Targeted bifunctional decomposition agent

Abstract

In one aspect, the present invention provides bifunctional compounds that can be used to promote or enhance the degradation of specific circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance the degradation of specific autoantibodies. In certain embodiments, the treatment or management of a disease and / or disorder requires the degradation, removal, or reduction of 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. TIFF2022551868000300.tif122170

Description

[Technical Field]

[0001] Description of research or development sponsored by the federal government. This invention was made possible with government support under GM067543, awarded by the National Institutes of Health, and W81XWH-13-1-0062, awarded by the Army Medical Research and Supplies Command. The government has certain rights in this invention.

[0002] Cross-reference of related applications This application claims priority under § 119(e) of U.S. Patent Act to U.S. Provisional Patent Application No. 62 / 913,665, U.S. Provisional Patent Application No. 62 / 913,668, and U.S. Provisional Patent Application No. 62 / 913,683, filed October 10, 2019, all of which are incorporated herein by reference in their entirety. [Background technology]

[0003] Background of Disclosure One mechanism that controls the transport of molecules into cells is receptor-mediated endocytosis. In this process, receptors on the cell surface bind to specific ligands (or molecules containing such ligands) located outside the cell. These ligands can be small molecules, metabolites, hormones, proteins, or even viruses. This binding process induces inward budding (invagination) of the plasma membrane, forming vesicles containing the receptor-ligand complex. These vesicles become endosomes, which then fuse with lysosomes, where the receptor is degraded along with its bound ligand cargo, or the receptor is recirculated to the cell surface for further collection of circulating ligands.

[0004] One such receptor is the asialoglycoprotein receptor (ASGPR). This receptor is a type C lectin whose primary biological role is to bind to glycoproteins (asialoglycoproteins) containing terminal galactose or N-acetylgalactosamine residues, internalize them, and subsequently remove them from circulation. ASGPR removes target glycoproteins from circulation through endocytosis and subsequent lysosomal degradation. ASGPR is highly expressed on the surface of hepatocytes, several human cancer cell lines, and liver cancer cells, and is lowly expressed by gallbladder and gastric glandular cells. These receptors are known to be involved in the removal of IgG subtypes and other antibody isotypes from circulation, removal of apoptotic cells, removal of low-density lipoprotein (LDL) and chylomicron remnants, and disposal of cellular fibronectin.

[0005] Tumor necrosis factor (TNF, also known as tumor necrosis factor α or TNFα) is a cell signaling protein (cytokine) involved in acute 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. A major role of TNF is the regulation of immune cells. TNF is an endogenous pyrogen that can induce fever, apoptosis, cachexia, and inflammation, while simultaneously inhibiting tumorigenesis and viral replication, and responding to sepsis by IL-1 and IL-6 producing cells. Dysregulation of TNF production is associated with diseases including, but not limited to, Alzheimer's disease, cancer, major depressive disorder, psoriasis, and inflammatory bowel disease (IBD).

[0006] Autoantibodies are antibodies produced by the immune system that react with one or more proteins of the target organism itself. Sometimes, the immune system stops recognizing one or more normal components of the body as "self," leading to 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.

[0007] Pathological autoantibodies may target specific organs or are essentially systemic. 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), childhood autoimmune streptococcal infection-associated neuropsychiatric disorders, and Sydenham's chorea.

[0008] Removal of disease-related autoantibodies has been shown to reduce symptoms and improve clinical outcomes. Currently, strategies for reducing antibody titers include plasmapheresis, in which the patient's plasma is separated extracorporeally from whole blood by centrifugation / filtration and replaced with plasma from a healthy donor or albumin; and intravenous immunoglobulin therapy (IVIG), in which antibodies are pooled from donor human plasma and injected intravenously into the patient. These approaches have limitations and drawbacks. Challenges of plasmapheresis 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).

[0009] There is a need in the art for novel compounds and methods that enable the inhibition, removal, and / or degradation of TNF in order to treat, ameliorate, and / or prevent specific diseases and / or disorders in a subject. There is a need in the art for novel compounds and methods that enable the inhibition, removal, and / or degradation of specific extracellular proteins in order to treat, ameliorate, and / or prevent specific diseases and / or disorders in a subject. There is a need in the art for novel compounds and methods that enable the inhibition, removal, and / or degradation of specific autoantibodies that mediate specific diseases and / or disorders in a subject. This disclosure addresses these needs. SUMMARY OF THE INVENTION

[0010] BRIEF SUMMARY OF THE DISCLOSURE This disclosure provides a compound of formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Protein binder] i , k' , ,

[0012] , j' , , , h' , h , , , ,

[0011] -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) Wherein the protein binder, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0011] This disclosure further provides a compound of formula (II), or a salt, geometric isomer, stereoisomer, or solvate thereof: [TNF binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (II) Wherein the TNF binder, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0012] This disclosure further provides compounds comprising formula (III), or salts thereof, geometric isomers, stereoisomers, or solvates thereof: [AATM] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (III) In the formula, AATM, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere in this specification.

[0013] This disclosure further provides a pharmaceutical composition comprising at least one compound as envisioned herein and at least one pharmaceutically acceptable excipient.

[0014] This disclosure further provides a method for treating a disease or disorder in a subject, comprising the step of administering a therapeutically effective amount of at least one compound as defined herein. [Brief explanation of the drawing]

[0015] The drawings illustrate, in general terms and not as an limitation, various aspects of this application.

[0016] As used herein, the term “REAG” means 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, REAG reacts with a TNF binder group to incorporate a TNF binder into one of the compounds of the Disclosure, or fragments thereof, derivatives thereof, or intermediates thereof. In certain embodiments, REAG reacts with a protein binder group to incorporate a protein binder into one of the compounds of the Disclosure, or fragments thereof, derivatives thereof, or intermediates thereof. In certain embodiments, REAG reacts with an AATM group to incorporate an AATM into one of the compounds of the Disclosure, or fragments thereof, derivatives thereof, or intermediates thereof. In certain embodiments, the symbol TIFF0007842459000001.tif2128 indicates non-restrictive positions where REAG and / or protein binders and / or AATM can covalently bind.

