and one or two heteroatoms independently selected from N, O, and S, where each of the aryl, heterocyclic, and heteroaryl may be substituted with one, two, three, or four substituents; (ii) ; (iii) Each may be substituted with one, two, three, or four substituents, -NR 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 ) 2 , -NR 8 C(O)NR 9 S(O) 2 R 3 , -NR 8 -S(O) 2 -R 10 , and -NR 8 -C(NR 6 )-R 3 ; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 More selected; R 10 These are aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 Alkyl-NR 6 R 8 , NR 8 -NR 6 -C(O)R 3 , NR 8 -S(O) 2 R 3 , alkenyl, allyl, alkinyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, R 10 Each of these may be substituted with one, two, three, or four substituents; R 1 and R 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, -O-alkenyl, -O-alkynyl, 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-OC(S)R 3 -N=S(O)(R 3 ) 2 , C 0 ~C 6 Alkyl N 3 , and C 0 ~C 6 Alkyl-OS(O) 2 R 3 More selections may be made, each of which may be substituted with one, two, three, or four substituents; R 3 Each instance independently produces hydrogen, alkyl, heteroalkyl, and haloalkyl (-CF) 3 , -CHF 2 ,-CH 2 F, -CH 2 CF 3 ,-CH 2 CH 2 F and -CF 2 CF 3 (including), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 8 , and -NR 8 R 9 More selected; R 4 Independently, each occurrence is hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 6 and R 7 Each of these independently appears as hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 8 and R 9 Each element is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic elements at each occurrence; The ring is a 3- to 8-membered fused cyclic group which may be substituted with one, two, three, or four substituents; Each linker A Is it binding, or linking the ASGPR ligand? B It is the part that is covalently connected to it; Linker B is a linker or a combination. A This is the portion that covalently links to an extracellular protein targeting ligand; Linker C Each linker A It is a chemical group that links to an extracellular protein targeting ligand; Linker D Each linker A It is a chemical group that links to an extracellular protein targeting ligand; Here, R 2 NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O) 2 -Alkenyl, -NR 8 -S(O) 2 -alkynyl, -NR 6 -heteroaryl, or -NR 6 - If it is an aryl ligand, the extracellular protein targeting ligand does not contain an oligonucleotide; The optional substituents can be alkyl, alkenyl, alkynyl, haloalkyl, or -OR, as long as their valence is acceptable, to obtain a stable compound. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , More likely to be selected.

2. A compound according to claim 1, selected from the group consisting of

2. .

3. A compound according to claim 1, selected from the group consisting of

3. .

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

5. R 2 R 10 The compound according to claim 1.

6. R 10 ga-NR 6 - The compound according to claim 1, wherein it is a heteroaryl compound.

7. R 6 The compound according to claim 1, wherein is H.

8. -NR 6 -heteroaryl A compound according to claim 1, selected from the group consisting of the following.

9. The bifunctional compound according to claim 1, wherein the extracellular protein targeting ligand is a TNF-binding moiety.

10. The compound according to claim 1, wherein the extracellular protein targeting ligand is an autoantibody.

11. Linker A but A compound according to claim 1, selected from the group consisting of the following.

12. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound according to any one of claims 1 to 11.

13. The pharmaceutical composition according to claim 12, further comprising another therapeutically active agent for treating, relieving, and / or preventing a disease or disorder.

14. A pharmaceutical composition for treating, relieving, and / or preventing a disease or disorder in a subject, comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 11.

15. The pharmaceutical composition according to claim 14, wherein the disease or disorder comprises an autoimmune disease, cancer, and / or inflammation.

16. Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, and essential mixed cryoplasmosis. Globulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult Still's disease, ankylosing spondylitis, Crest syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, Undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia dysthesia, multiple sclerosis, pattern II, Oshtoran syndrome, childhood autoimmune streptococcal neuropsychiatric disorders (PANDAS), Inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mollen's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),The pharmaceutical composition according to claim 15, which is IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum.

17. The pharmaceutical composition according to claim 15, wherein the cancer is prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, or lymphoma.

18. The pharmaceutical composition according to claim 15, wherein the inflammation is an inflammatory neurodegenerative disease, an immunocompromised immune response disease that causes inflammation, a chronic inflammatory disease, hyperglycemic disorder, diabetes mellitus (type 1 and type 2), pancreatic β-cell death and associated hyperglycemic disorder, liver disease, kidney disease, cardiovascular disease, muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis.

19. The pharmaceutical composition according to claim 14, administered to a subject in combination with at least one additional therapeutic agent for treating, relieving, and / or preventing the aforementioned disease or disorder.

20. The pharmaceutical composition according to claim 14, wherein the target is a mammal.

21. The pharmaceutical composition according to claim 14, wherein the target is human.

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