[0017] [Figure 1] This document describes non-limiting preparations of the compounds of this disclosure, including folate receptor binders. [Figure 2] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 3] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 4] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 5] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 6] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 7] This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 8]This document describes non-limiting preparations of the compounds of this disclosure, including mannose receptor binders. [Figure 9] This demonstrates the non-limiting preparation of polymer compounds containing a mannose-6-phosphate receptor binder. [Figure 10] This shows non-restrictive examples of R1 and / or R3 groups in ASGPRBM. [Figure 11] This shows a non-restrictive example of the R2 group in ASGPRBM. [Figure 12] Non-limiting synthesis of the compounds of this disclosure is shown. [Figure 13] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 14] Non-limiting synthesis of the compounds of this disclosure is shown. [Figure 15] Non-limiting synthesis of the compounds of this disclosure is shown. [Figure 16] Non-limiting synthesis of the compounds of this disclosure is shown. [Figure 17] Non-limiting synthesis of the compounds of this disclosure is shown. [Figure 18] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 19] This document presents non-limiting synthesis of intermediates useful for preparing specific compounds of the present disclosure, such as but not limited to formula (2a). [Figure 20] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 21] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 22] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 23] This document describes the non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and the coupling thereof with REAG to produce the compounds of this disclosure. [Figure 24A] Figures 24A and 24B show non-restrictive synthesis of the ASGRBM group. [Figure 24B] See the explanation in Figure 24A. [Figure 25A] Figures 25A–25D show non-restrictive synthesis of a specific ASGRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 25B] See the explanation in Figure 25A. [Figure 25C] See the explanation in Figure 25A. [Figure 25D] See the explanation in Figure 25A. [Figure 26A] Figures 26A to 26L show non-restrictive synthesis of a specific ASGRBM group. This example discloses non-restrictive Cbz protecting groups, but synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 26B] See the explanation in Figure 26A. [Figure 26C] See the explanation in Figure 26A. [Figure 26D] See the explanation in Figure 26A. [Figure 26E] See the explanation in Figure 26A. [Figure 26F] See the explanation in Figure 26A. [Figure 26G] See the explanation in Figure 26A. [Figure 26H] See the explanation in Figure 26A. [Figure 26I] See the explanation in Figure 26A. [Figure 26J] See the explanation in Figure 26A. [Figure 26K]See the explanation in Figure 26A. [Figure 26L] See the explanation in Figure 26A. [Figure 27A] Figures 27A–27O show non-restrictive synthesis of specific ASGPRBM groups. While this example discloses non-restrictive Cbz protecting groups, synthesis may be carried out using any other suitable protecting groups known to those skilled in the art. Protecting groups in each intermediate and / or final product can be deprotected as appropriate. [Figure 27B] See the explanation in Figure 27A. [Figure 27C] See the explanation in Figure 27A. [Figure 27D] See the explanation in Figure 27A. [Figure 27E] See the explanation in Figure 27A. [Figure 27F] See the explanation in Figure 27A. [Figure 27G] See the explanation in Figure 27A. [Figure 27H] See the explanation in Figure 27A. [Figure 27I] See the explanation in Figure 27A. [Figure 27J] See the explanation in Figure 27A. [Figure 27K] See the explanation in Figure 27A. [Figure 27L] See the explanation in Figure 27A. [Figure 27M] See the explanation in Figure 27A. [Figure 27N] See the explanation in Figure 27A. [Figure 27O] See the explanation in Figure 27A. [Figure 28A] Figures 28A and 28B show non-limiting compounds of this disclosure containing a PCSK9 binder and their preparations. [Figure 28B] See the explanation in Figure 28A. [Figure 29] This disclosure shows non-limiting compounds containing PCSK9 binder and their preparations. [Figure 30]This disclosure shows non-limiting compounds containing PCSK9 binder and their preparations. [Figure 31] This disclosure shows non-limiting compounds containing PCSK9 binder and their preparations. [Figure 32] This disclosure shows non-limiting compounds containing a VEGF binder and their preparations. [Figure 33] This disclosure shows non-limiting compounds containing a VEGF binder and their preparations. [Figure 34] This disclosure shows non-limiting compounds containing a TGF-β binder and their preparations. [Figure 35] This disclosure shows non-limiting compounds containing a TGF-β binder and their preparations. [Figure 36] This disclosure shows non-limiting compounds containing a TSP-1 binder and their preparations. [Figure 37A] Figures 37A to 38B show non-limiting compounds of this disclosure containing a soluble uPAR binder and their preparations. [Figure 37B] See the explanation in Figure 37A. [Figure 38A] Figures 38A and 38B show non-limiting compounds of this disclosure containing a PSMA binder and their preparations. [Figure 38B] See the explanation in Figure 38A. [Figure 39A] Figures 39A and 39B show non-limiting compounds of this disclosure containing an IL-2 binder and their preparations. [Figure 39B] See the explanation in Figure 39A. [Figure 40A] Figures 40A and 40B show non-limiting compounds of this disclosure containing a GP120 binder and their preparations. [Figure 40B] See the explanation in Figure 40A. [Figure 41] This disclosure shows non-limiting compounds containing GP120 binder and their preparations. [Figure 42] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 43]This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 44] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 45] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 46] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 47] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 48] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 49] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 50] This document describes non-limiting preparations of the compounds of this disclosure, including MIF binders. [Figure 51A] Figures 51A and 51B show non-restrictive PCSK9 ligands and their exemplary synthesis. [Figure 51B] See the explanation in Figure 51A. [Figure 52A] Figures 52A and 52B show non-restrictive PCSK9 ligands and their exemplary synthesis. [Figure 52B] See the explanation in Figure 52A. [Figure 53] Figures 53A and 53B show non-restrictive PCSK9 ligands and their exemplary synthesis. [Figure 54] This document describes non-restrictive PCSK9 ligands and their exemplary synthesis. [Figure 55A] Figures 55A–55N show non-limiting synthesis of specific ASGRBM groups and / or compounds of the present disclosure using an 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 the explanation in Figure 55A. [Figure 55C] See the explanation in Figure 55A. [Figure 55D] See the explanation in Figure 55A. [Figure 55E] See the explanation in Figure 55A. [Figure 55F] See the explanation in Figure 55A. [Figure 55G] See the explanation in Figure 55A. [Figure 55H] See the explanation in Figure 55A. [Figure 55I] See the explanation in Figure 55A. [Figure 55J] See the explanation in Figure 55A. [Figure 55K] See the explanation in Figure 55A. [Figure 55L] See the explanation in Figure 55A. [Figure 55M] See the explanation in Figure 55A. [Figure 55N] See the explanation in Figure 55A. [Figure 56A] Figures 56A–56O show non-limiting synthesis of specific ASGRBM groups and / or compounds of the present disclosure using an 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 the explanation in Figure 56A. [Figure 56C] See the explanation in Figure 56A. [Figure 56D] See the explanation in Figure 56A. [Figure 56E] See the explanation in Figure 56A. [Figure 56F] See the explanation in Figure 56A. [Figure 56G] See the explanation in Figure 56A. [Figure 56H] See the explanation in Figure 56A. [Figure 56I] See the explanation in Figure 56A. [Figure 56J] See the explanation in Figure 56A. [Figure 56K] See the explanation in Figure 56A. [Figure 56L]See the explanation in Figure 56A. [Figure 56M] See the explanation in Figure 56A. [Figure 56N] See the explanation in Figure 56A. [Figure 56O] See the explanation in Figure 56A. [Figure 57A] Figures 57A to 57M show non-limiting synthesis of TNF binders assumed to be within the scope of this disclosure, and coupling thereof with REAG to produce compounds of this disclosure, such as but not limited to formula (2b). [Figure 57B] See the explanation in Figure 57A. [Figure 57C] See the explanation in Figure 57A. [Figure 57D] See the explanation in Figure 57A. [Figure 57E] See the explanation in Figure 57A. [Figure 57F] See the explanation in Figure 57A. [Figure 57G] See the explanation in Figure 57A. [Figure 57H] See the explanation in Figure 57A. [Figure 57I] See the explanation in Figure 57A. [Figure 57J] See the explanation in Figure 57A. [Figure 57K] See the explanation in Figure 57A. [Figure 57L] See the explanation in Figure 57A. [Figure 57M] See the explanation in Figure 57A. [Figure 58] In a non-limiting embodiment, a specific compound of formula (2b) is shown, where R represents R3b. [Figure 59] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 60] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 61] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 62] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 63] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 64] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 65] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 66] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 67] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 68] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 69] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2b). [Figure 70A] Figures 70A to 70C show non-limiting synthesis of specific intermediates that can be used to prepare the compound of formula (2b) (showing R3) or the compound of formula (2c) (showing R2). [Figure 70B] See the explanation in Figure 70A. [Figure 70C] See the explanation in Figure 70A. [Figure 71] Formula (2c), etc., and other non-limiting synthesis examples of the particular compounds of this disclosure are shown. [Figure 72] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2c). [Figure 73] This describes a non-restrictive synthesis of intermediates that can be used to prepare the compound of formula (2c). [Figure 74] The non-restrictive synthesis of the compound of formula (2c) is shown. [Figure 75] The structure of GalNAc-NH2 is shown. [Figure 76]This paper demonstrates a non-restrictive synthesis of indole-GN3, a bifunctional molecule targeted at the degradation of human IgG / IgE / IgM. [Figure 77] This paper demonstrates a non-restrictive synthesis of AMD-GN3, a bifunctional molecule targeted at the selective degradation of human IgG. [Figure 78] This paper demonstrates a non-restrictive synthesis of FcIII-GN3, a bifunctional molecule targeted at the selective degradation of human IgG. [Figure 79] Figures 79A and 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 a negative control molecule or medium control did not show this effect. Purple arrows: Mice were intraperitoneally injected with anti-DNP IgG antibody; Green arrows: Mice were intraperitoneally injected with PBS (medium), DNP-(OH)3 (negative control), or DNP-GN3. Figure 79B: Structure of DNP-GN3. [Figure 80] This disclosure shows non-limiting synthesis of specific bifunctional compounds. [Figure 81] This disclosure shows non-limiting synthesis of specific bifunctional compounds. [Figure 82] This disclosure shows non-limiting synthesis of specific bifunctional compounds. [Figure 83] This disclosure shows non-limiting synthesis of specific bifunctional compounds. [Figure 84] This disclosure shows non-limiting synthesis of specific bifunctional compounds. [Figure 85] The synthesis of DNP-OH3 is shown. [Figure 86]Figures 86A to 86C show that DNP-GN3 mediates the formation of a ternary complex. Figure 86A: DNP-GN3 mediates the formation of a ternary complex between hepatocytes and α-DNP antibodies. Figure 86B: DNP-GN3-mediated ternary complex formation is inhibited by competitive binders of ASGPR or α-DNP antibodies. Figure 86C: DNP-GN3-mediated ternary complex formation is inhibited by the previously reported ASGPR-binding proteins asialofetuin and asialoolosomucoid. [Figure 87] Figures 87A and 87B show that endocytosis of α-DNP antibody depends on the concentrations 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] This study demonstrates that DNP-GN3-mediated endocytosis is reduced by competitive binders of ASGPR or α-DNP antibodies. Controls are shown in gray, compounds expected to inhibit the intended mode of action of DNP-GN3 are shown in blue, and compounds not expected to inhibit are shown in red. Data are presented as mean ± SD over nine repeated trials across four experiments. Statistical significance was determined by the 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] This study demonstrates that clathrin-dependent endocytosis inhibitors reduce the uptake of α-DNP antibodies mediated by DNP-GN3. Data are presented as mean ± SD of nine replicate trials across four experiments. Statistical analysis is outlined in Figure 88. [Figure 90] This study demonstrates 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 and 91B show that endocytized α-DNP antibodies are transported to lysosomes after 12 hours. Figure 91A: Endocytized α-DNP antibodies do not coexist with the early endosomal marker EEA1. Figure 91B: Endocytized α-DNP antibodies do not coexist with late endosomes and lysosomal protein LAMP2 in cells. [Figure 92] Figures 92A and 92B show the accumulation test of α-DNP antibody-derived protein fragments. Figure 92A: α-DNP antibody-derived protein fragments accumulate in the cell lysate over time. Figure 92B: The cell supernatant does not accumulate α-DNP antibody fragments over time. [Figure 93] Figures 93A to 93C show that DNP-GN3 and DNP-OH3 do not show toxicity to mice at all test 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 study demonstrates that serum levels of α-DNP antibody decrease more rapidly after repeated treatment with DNP-GN3. Serum antibody levels were measured using an ELISA assay. Each experimental group consisted of three mice. Statistical significance in experiments including in vivo depletion of α-DNP antibody was assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc simple effects comparisons between each treatment group and the PBS group. [Figure 95] This study shows a significant decrease in serum levels of α-DNP antibody after treatment with DNP-GN3, but not after treatment with DNP-OH3. Each experimental group consisted of at least five mice. [Figure 96]This study demonstrates that a single dose of DNP-GN3 mediates a decrease in serum levels of α-DNP antibody. Each experimental group consisted of at least eight mice. Statistical significance was assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparisons of simple effects between each treatment group and the PBS group. [Figure 97] This study demonstrates that treatment with DNP-GN3 accelerates the depletion of polyclonal α-DNP antibodies from serum. The PBS-treated group consisted of two mice, while the DNP-GN3 group consisted of three mice. [Figure 98] This shows that the binding of α-DNP antibody to HepG2 cells is dependent on the concentration of DNP-AF3. Error bars represent standard deviation (SD) of three biological replicate studies. [Figure 99] This shows that the binding of DNP-AF3-mediated antibodies to HepG2 cells is inhibited by gradually increasing concentrations of α-DNP antibody-conjugated control DNP-OH3. Error bars represent the standard deviation of three biological replicate trials. [Figure 100] This shows that the binding of α-DNP antibody to HepG2 cells mediated by DNP-AF3 is inhibited by gradually increasing concentrations of ASGPR-bound control monosaccharide AF. Error bars represent the standard deviation of three biological replicate studies. [Figure 101] This shows that the binding of α-DNP antibody to HepG2 cells, mediated by DNP-AF3, is inhibited by the ASGPR-binding protein ASOR at increasing concentrations, but not by ORM. The error bars represent the standard deviation of three biological replicate trials. [Figure 102] This study demonstrates that the binding of α-DNP antibody to HepG2 cells, mediated by DNP-AF3, is not inhibited by gradually increasing concentrations of ASGPR-binding protein ASF or 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–103C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentrations 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–103C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentrations 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–103C show that DNP-AF3-mediated endocytosis of α-DNP antibody depends on the concentrations 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] This shows that intracellular fluorescence induced by DNP-AF3-mediated endocytosis of α-DNP antibody increases over time. The α-DNP antibody was present at a concentration of 100 nM. Each data point represents an individual biological experiment. [Figure 105] This study demonstrates that DNP-AF3-mediated endocytosis of antibodies by HepG2 cells is inhibited by competitive binders for both ASGPR and α-DNP antibodies. Antibodies were present at a concentration of 100 nM, and DNP-AF3 at a concentration of 40 nM. Error bars represent the standard deviation of three biological replicate studies. Significance was analyzed using one-way ANOVA with multiple comparisons against the unadded control. The 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]This study demonstrates that DNP-AF3-mediated endocytosis of antibodies by HepG2 cells is inhibited by clathrin-mediated endocytosis inhibitors and global endocytosis inhibitors. Antibodies were present at a concentration of 100 nM, and DNP-AF3 at a concentration of 40 nM. Each data point represents an individual biological experiment. Black bars represent the control condition, red represents metabotoxins, green represents phagocytic and macrophagic inhibitors, blue represents caveolin-dependent endocytosis inhibitors, and gray represents clathrin-dependent endocytosis inhibitors. Significance was analyzed using one-way ANOVA with multiple comparisons against the unadded control. The p-values ​​are as follows: NaN3 / DOG p=0.0001(****); CytD p=0.0710(ns); EIPA p=0.9994(ns); Amyloride p=0.4812(ns); Nistatin 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] This study demonstrates the time-dependent accumulation of endocytotic α-DNP antibody in spots within HepG2 cells. 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 spots increased over time. [Figure 108] This study demonstrates that both DNP-AF3 and α-DNP antibodies are necessary for observing fluorophore-containing spots within HepG2 cells. In the absence of either DNP-AF3 or α-DNP antibody, the spots are not observed. [Figure 109] This shows that the fluorescence signal generated by endocytized α-DNP antibody does not coexist with the early endosomal protein EEA1. [Figure 110] This study demonstrates that the fluorescence signal generated by endocytized α-DNP antibody coexists with the late endosome and lysosomal protein LAMP2. [Figure 111] This shows the direct fluorescence visualization of α-DNP antibody protein fragments in samples collected from cell culture supernatant. α-DNP antibody was present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM. [Figure 112] This shows the direct fluorescence visualization of α-DNP antibodies in samples collected from cell culture lysates. Low accumulation of α-DNP antibodies in the cell lysates was observed in samples not treated with DNP-AF3. In contrast, DNP-AF3 treated cells showed a time-dependent increase in α-DNP antibody-derived Alexa 488 signaling. [Figure 113] This shows the ratiometric visualization of the fluorescence intensity produced by α-DNP antibody fragments. Densitometry was performed using Photoshop image analysis. [Figure 114] This shows how the intensity of fluorescence produced by proteins of different molecular weights in cell lysates changes over time. The error bars represent standard deviations (SD) across three biological replicate studies. [Figure 115] This shows a ratiometric representation of the accumulation of relatively low molecular weight Alexa 488-modified protein fragments in cell culture medium. At 12 hours, the 25 kDa band is brighter than the 50 kDa band. Error bars represent standard deviations (SD) of three biological replicate studies. [Figure 116] This shows the effects of different protease inhibitors on the degradation of endocytized α-DNP antibodies. A lower ratio indicates greater degradation, while a higher ratio indicates less degradation. Data points represent a single biological replicate trial. [Figure 117] This graph shows the effect of protease inhibitors on the degradation of endocytized α-DNP antibodies in HepG2 cells. A lower ratio indicates greater degradation. Error bars represent standard deviations (SD) across three biological replicate studies. [Figure 118]This chart shows the effect of selected protease inhibitors on the degradation of endocytized α-DNP antibodies in HepG2 cells. A lower ratio indicates greater degradation. Error bars represent standard deviations (SD) of three biological replicate studies. Significance was analyzed using one-way ANOVA with multiple comparisons against a protease inhibitor-free control. The p-values ​​are as follows: leupeptin p=.0504(ns); E64 p=.0461(*); pepstatin p=.9419(ns); antipyne p=.0252(*); ALLN 100 p=.0418(*); ALLN 10 p=.0267(*). [Figure 119A] Figures 119A and 119B show the synthesis of the bifunctional molecule MIF-GN3. [Figure 119B] See the explanation in Figure 119A. [Figure 120] The synthesis of MIF inhibitor 3w is shown. [Figure 121] This document describes the synthesis of the MIF-binding bifunctional molecule MIF-PEG2-GN3. [Figure 122] This shows the synthesis of the MIF-binding bifunctional molecule MIF-PEG4-GN3. [Figure 123] This shows the synthesis of the MIF-binding bifunctional molecule MIF-NVS-PEG3. [Figure 124] This describes the synthesis of the MIF-binding bifunctional molecule MIF-AF1. [Figure 125] This describes the synthesis of the MIF-binding bifunctional molecule MIF-AF2. [Figure 126] This describes the synthesis of the MIF-binding bifunctional molecule MIF-AF3. [Figure 127] The structures of small molecules analyzed for their inhibition of mouse MIF enzyme activity are shown. [Figure 128] Figures 128A and 128B show the MIF depletion test from cell culture supernatant. Figure 128A: A bifunctional MIF-binding molecule mediates the depletion of human MIF from cell culture supernatant. Figure 128B: The MIF inhibitor 3w does not mediate the depletion of MIF from cell culture supernatant. [Figure 129]This study demonstrates that a bifunctional MIF-binding molecule with an optimized ASGPR-binding motif depletes MIF from cell culture supernatant. Error bars represent the standard deviation of nine biological replicate tests. Human MIF protein was present at a concentration of 100 nM. [Figure 130] This shows that MIF-GN3 mediates the endocytosis of fluorescently labeled human MIF protein. Each data point represents the mean of three biological replicate studies. Error bars represent the standard deviation. [Figure 131] This shows that MIF-GN3 mediates the uptake of fluorescently labeled MIF proteins across a wide range of target protein concentrations. Each value represents a single biological replication study. [Figure 132] This study demonstrates that MIF-GN3-mediated MIF endocytosis by HepG2 cells is inhibited by clathrin-mediated inhibitors. Antibodies were 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 the control condition, red represents metabotoxins, green represents phagocytic and macrophagic inhibitors, blue represents caveolin-dependent endocytosis inhibitors, and gray represents clathrin-dependent endocytosis inhibitors. Values ​​represent the mean of three biological replicate studies. Error bars represent the standard deviation. Statistical significance was determined by the Kruskall-Wallace test and post-hoc comparisons between each inhibitor group and the control group (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, "ns" P>0.9999). [Figure 133] This study demonstrates that cells treated with MIF-GN3 and exogenous MIF accumulate MIF spots within the cells. MIF signaling shows strong coexistence 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 study shows that cells treated with MIF-GN3 exhibited faster clearance of human MIF from circulation in mice 4 hours after treatment. Each data point represents the mean and standard deviation of three mice in each group. T-test analysis at 4 hours showed no significant difference (p=.1525). [Figure 135] This shows that cells treated with MIF-GN3 exhibited faster clearance of human MIF from circulation in mice. Each data point represents the mean of two (MIF intraperitoneal PBS group) or three (all other groups) serum sample readings. [Figure 136] This study shows that mice treated with MIF-GN3 exhibit rapid clearance of human MIF from circulation at an early stage. Each data point represents the mean concentration of MIF in serum collected from 4 or 5 mice. Statistical significance was assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparisons of simple effects between each treatment group and the PBS group. [Figure 137] This shows that treatment of mice with MIF-GN3 did not reduce serum levels of mouse MIF. Each point represents the mean of 10 serum samples, and the error bars are SD. Immediately after the 0 hour point, the animals received a single dose of MIF-GN3. [Figure 138] This study demonstrates that administration of MIF-GN3 and α-MIF antibodies slows the proliferation of PC3 human prostate cancer cells in mice. Each group consists of 5 mice (with the exception of the DNP-GN3 group, which has 4 mice). [Figure 139] This study demonstrates 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 consists of 5 mice (with the exception of the DNP-GN3 group, which has 4 mice). [Figure 140] This study demonstrates that administration of MIF-GN3 and α-MIF antibodies increases the survival rate of mice injected with human prostate cancer PC3 cells. Each group consists of 5 mice (with the exception of the DNP-GN3 group, which has 4 mice). [Figure 141] The synthesis of the bifunctional molecule FcIII-BCN-GN3 is shown. [Figure 142]This study demonstrates that FcIII-GN3 mediates human IgG endocytosis across a range of concentrations. Cellular autofluorescence and small molecule-unmediated endocytosis are revealed by subtracting the fluorescence of a population of cells treated with human IgG but not with the compound from these samples. Each data point represents the mean of three biological replicate trials. Error bars represent the standard deviation. [Figure 143] This shows that FcIII-BCN-GN3 mediates IgG endocytosis across a range of concentrations over time. Each data point represents a single biological replicate study. [Figure 144] This study demonstrates an increase in intracellular human IgG fluorescence 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] This study demonstrates that FcIII-GN3 mediates the 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 channels represent Hoechst nucleus staining. [Figure 146A] Figures 146A and 146B 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 the explanation in Figure 146A. [Figure 147A] Figures 147A and 147B show the characterization of the TNF binder shown in Figure 159A. Figure 147A: Mass spectrum of the TNF binder. Figure 147B: HPLC purification of the TNF binder. [Figure 147B] See the explanation in Figure 147A. [Modes for carrying out the invention]

[0018] Detailed explanation of disclosure In one aspect, the 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 may be circulating proteins and / or cell surface proteins that can bind to or embed in cell membranes) in a subject. In certain embodiments, the treatment or management of the diseases and / or disorders envisioned in the Disclosure requires the degradation, removal, and / or reduction of the concentration of extracellular proteins in the subject. Thus, in certain embodiments, administration of the compounds of the Disclosure to a subject removes extracellular proteins and / or reduces the circulating concentration of extracellular proteins, and thus the disease and / or disorder is treated, remitted, and / or prevented in the subject. In some embodiments, the extracellular proteins include TNF. In some embodiments, the extracellular proteins are TNF.

[0019] In certain embodiments, the compounds of the Disclosure include a group that binds to an extracellular protein. In other embodiments, the compounds of the Disclosure further include another group (such as a small molecule) that binds to a cell receptor, and this binding causes endocytosis of the compound (and / or the extracellular protein-compound complex). The receptor binder and the extracellular protein binder may be linked by linkers such as polyethylene glycol (PEG), any other linker described herein having an adjustable length, or other linkers described herein and containing one or more connecting molecules referred to herein as CON. When the extracellular protein-compound complex undergoes endocytosis, the extracellular protein is ultimately degraded, and the compound may be degraded or recycled outside the cell. In some embodiments, the extracellular protein is TNF, and the compounds of the Disclosure are TNF binders.

[0020] In another aspect, the Disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of specific autoantibodies of interest. In certain embodiments, autoantibodies mediate disease and / or impairment in a subject, and treatment or management of the disease and / or impairment requires the degradation, removal, or reduction of the concentration of autoantibodies in the subject. Accordingly, in certain embodiments, administration of the compounds of the Disclosure to a subject removes autoantibodies and / or reduces the circulating concentration of autoantibodies, thereby treating, relieving, or preventing the disease and / or impairment in the subject.

[0021] In certain embodiments, the compounds of the Disclosure include another group (such as a small molecule) that binds to a cell receptor, and this binding causes endocytosis of the compound (and / or extracellular protein-compound complex). Furthermore, in certain embodiments, the compounds of the Disclosure include an autoantibody targeting moiety (AATM), such as a small molecule, a peptide, and / or a nucleic acid aptamer, or an autoantibody ligand, which can bind to an autoantibody of interest. The receptor binder and the AATM may be linked by a linker, such as polyethylene glycol (PEG), any other linker described herein having an adjustable length, or another linker described herein and containing one or more connecting molecules referred to herein as CON. When the autoantibody-compound complex undergoes endocytosis, the autoantibody is ultimately degraded, and the compound may be degraded or recycled outside the cell.

[0022] While it is undesirable to be constrained by theory, the bifunctional compounds of this 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. By using ATM, it is possible to target specific populations of autoantibodies. As shown elsewhere in this specification, the compounds of this disclosure, including anti-DNP IgG as a model autoantibody, successfully induced the degradation of anti-DNP IgG injected into mice.

[0023] This disclosure provides a molecular approach to achieve similar goals to plasmapheresis in diseases caused by autoantibodies. Unlike plasmapheresis, this technology can be easily implemented by a variety of healthcare professionals (not limited to transfusion specialists). Because this approach is based on small molecules derived from synthetic approaches, this disclosure avoids the need for expensive equipment and materials as well as complex manufacturing practices. This approach is more cost-effective, safer, and more patient-friendly than plasmapheresis and IVIG.

[0024] Furthermore, this disclosure provides a less invasive and safer route of administration compared to in vitro procedures that may lead to further complications. The compounds described herein are modular and versatile. The targeting motifs (CRBM and AATM) at either end of the linker can be modified to bind with high specificity to a variety of autoantibodies of interest. In addition, the specified composition of the compounds enables simpler and more consistent manufacturing practices and reduces batch-to-batch variability. The fact that AATM binds to autoantibodies as predicted allows for prediction of treatment outcomes, drug interactions, and possible side effects.

[0025] In certain embodiments, the receptor is the hepatocyte asialoglycoprotein receptor (ASGPR). In this case, the binding site is referred to herein as the ASGPR binding site or ASGRBM. This disclosure is not limited to this receptor, but rather envisions the use of other receptors described herein or any other endocytosis receptor known in the art.

[0026] Furthermore, this disclosure is not limited to degradation occurring in hepatocytes. Rather, this disclosure assumes that non-hepatocytes in the body present specific degradation receptors, and such receptors are assumed to be within the scope of this disclosure.

[0027] In one aspect, the compounds of the Disclosure bind to extracellular proteins and / or autoantibodies and remove them from the circulation (and body) through the liver. In some embodiments, the extracellular protein is extracellular TNF. Thus, the compounds of the Disclosure utilize the body's own mechanisms to degrade proteins and / or autoantibodies. While not to be limited to theory, the compounds of the Disclosure bind to specific receptors located in specific cells, such as but not limited to hepatocytes, such as ASGPR. This binding induces degradation of the protein target by intralysosomal proteolysis. As a result of this mechanism, the circulating levels of extracellular protein targets and / or extracellular autoantibodies decrease. In some embodiments, the extracellular protein target is TNF. Consequently, the corresponding disease symptoms are attenuated and / or disappear from the patient in subjects to whom the compounds are administered.

[0028] ASPGR has the function of eliminating desialylated glycoproteins having exposed unreduced D-galactose (Gal) or N-acetylgalactosamine (GalNac) as terminal groups. ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is present only minimally in other parts of the body. Internalization of target glycoproteins by ASGPR exhibits a half-life of approximately 3 minutes. The bifunctional compound claimed herein selectively binds to extracellular proteins through the extracellular protein binder portion of the compound, thereby forming a protein complex. Upon reaching the liver, the asialoglycoprotein receptor-binding portion (ASGPRBM) of the molecule engages with the hepatocyte's lysosomal pathway via ASGPR. Endosome-bound ASPGR releases the extracellular protein ligand at pH 5.4, and the ligand is removed from circulation by the hepatocyte. However, ASPGR remains available for recirculation, escaping lysosomal degradation and budding into recirculating endosomes. In fact, depending on the cell line, ASPGR can be recirculated up to approximately 200 times at a recirculation rate of about 15-20 minutes. ASPGR exhibits very coarse ligand size requirements, possibly reaching a diameter of about 70 nm. In contrast, IgM pentamers are approximately 20 nm in diameter and therefore meet the ligand size requirements of ASPGR.

[0029] The disclosures of international patent application number PCT / US2019 / 026260, filed on April 8, 2019 (and published on October 17, 2019 as WO 2019 / 199634), and international patent application number PCT / US2019 / 026239, filed on April 8, 2019 (and published on October 17, 2019 as WO 2019 / 199621), are incorporated herein by reference in their entirety.

[0030] In accordance with this disclosure, conventional chemical synthesis and pharmaceutical formulation methods, as well as pharmacological, molecular biological, microbiological, and recombinant DNA techniques within the scope of the skills in the art, can be used. These techniques are well known and are described elsewhere in the literature.

[0031] Herein, specific aspects of the disclosed subject matter will be mentioned in detail. Some examples of these aspects are shown in the accompanying drawings. The disclosed subject matter will be described in relation to the numbered claims, but it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0032] Throughout this document, values ​​expressed in the form of a range should be interpreted flexibly to include not only the numerical values ​​explicitly stated as the limits of the range, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also individual values ​​within the indicated range (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%). Unless otherwise specified, the notation "approximately X to Y" is equivalent to "approximately X to approximately Y". Similarly, unless otherwise specified, the notation "approximately X, Y, or approximately Z" is equivalent to "approximately X, approximately Y, or approximately Z".

[0033] In the methods described herein, the actions may be performed in any order unless a chronological or operational order is explicitly stated. Furthermore, unless the express language of the claim states that certain actions must be performed separately, they may be performed simultaneously. For example, the action of performing X and the action of performing Y described in the claim may be performed simultaneously in a single operation, and the resulting process is within the literal scope of the process described in the claim.

[0034] definition As used herein, the term “approximately” allows for a variation in the value or range of the stated value or range within, for example, 10%, 5%, or 1% of the stated value or range limit, and includes the exact value or range stated.

[0035] In this document, unless otherwise indicated by context, the terms “a,” “an,” or “the” are used to refer to one or more items. Unless otherwise indicated, the term “or” is used to mean non-exclusive “or.” The phrases “at least one of A and B” or “at least one of A or B” are synonymous with “A, B, or A and B.” Furthermore, any words or terms used herein and not otherwise defined should be understood to be for descriptive purposes only and not to be restrictive. Any use of section headings is intended to aid in the reading of this document and should not be interpreted as restrictive. Information related to section headings may arise inside or outside that particular section. All publications, patents, and patent documents referenced herein are incorporated herein by reference in whole, as if each individual were incorporated by reference.

[0036] When used in the context of organisms, tissues, cells, or components thereof, the term “abnormal” means an organism, tissue, cell, or component thereof in which at least one observable or detectable feature (e.g., age, treatment, time, etc.) differs from that which exhibits each “normal” (expected) feature. A feature that is normal or expected in one cell type or tissue type may be abnormal in a different cell type or tissue type.

[0037] As used herein, the term “acyl” means a group containing a carbonyl moiety, bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen atom that forms a “formyl” group, or to another carbon atom that may be part of an alkyl group, aryl group, aralkyl group, cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, heteroaryl group, heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 further carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the scope of its meaning as herein. The acryloyl group is an example of an acyl group. The acyl group may contain heteroatoms within the scope of its meaning as herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the scope of its meaning as herein. Other examples include the acetyl group, benzoyl group, phenylacetyl group, pyridylacetyl group, cinnamoyl group, and acryloyl group. When a group containing a carbon atom bonded to a carbonyl carbon atom also contains a halogen, the group is called a "haloacyl" group. One example is the trifluoroacetyl group.

[0038] As used herein, the term “alkyl” means linear and branched alkyl groups, as well as 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 linear 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 groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl groups, isoalkyl groups, and anteisoalkyl groups, as well as other branched alkyl groups. Typical substituted alkyl groups may be substituted once or more times with any of the groups listed herein, such as amino groups, hydroxyl groups, cyano groups, carboxyl groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0039] As used herein, the term “alkenyl” means linear, branched, and cyclic alkyl groups, as defined herein, except that at least one double bond is present between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 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.

[0040] As used herein, the term “alkoxy” means an oxygen atom connected to an alkyl group, including cycloalkyl groups as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further contain double or triple bonds, and may also contain heteroatoms. For example, the allyloxy group or methoxyethoxy group are alkoxy groups within the scope of meaning as defined herein, as is the methylenedioxy group in the context of substituting two adjacent atoms in the structure with them.

[0041] As used herein, the term "alkynyl" means linear and branched alkyl groups as defined herein, except that at least one triple bond is present between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0042] As used herein, the term "amine" means primary, secondary, and tertiary amines having, for example, a formula N(group)3 in which each group can independently be H or non-H such as alkyl or aryl. Examples of amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, and alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, and heterocyclylamines; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, and triarylamines. The term "amine" as used herein also includes ammonium ions.

[0043] The term "amino acid sequence variant" refers to a polypeptide that has an amino acid sequence that differs to some extent from the natural sequence polypeptide. Typically, amino acid sequence variants exhibit at least approximately 70%, at least approximately 80%, at least approximately 90%, or at least approximately 95% homology to the natural polypeptide. Amino acid sequence variants exhibit substitutions, deletions, and / or insertions at specific positions within the amino acid sequence of the natural sequence.

[0044] As used herein, the term "amino group" refers to the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + The substituents, and the non-protonable -NR3 + This refers to the protonated forms of each form except for the one specified. Therefore, any compound substituted with an amino group can be considered an amine. Within the scope of meaning as used herein, “amino group” can be a primary, secondary, tertiary, or quaternary amino group. The “alkylamino” group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0045] As used herein, the term "aminoalkyl" means an amine connected to an alkyl group as defined herein. The amine group may appear at any preferred position within the alkyl chain, for example, at the end of the alkyl chain or at any other location within the alkyl chain.

[0046] As used herein, the term "aralkyl" means an alkyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein. Typical aralkyl groups include benzyl and phenylethyl groups, as well as condensed (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined herein.

[0047] As used herein, the term "aryl" means a cyclic aromatic hydrocarbon group that does not contain a heteroatom in the ring. Therefore, aryl groups include, but are not limited to, phenyl, azlenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains about 6 to about 14 carbon atoms in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Typical substituted aryl groups include, but are not limited to, a phenyl group substituted at one or more of the 2, 3, 4, 5, or 6 positions of the phenyl ring, or a naphthyl group substituted at one or more of the 2 to 8 positions of the phenyl ring, and can be monosubstituted or doubly or more substituted groups.

[0048] As used herein, the term “antibody” means an immunoglobulin molecule that specifically binds to an antigen. Antibodies may be intact immunoglobulins derived from natural or recombinant sources, or they may be the immunoreactive portion of intact immunoglobulins. Typically, antibodies are tetramers of immunoglobulin molecules. Antibodies in this disclosure may 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).

[0049] The term "antibody fragment" refers to a portion of an intact antibody, specifically the antigen-determining variable region of an 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 sdAb(VL or VH), such as camel antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38); camel VHH domains, which consist of a VL domain or VH domain that exhibits sufficient affinity for the target; and bivalent fragments containing two Fab fragments linked by disulfide crosslinks in 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, intracellular antibodies, bispecific antibodies, triplicate antibodies, quadruplicate antibodies, v-NARs, and bis-scFvs (see, for example, Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments may be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, describing fibronectin polypeptide mini-antibodies). Antibody fragments may include human antibodies or humanized antibodies, or portions of human antibodies or humanized antibodies.

[0050] As used herein, the terms “antigen” or “Ag” are defined as molecules that induce an immune response. This immune response may include antibody production, activation of specific immune cells, or both. Those skilled in the art will understand that virtually any macromolecule, including any protein or peptide, can act as an antigen. Furthermore, antigens may originate from recombinant DNA 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 induces an immune response, therefore, encodes the term “antigen” as used herein. Furthermore, those skilled in the art will understand that antigens are not necessarily encoded only by the full-length nucleotide sequence of a gene. It is obvious that this disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and that these nucleotide sequences are composed of various combinations to induce a desired immune response. Furthermore, those skilled in the art will understand that antigens are not necessarily encoded by a “gene.” It is obvious that antigens may be synthetically produced or derived from biological samples. These biological samples may include, but are not limited to, tissue samples, tumor samples, cells, or biological fluids.

[0051] As used herein, "aptamer" refers to a small molecule capable of specifically binding to another molecule. Typically, aptamers are molecules based on polynucleotides or peptides. Polynucleotide aptamers are DNA or RNA molecules and usually contain several nucleic acid chains in a highly specific three-dimensional higher-order structure designed to exhibit appropriate binding affinity and specificity to specific target molecules, such as peptides, proteins, drugs, and vitamins, among organic and inorganic molecules. These polynucleotide aptamers can be selected from a vast population of random sequences through the use of in vitro evolution methods. Typically, peptide aptamers are loops of about 10 to 20 amino acids bound 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.

[0052] As used herein, the terms “asiaroglycoprotein receptor binding moiety” or “ASGPRBM” mean a group capable of binding to at least one hepatocyte asiaroglycoprotein receptor on the surface of a cell, including but not limited to hepatocytes. When ASGPRBM, and any further moiety to which it is bound, binds to the receptor on the surface of a hepatocyte, the molecule containing ASGPRBM is taken up by the hepatocyte through a phagocytic mechanism, where the molecule is at least partially degraded through lysosomal degradation.

[0053] When used herein, "C 6~10 -C 6~10 The term "biaryl" refers to another C through a single bond. 6~10 C covalently bonded to the aryl portion 6~10 This refers to the aryl portion. C 6~10 The aryl portion may be any preferred aryl group as described herein. 6~10 -C 6~10 Non-limiting examples of biaryls include biphenyls and binaphthyls.

[0054] As used herein, the term “coding sequence” means a sequence or portion thereof of a nucleic acid or its complement that is transcribed and / or translateable to produce mRNA and / or polypeptides or fragments thereof. A coding sequence includes exons in genomic DNA or immature primary RNA transcripts that are joined together by the cellular biochemical mechanisms to obtain mature mRNA. The antisense strand is the complement of the nucleic acid, from which the coding sequence can be inferred. In contrast, as used herein, the term “non-coding sequence” means a sequence or portion thereof of a nucleic acid or its complement that is not translated in vivo into amino acids or does not interact in such a way that tRNA positions or attempts to position amino acids. Non-coding sequences include both intron sequences in genomic DNA or immature primary RNA transcripts and gene-associated sequences such as promoters, enhancers, and silencers.

[0055] As used herein, the terms “complementary” or “complementarity” are used in reference to polynucleotides (i.e., nucleotide sequences) linked by base pairing rules. For example, the sequence “AGT” is complementary to the sequence “TCA”. Complementarity may be “partial,” in which case only some of the bases of the nucleic acid are matched according to base pairing rules. Alternatively, “complete” or “full” complementarity may exist 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.

[0056] As used herein, the terms “composition” or “pharmaceutical composition” mean a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to a patient or subject. Multiple techniques exist in the art for administering compounds, including but not limited to intravenous, oral, aerosol, parenteral, intraocular, intrapulmonary, and topical administration.

[0057] As used herein, the terms “conservative variation” or “conservative substitution” mean the replacement of an amino acid residue with another biologically similar residue. Conservative variations or substitutions do not likely alter the shape of the peptide chain. Examples of conservative variations or substitutions 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, for example, replacing arginine with lysine, glutamic acid with aspartic acid, or glutamine with asparagine.

[0058] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups can have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Furthermore, cycloalkyl groups include but not limited to polycyclic cycloalkyl groups, such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as dekalinyl. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined herein. Typical substituted cycloalkyl groups include, but are not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups; they can be monosubstituted or two or more substituted groups, which may be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0059] A "disease" is a state of animal health in which the animal is unable to maintain homeostasis, and unless the disease goes into remission, the animal's health will continue to deteriorate.

[0060] In contrast, a “disorder” in animals refers to a health condition in which the animal can maintain homeostasis, but its health is less favorable than it would be in the absence of the disorder. Leaving the disorder untreated does not necessarily lead to a further decline in the animal's health.

[0061] A disease or disorder is considered to be in "remission" when the severity of its symptoms, the frequency with which the patient experiences those symptoms, or both, decreases.

[0062] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” mean an amount of an agent that is non-toxic but sufficient to obtain the desired biological effect. The effect may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in the biological system. The appropriate therapeutic dose in any individual case can be determined by those skilled in the art using routine experiments.

[0063] As used herein, the term "efficacy" refers to the maximum effect achieved within the assay (E max ) means.

[0064] "Code" means that a specific sequence of nucleotides in a polynucleotide such as a gene, cDNA, or mRNA has the inherent characteristic of serving as a template for the synthesis of other polymers and macromolecules in biological processes, possessing a defined nucleotide sequence (i.e., rRNA, tRNA, and mRNA) or amino acid sequence, and the resulting biological properties. Thus, a gene codes for a protein when that protein is produced in a cell or other biological system by the 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 sequence listings, and the non-coding strand, which is used as a template for the transcription of the gene or cDNA, can be said to code for the protein or other product of that gene or cDNA.

[0065] As used herein, when applied to nucleic acids, the term “fragment” means a subsequence of a larger nucleic acid. A “fragment” of nucleic acid may have a length of at least about 15 nucleotides; for example, at least about 50 to about 100 nucleotides; at least about 100 to about 500 nucleotides; at least about 500 to about 1000 nucleotides; at least about 1000 to about 1500 nucleotides; at least about 1500 to about 2500 nucleotides; or about 2500 nucleotides (and any integer value in between). As used herein, when applied to proteins or peptides, the term “fragment” means a subsequence of a larger protein or peptide. A “fragment” of protein or peptide may have a length of at least about 20 amino acids; for example, at least about 50 amino acids; at least about 100 amino acids; at least about 200 amino acids; at least about 300 amino acids; or at least about 400 amino acids (and any integer value in between).

[0066] As used herein, the term "GN3" means the following base: TIFF0007842459000002.tif79128

[0067] As used herein, the terms “halo,” “halogen,” or “halide” group, either by itself or as part of another substituent, mean a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, unless otherwise specified.

[0068] As used herein, the term "haloalkyl" group 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 by halogen atoms such as fluoro. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, and perfluorobutyl.

[0069] 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, a heteroaryl ring can have five to about eight to twelve ring members. A heteroaryl group is a variety of heterocyclyl groups having an aromatic electronic structure. A heteroaryl group called 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, and so on. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and heteroatoms is equal to the total number of ring atoms. Examples of 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, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be unsubstituted or substituted with the groups described herein. Typical substituted heteroaryl groups may be substituted once or multiple times with groups such as those listed herein.

[0070] 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, and Nzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrrolyl), 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-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl), 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]furanil (2-benzo[b]furanil, 3-benzo[b]furanil, 4-benzo[b]furanil, 5-benzo[b]furanil, 6-benzo[b]furanil, 7-benzo[b]furanil), 2,3-dihydro-benzo[b]furanil (2-(2,3-dihydro-benzo[b]furanil), 3-(2,3-dihydro-benzo[b]furanil), 4-(2,3-dihydro-benzo[b]furanil), 5-(2,3-dihydro-benzo[b]furanil), 6-(2,3-dihydro-benzo[b]furanil), 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) 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), 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-benzoimidazolyl, 8-benzoimidazolyl), 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]azepine-1-yl, 5H-dibenzo[b,f]azepine-2-yl, 5 H-dibenzo[b,f]azepine-3-yl, 5H-dibenzo[b,f]azepine-4-yl, 5H-dibenzo[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenzo[b,Examples include, but are not limited to, azepine-5-yl (f).

[0071] As used herein, the term “heteroarylalkyl” means an alkyl group as defined herein, in which the hydrogen bonds or carbon bonds of the alkyl group are replaced by bonds to a heteroaryl group as defined herein.

[0072] When used herein, "C 6~10 The term "-5~6 member heterobiaryl" refers to a C18 covalent bond to a 5 or 6 member heteroaryl portion via a single bond. 6~10 This refers to the aryl portion. C 6~10 The aryl moiety and the 5-6 membered heteroaryl moiety may be any preferred aryl group and heteroaryl group as described herein. 6~10 - Non-exclusive examples of 5- to 6-membered heterobiaryls include: TIFF0007842459000003.tif20128 is one example. C 6~10 -When a 5- to 6-membered heterobiaryl is listed as a substituent (for example, as an "R" group), C 6~10 -5~6 member heterobiaryls are C 6~10 It is bonded to the rest of the molecule through that portion.

[0073] As used herein, "5-6 member-C" 6~10 The term "heterobiaryl" refers to a 5-6 member C 6~10 When heterobiaryls are listed as substituents (e.g., as "R" groups), they are 5-6 member-C 6~10 Aside from the fact that the heterobiaryl is bonded to the rest of the molecule through the 5-6 member heteroaryl moiety, C 6~10 - It is the same as a 5- to 6-member heterobiaryl.

[0074] 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. Therefore, a heterocyclyl can be a cycloheteroalkyl, heteroaryl, or any combination thereof, as long as it is polycyclic. In some embodiments, a heterocyclyl group contains 3 to about 20 ring members, while other similar groups have 3 to about 15 ring members. A heterocyclyl group called a C2-heterocyclyl may be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl may be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The number of carbon atoms and heteroatoms are equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the scope of this specification. This term also includes polycyclic systems containing heteroatoms, such as quinuclidyls, but not limited to them. Heterocyclyl groups may be unsubstituted or substituted as described herein.Examples of 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, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Typical substituted heterocyclyl groups include, but are not limited to, monosubstituted or two- or more substituted piperidinyl or quinolinyl groups, and these groups are 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as those listed herein.

[0075] As used herein, the term “heterocyclylalkyl” means an alkyl group as defined herein, in which the hydrogen or carbon bonds of the alkyl group as defined herein are replaced by bonds to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0076] As used herein, the term "selected independently from" means that the groups referred to are the same group, different groups, or a mixture thereof, unless the context clearly indicates otherwise. Therefore, based on this definition, "X 1 , X 2 , and X 3 The phrase "is selected independently of noble gases" is, for example, X 1 , X 2 , and X3 The scenario where all X is the same. 1 , X 2 , and X 3 A scenario where everything is different, X 1 and X 2 Although X is the same 3 This would include scenarios where the values ​​are different, as well as other similar permutation scenarios.

[0077] As used herein, the terms “immunoglobulin” or “Ig” are 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. The five members of this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is a primary antibody found 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 binding, and other antibody responses and is important in defense against bacteria and viruses. IgD is an immunoglobulin that does not have known antibody function but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate-type hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0078] "Isolated" means that it has been altered or removed from its natural state. For example, nucleic acids or polypeptides that are naturally present in living animals are "not isolated," but the same nucleic acids or polypeptides that have been partially or completely separated from coexisting substances in their natural state are "isolated." Isolated nucleic acids or proteins may exist in a substantially purified form and may exist in a non-natural environment, such as a host cell.

[0079] As used herein, the term “modulate” means mediating a detectable increase or decrease in the activity and / or levels of mRNA, polypeptide, or response in a subject compared to the activity and / or levels of mRNA, polypeptide, or response in the absence of the treatment or compound in the subject, and compared to the activity and / or levels of mRNA, polypeptide, or response in an otherwise identical but untreated subject. This term encompasses mediating a beneficial therapeutic response in a subject, preferably a human, by activating, inhibiting, and / or otherwise influencing a native signal or native response.

[0080] As used herein, the term “monovalent” means that the substituent is attached to the substituted molecule by a single bond. When the substituent is monovalent, for example, F or Cl, the substituent is attached by a single bond to the atom it substitutes.

[0081] As used herein, the term “organic group” means 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, carboxylate salts, and carboxylic acid esters; sulfur-containing groups such as alkyl sulfide groups and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, O(O)R, C(O)N(R)2, O(O)N(R)2, C(S)N(R)2, (CH2) 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 is an example, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based moiety, and the carbon-based moiety may or may not be substituted.

[0082] The terms “patient,” “subject,” or “individual” are used interchangeably herein and mean any animal or its cells, whether in vitro or in situ, to which the methods described herein are permitted. In a non-limiting aspect, patient, subject, or individual is human.

[0083] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not inhibit the biological activity or biological properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or harmful interactions with any components of the composition contained in the composition.

[0084] As used herein, the term "pharmaceutically acceptable salt" means a salt of a administered compound, or a solvate, hydrate, or clathrate thereof, prepared from a pharmaceutically acceptable, non-toxic acid or base, including an inorganic acid or inorganic base, or an organic acid or organic base.

[0085] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and bisulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid classes, and examples 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, saccharic 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.

[0086] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including alkali metal salts such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts, alkaline earth metal salts, and transition metal salts. Examples of pharmaceutically acceptable base addition salts 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 compounds, for example, by reacting the compound with a suitable acid or base.

[0087] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in transporting or delivering the compound described herein into or to a patient so that it can perform its intended function. Typically, these compounds are transported or delivered from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation containing the compound described herein and is not harmful to the patient. Some examples of materials that 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; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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 buffer; and other non-toxic and suitable substances used in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carriers” include any coatings, antimicrobial and antifungal agents, as well as absorption retarders, that are compatible with the activity and efficacy of the compounds described herein and are physiologically acceptable to patients. Supplementary active compounds may be incorporated into the composition. “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of the compounds described herein.Other additional components 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.

[0088] As used herein, the term "polypeptide" means a polymer composed of amino acid residues, associated native structural variants, and their synthetic non-native analogs linked by peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Generally as used herein, the term "protein" means a large polypeptide. Generally as used herein, the term "peptide" means a short polypeptide. In this specification, the usual notation is used to represent polypeptide sequences; that is, the left end of a polypeptide sequence is the amino terminus and the right end is the carboxyl terminus.

[0089] As used herein, the term "effectiveness" means half of the maximum response (ED). 50 This refers to the amount required to produce ).

[0090] As used herein, the term "protein" means the extracellular protein of interest.

[0091] As used herein, the term "REAG" means 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, REAG reacts with a TNF binder group to incorporate the TNF binder into the compounds of the Disclosure, or fragments thereof, derivatives thereof, or intermediates thereof.

[0092] As used herein, the term "room temperature" refers to a temperature between approximately 15°C and 28°C.

[0093] As used herein with respect to antibodies, the term “specifically binding” means an antibody that recognizes a particular antigen but substantially does not recognize or bind to other molecules in the sample. For example, an antibody that specifically binds to an antigen from one species may also bind to the same antigen from one or more species. However, this interspecies reactivity 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 allele forms of the antigen. However, this cross-reactivity itself does not change the classification of the antibody as specific. In some cases, the term “specific binding” or “specifically binding” may be used with respect to the interaction between an antibody, protein, or peptide and a second chemical species to mean that the interaction depends on the presence of a specific structure on the chemical species (e.g., an antigenic determinant or epitope), for example, that the antibody recognizes and binds to a specific protein structure rather than the protein in general. If an antibody is specific to epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A) in the reaction involving labeled “A” and the antibody reduces the amount of labeled A that binds to the antibody.

[0094] As used herein, the term “solvent” means a solid, liquid, or liquid capable of dissolving a gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0095] As used herein, the terms “standard temperature” and “standard pressure” mean 20°C and 101 kPa, respectively.

[0096] As used herein, the term “substantially” means “a majority of” or “mostly” as equivalent to 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 absent” may mean not having any material at all or having it in negligible amounts. Therefore, the amount of material present does not affect the material properties of the composition containing the material. Thus, the material is present in an amount of about 0% to about 5% by weight of the composition, or about 0% to about 1% by weight, or less than or equal to about 5% by weight, or less than about 4.5% by weight, equivalent to about 4.5% by weight, or greater than about 4.5% by weight, 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 less than or equal to about 0.001% by weight. The term "substantially absent" can mean having in negligible amounts, and therefore the material is present in about 0% to about 5% by weight of the composition, or about 0% to about 1% by weight, or about 5% or less by weight, or less than about 4.5% by weight, equivalent to about 4.5% by weight, or more than about 4.5% by weight, 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 by weight, or about 0% by weight.

[0097] As used herein, the term “substituted” in relation to a molecule or organic group as defined herein means a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. As used herein, the terms “functional group” or “substituent” mean a group that can be substituted on or performs substitution on a molecule or organic group. Examples of substituents or functional groups include halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxyl groups including carboxyl groups; sulfur atoms in thiol groups, alkyl sulfide groups and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 Examples include N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)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, and C(=NOR)R, where R can be a hydrogen or carbon-based part, for example, R is hydrogen, (C1~C 100) can be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to a nitrogen atom or multiple adjacent nitrogen atoms can combine with one or more of the nitrogen atoms to form a heterocycline.

[0098] As used herein, the term “synthetic antibody” means an antibody produced using recombinant DNA technology, for example, an antibody expressed by a bacteriophage as described herein. This term should also be interpreted to mean an antibody produced by the synthesis of a DNA molecule that encodes an antibody and expresses an antibody protein, or by the synthesis of an amino acid sequence that identifies the antibody, wherein the DNA or amino acid sequence is obtained using DNA and amino acid sequence synthesis techniques available and well known in the art.

[0099] A "therapeutic" treatment is a procedure performed on an individual exhibiting signs of a disease with the aim of reducing or eliminating those signs.

[0100] As used herein, the term "thioalkyl" means a sulfur atom connected to an alkyl group as defined herein. The alkyl group in a thioalkyl group may be linear or branched. Examples of linear thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, and thiohexyl. Examples of branched alkoxy groups include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, and isothiohexyl. The sulfur atom may appear at any preferred position within the alkyl chain, for example, at the end of the alkyl chain or at any other location within the alkyl chain.

[0101] As used herein, the terms “to treat,” “to treat,” and “treatment” mean 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.

[0102] As used herein, the term “wild-type” means a gene or gene product isolated from a natural source. A wild-type gene is the 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 terms “modified” or “mutant” mean a gene or gene product that exhibits modifications to its sequence and / or functional properties (i.e., changes in its characteristics) compared to a wild-type gene or gene product. It should be noted that natural mutants are isolated. Natural mutants are identified by the fact that they exhibit changes in characteristics (including changes in nucleic acid sequence) compared to a wild-type gene or gene product.

[0103] The term "autoimmune disease" refers to a disease or illness that occurs when body tissues are attacked by their own immune system. Examples of autoimmune diseases include, but are not limited to, systemic lupus erythematosus, Sjögren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes mellitus, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis.

[0104] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of this disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes mellitus, 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, and autoimmune neutrophil Phenophobia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, 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's 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, Vickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia gravis, multiple sclerosis, Patter Oshtoran syndrome, pediatric autoimmune streptococcal neuropsychiatric disorders (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mohren'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,This includes, in particular, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), 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 disorders, and pyoderma gangrenosum.

[0105] Throughout this specification, the terms “cancer” or “neoplasia” are used to mean cancerous or malignant neoplasms, which are pathological processes resulting in the formation and proliferation of abnormal tissues that grow more rapidly by cell proliferation than normal tissue 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 tissue, mostly invading surrounding tissues, metastasizing to several sites, likely recurring after attempts at removal, and likely causing death to the patient if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and encompasses or includes pathological processes associated with malignant hematogenous neoplasms, ascites tumors, and solid tumors. Neoplasms include, but are not limited to, morphological irregularities in cells within the tissue of the subject or host, and the proliferation of cells within the tissue of the subject that is pathological compared to normal proliferation in the same type of tissue. Furthermore, neoplasms include benign and malignant tumors (e.g., colon tumors), which may be invasive or non-invasive. Malignant neoplasms (cancers) and benign neoplasms are distinguished by the fact that the former exhibit a greater degree of anaplasia, or loss of cell differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoforms from which the target cells of this disclosure may originate include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwannoma); Germline tumors (e.g., intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed neoplasia, especially carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratoma (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 can be treated using the compounds of this disclosure.

[0106] Typical common cancers treated with the compounds of this disclosure include, for example, 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, oropharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, and lymphoma, all of which can be treated with one or more compounds of this disclosure. Due to the activity of the compound, the disclosure is generally applicable to treating substantially any cancer in any tissue, and therefore the compounds, compositions, and methods of the disclosure are generally applicable to treating cancer and reducing the likelihood of cancer development and / or metastasis of existing cancer.

[0107] In the specific aspects of this disclosure, the cancers being treated are metastatic cancers, recurrent cancers, or drug-resistant cancers, and in particular, drug-resistant cancers. Separately, metastatic cancers can be found in virtually any tissue of cancer patients in the later stages of the disease, and typically metastatic cancers are found in virtually any tissue, including the lymphatic system / lymph nodes (lymphoma), bone, lungs, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor). Thus, this disclosure is generally applicable to and can be used to treat any cancer in any tissue, regardless of etiology.

[0108] The terms “anticancer agent” or “additional anticancer agent” mean compounds other than the chimeric compounds of the Disclosure that can be used in combination with the compounds of the Disclosure for the treatment of cancer. Exemplary anticancer agents that can be administered concurrently in combination with one or more chimeric compounds of the Disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., Taxol). Exemplary anticancer compounds for use in this 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, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab (Arzerra), zanorimumab, edotecarin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Jaimatekan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY 317615, Neuradiab, Vitespan, Rta744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), E Stradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazine methyl)-indolyl j-quinolone, batalanib, 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 = 1~2.4], 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, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifanib; Amifostin, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus carmette-Guélain (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, leva Misol, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine, Altretamine, Phloxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Barrubicin, Mithramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin,Marimast, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin difutitox, gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody), and Erbitux, cremohol-free paclitaxel, epithilone B B) BMS-247550, BMS-310705, Droloxifen, 4-Hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, 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, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prednisone, Cetuximab, Granulocyte Macrophage Colony Stimulating factors, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-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, drasetron, tropisetron, PEG Examples include filgrastim, erythropoietin, epoetin alfa, and darbepoetin alfa, and vemurafenib; particularly, immunotherapeutic agents, such as IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) including indoximod (NLG-8187), navoximod (GDC-0919), and NLG802; PDL1 inhibitors (programmed death ligand 1 inhibitors) including nivolumab, durvalumab, and atezolizumab; PD1 inhibitors such as pembrolizumab (Merck); and CTLA-4 inhibitors (cytotoxic T lymphocyte-associated protein 4 / surface antigen classification 152 inhibitors) including ipilimumab and tremelimumab.

[0109] In the treatment of cancer, in addition to anticancer drugs, several other agents may be administered concurrently with the chimeric compounds of this disclosure. These include active ingredients, minerals, vitamins, and nutritional supplements that have shown some efficacy in inhibiting cancer tissue or its growth, or that are otherwise useful in the treatment of cancer. For example, one or more of the following may be used in combination with the compounds to treat cancer: dietary selenium, vitamin E, lycopene, soy products, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and phytoestrogens including β-sitosterol.

[0110] The term "inflammatory disease" is used to describe diseases or illnesses that are characterized by inflammation, which is acute but often becomes chronic, as a major symptom of the disease or illness. Inflammatory diseases include neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease; and other ataxias, for example); immunocompromised immune response diseases that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis, and counteracting damaging inflammation); inflammatory bowel disease, including Crohn's disease; chronic inflammatory diseases, including rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, and Sjögren's disease, for example; hyperglycemia disorders; and lipid metabolism disorders. Diabetes mellitus (Type 1 and Type 2), pancreatic β-cell death, and related conditions affecting the function and / or structure of the pancreatic islets, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, pyelonephrosis, 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). Examples of conditions that may be affected include hyperglycemia, liver disease, kidney disease (apoptosis in plaque, glomerular disease), cardiovascular disease (particularly complications during infarction, ischemia, stroke, pressure overload, and reperfusion), muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological signs (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. Since elevated MIF levels are often observed in these diseases, these disease conditions and / or conditions respond to treatment with the compounds and / or pharmaceutical compositions of this disclosure. It should be noted that there is some overlap between the specific autoimmune diseases and inflammatory diseases described herein.

[0111] Throughout this disclosure, various aspects of the disclosure can be presented in the form of scope. It should be understood that descriptions in the form of scope are merely for convenience and conciseness and should not be interpreted as rigid limitations on the scope of the disclosure. Therefore, descriptions of scope should be considered as specifically disclosing all possible sub-scopes and the individual numbers within those scopes. For example, a description of a scope such as 1 to 6 should be considered as specifically disclosing sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the scope.

[0112] compound In one aspect, the present disclosure provides compounds comprising formula (I), or salts thereof, geometric isomers, stereoisomers, or solvates thereof. [Protein Binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I)

[0113] In certain embodiments, the compound comprises formula (Ia), or its salts, geometric isomers, stereoisomers, or solvates. [Protein Binder]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] (Ia)

[0114] In (I) and / or (Ia), the protein binder is a molecule, such as a small molecule and / or a peptide, that binds to an extracellular protein of interest ("protein"). In certain embodiments, treatment or management of a disease and / or disorder requires the degradation, removal, and / or reduction of the concentration of extracellular proteins in the subject. In certain embodiments, the extracellular protein binder in (I) and / or (Ia) is capable of binding to circulating extracellular proteins in the plasma of the subject with the same or substantially similar affinity as the extracellular protein binder itself.

[0115] In (I) and / or (Ia), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradable cells in the subject, and the binding of (I) or (Ia) thereto results in endocytosis and degradation of (I) and / or (Ia) as well as extracellular proteins. In a particular embodiment, the CRBM is an ASGRBM, which is a cell receptor-binding moiety that binds to at least one asial glycoprotein receptor on the surface of hepatocytes or other degradable cells in the subject.

[0116] In (I) and / or (Ia), each CON is a group that binds independently or covalently links the protein binder to the CRBM, the protein binder to the linker, and / or the linker to the CRBM.

[0117] In (I) and / or (Ia), the linker is a group having a valency in the range of 1 to 15. In certain embodiments, the valency of the linker is 1 to 10. In certain embodiments, the valency of the linker is 1 to 5. In certain embodiments, the valency of the linker is 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or protein binder groups, optionally via CON, where the linker itself may contain one or more CON groups.

[0118] In certain embodiments, k' is an integer in the range of 1 to 15. In certain embodiments, k' is an integer in the range of 1 to 10. In certain embodiments, k' is an integer in the range of 1 to 5. In certain embodiments, k' is an integer in the range of 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0119] In certain embodiments, j is an integer in the range of 1 to 15. In certain embodiments, j is an integer in the range of 1 to 10. In certain embodiments, j is an integer in the range of 1 to 5. In certain embodiments, j is an integer in the range of 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0120] In certain embodiments, h is an integer in the range of 0 to 15. In certain embodiments, h is an integer in the range of 1 to 15. In certain embodiments, h is an integer in the range of 1 to 10. In certain embodiments, h is an integer in the range of 1 to 5. In certain embodiments, h is an integer in the range of 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0121] In certain embodiments, h' is an integer in the range of 0 to 15. In certain embodiments, h' is an integer in the range of 1 to 15. In certain embodiments, h' is an integer in the range of 1 to 10. In certain embodiments, h' is an integer in the range of 1 to 5. In certain embodiments, h' is an integer in the range of 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0122] In certain embodiments, i is an integer in the range of 0 to 15. In certain embodiments, i is an integer in the range of 1 to 15. In certain embodiments, i is an integer in the range of 1 to 10. In certain embodiments, i is an integer in the range of 1 to 5. In certain embodiments, i is an integer in the range of 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0123] In certain embodiments, at least one of h, h', and i is at least 1.

[0124] In certain embodiments, k', j', h, h', and i are independently 1, 2, or 3.

[0125] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0126] In another aspect, the present disclosure provides compounds comprising formula (II), or salts, geometric isomers, stereoisomers, or solvates thereof. [TNF Binder] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (II)

[0127] In certain embodiments, the compound comprises formula (IIa), or its salts, geometric isomers, stereoisomers, or solvates. [TNF Binder]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (IIa)

[0128] In (II) and / or (IIa), the TNF binder is a molecule, such as but not limited to small molecules and / or peptides, that binds to TNF. In certain embodiments, treatment or management of a disease and / or disorder requires the degradation, removal, and / or reduction of TNF concentration in the subject. In certain embodiments, the TNF binder in (II) and / or (IIa) is capable of binding to circulating TNF in the plasma of the subject with the same or substantially similar affinity as the TNF binder itself.

[0129] In (II) and / or (IIa), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradable cells in the subject, and the binding of (II) and / or (IIa) thereto results in endocytosis and degradation of (II) and / or (IIa) and / or TNF. In a particular embodiment, the CRBM is an ASGRBM, which is a cell receptor-binding moiety that binds to at least one asial glycoprotein receptor on the surface of hepatocytes or other degradable cells in the subject.

[0130] In (II) and / or (IIa), each CON is a group that independently bonds, or covalently links the TNF binder to the CRBM, the TNF binder to the linker, and / or the linker to the CRBM.

[0131] In (II) and / or (IIa), the linker is a group having a valency in the range of 1 to 15. In certain embodiments, the valency of the linker is 1 to 10. In certain embodiments, the valency of the linker is 1 to 5. In certain embodiments, the valency of the linker is 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or TNF binder groups, optionally via CON, where the linker itself may contain one or more CON groups.

[0132] In certain embodiments, k' is an integer in the range of 1 to 15. In certain embodiments, k' is an integer in the range of 1 to 10. In certain embodiments, k' is an integer in the range of 1 to 5. In certain embodiments, k' is an integer in the range of 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0133] In certain embodiments, j is an integer in the range of 1 to 15. In certain embodiments, j is an integer in the range of 1 to 10. In certain embodiments, j is an integer in the range of 1 to 5. In certain embodiments, j is an integer in the range of 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0134] In certain embodiments, h is an integer in the range of 0 to 15. In certain embodiments, h is an integer in the range of 1 to 15. In certain embodiments, h is an integer in the range of 1 to 10. In certain embodiments, h is an integer in the range of 1 to 5. In certain embodiments, h is an integer in the range of 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0135] In certain embodiments, h' is an integer in the range of 0 to 15. In certain embodiments, h' is an integer in the range of 1 to 15. In certain embodiments, h' is an integer in the range of 1 to 10. In certain embodiments, h' is an integer in the range of 1 to 5. In certain embodiments, h' is an integer in the range of 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0136] In certain embodiments, i is an integer in the range of 0 to 15. In certain embodiments, i is an integer in the range of 1 to 15. In certain embodiments, i is an integer in the range of 1 to 10. In certain embodiments, i is an integer in the range of 1 to 5. In certain embodiments, i is an integer in the range of 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0137] In certain embodiments, at least one of h, h', and i is at least 1.

[0138] In certain embodiments, k', j', h, h', and i are independently 1, 2, or 3.

[0139] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0140] In another aspect, the present disclosure provides compounds comprising formula (III), or salts, geometric isomers, stereoisomers, or solvates thereof. [AATM] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (III)

[0141] In certain embodiments, the compound comprises formula (IIIa), or its salts, geometric isomers, stereoisomers, or solvates. [AATM]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (IIIa)

[0142] In (III) or (IIIa), AATM is a ligand for an autoantibody. The ligand may 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 the subject, and treatment or management of the disease and / or disorder requires the degradation, removal, or reduction of the autoantibody concentration in the subject. In certain embodiments, AATM in (III) or (IIIa) is capable of binding to the autoantibody in the plasma of the subject with the same or substantially similar affinity as AATM itself.

[0143] In (III) or (IIIa), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradable cells in the subject, and by binding thereto, endocytosis and degradation of (III) and / or (IIIa) and / or autoantibodies. In a particular embodiment, the CRBM is an ASGRBM, which is a cell receptor-binding moiety that binds to at least one asial glycoprotein receptor on the surface of hepatocytes or other degradable cells in the subject.

[0144] In (III) or (IIIa), each CON is a group that is independently bonded, or a group that covalently links AATM to CRBM, AATM to the linker, and / or the linker to CRBM.

[0145] In (III) or (IIIa), the linker is a group having a valency in the range of 1 to 15. In certain embodiments, the valency of the linker is 1 to 10. In certain embodiments, the valency of the linker is 1 to 5. In certain embodiments, the valency of the linker is 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or AATM groups, optionally via CON, where the linker itself may contain one or more CON groups.

[0146] In certain embodiments, k' is an integer in the range of 1 to 15. In certain embodiments, k' is an integer in the range of 1 to 10. In certain embodiments, k' is an integer in the range of 1 to 5. In certain embodiments, k' is an integer in the range of 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0147] In certain embodiments, j is an integer in the range of 1 to 15. In certain embodiments, j is an integer in the range of 1 to 10. In certain embodiments, j is an integer in the range of 1 to 5. In certain embodiments, j is an integer in the range of 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0148] In certain embodiments, h is an integer in the range of 0 to 15. In certain embodiments, h is an integer in the range of 1 to 15. In certain embodiments, h is an integer in the range of 1 to 10. In certain embodiments, h is an integer in the range of 1 to 5. In certain embodiments, h is an integer in the range of 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0149] In certain embodiments, h' is an integer in the range of 0 to 15. In certain embodiments, h' is an integer in the range of 1 to 15. In certain embodiments, h' is an integer in the range of 1 to 10. In certain embodiments, h' is an integer in the range of 1 to 5. In certain embodiments, h' is an integer in the range of 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0150] In certain embodiments, i is an integer in the range of 0 to 15. In certain embodiments, i is an integer in the range of 1 to 15. In certain embodiments, i is an integer in the range of 1 to 10. In certain embodiments, i is an integer in the range of 1 to 5. In certain embodiments, i is an integer in the range of 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0151] In certain embodiments, at least one of h, h', and i is at least 1.

[0152] In certain embodiments, k', j', h, h', and i are independently 1, 2, or 3.

[0153] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0154] CRBM Folate receptor In certain embodiments, CRBM is folate, or any fragment or derivative thereof capable of binding to the folate receptor. The folate receptor binds to folate and reduced folate derivatives, mediating the delivery of tetrahydrofolate into the cell, where it is converted from monoglutamate to polyglutamate (e.g., 5-methyltetrahydrofolate), since only the monoglutamate form can be transported across the cell membrane. Human proteins derived from this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor γ.

[0155] In certain embodiments, folic acid CRBM is methotrexate or its bioactive fragment: Includes TIFF0007842459000004.tif29128.

[0156] In certain embodiments, folic acid CRBM is pemetrexed or its bioactive fragment: Includes TIFF0007842459000005.tif27128.

[0157] In certain embodiments, as shown in Figure 1, folate CRBM may be incorporated into the compounds of the Disclosure through one of its carboxylic acids. In other embodiments, as shown in Figure 1 for folate, folate CRBM may be incorporated into the compounds of the Disclosure using N-hydroxysuccinamidyl (NHS) activated folate (similar chemistry applies to methotrexate and pemetrexed). TIFF0007842459000006.tif77128

[0158] Mannose receptor In certain embodiments, CRBM is a group that binds to a mannose receptor. In certain embodiments, CRBM includes the following groups: TIFF0007842459000007.tif19128

[0159] In certain embodiments, the mannose receptor CRBM may be conjugated to the compound of the Disclosure (such as, but not limited to, REAG) using one of the following reagents (which may be protected with a suitable protecting group): In formula TIFF0007842459000008.tif18128, X is S or O, and R is Selected from the group consisting of TIFF0007842459000009.tif19149, 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.

[0160] In certain embodiments, the mannose receptor CRBM is part of a polymer molecule. This molecule may contain one or more independently selected mannose receptor CRBMs as part of a polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using CRBM reagents described elsewhere in this specification.

[0161] Mannose-6-phosphate (M6P) receptor In certain embodiments, CRBM is a group that binds to the mannose-6-phosphate (M6P) receptor. In certain embodiments, CRBM includes the following groups: In formula TIFF0007842459000010.tif18128, X is either O or S, and R 1 The following group was selected: TIFF0007842459000011.tif52128

[0162] In certain embodiments, CRBM may be conjugated to the compound of the Disclosure (such as REAG, but not limited to REAG) using one of the following reagents (which may be protected with a suitable protecting group): In formula TIFF0007842459000012.tif18128, X and R 1 R is defined elsewhere in this specification, 2 teeth, Selected from the group consisting of TIFF0007842459000013.tif41150, 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.

[0163] In certain embodiments, the M6P receptor CRBM is part of a polymer molecule. This molecule may contain one or more independently selected M6P receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using CRBM reagents described elsewhere in this specification. Figures 2–9 show exemplary mannose receptor binders and their preparations.

[0164] In certain embodiments, the M6P receptor CRBM is one of the following (Yamaguchi, et al., 2016, J. Am. Chem. Soc. 138(38):12472-12485). TIFF0007842459000014.tif116128

[0165] In certain embodiments, the M6P receptor CRBM is one of the following (US 2011 / 0110960, attributed to Platenburg): TIFF0007842459000015.tif111156

[0166] Low-density lipoprotein receptor-associated protein 1 (LRP1) receptor In certain embodiments, CRBM is an LRP1 [Low-density lipoprotein receptor-associated protein 1; also known as α-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or surface antigen classification 91 (CD91)] binding group containing one of the following amino acid sequences. TIFF0007842459000016.tif128158

[0167] Low-density lipoprotein receptor (LDLR) In certain embodiments, CRBM is an LDLR (low-density lipoprotein receptor) binding group containing one of the following amino acid sequences. TIFF0007842459000017.tif172159TIFF0007842459000018.tif202159

[0168] FcγRI receptor In certain embodiments, CRBM is an FcγRI binding group containing one of the following amino acid sequences. TIFF0007842459000019.tif245159

[0169] transferrin receptor In certain embodiments, CRBM is a transferrin receptor binding group comprising one of the following amino acid sequences. TIFF0007842459000020.tif114154

[0170] Macrophage scavenger receptors In certain embodiments, CRBM is a macrophage scavenger receptor binding site containing one of the following amino acid sequences. TIFF0007842459000021.tif85159

[0171] 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.

[0172] G protein-coupled receptors In certain embodiments, the CRBM is a G protein-coupled receptor (GPCR) binding site. In certain embodiments, the binding site binds to the GPCR and induces receptor internalization. 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 site It includes TIFF0007842459000022.tif37128, wherein each R is independently H or C1-C6 alkyl. In certain embodiments, CRBM can be attached to a compound of the present disclosure (such as but not limited to REAG) using one of the following reagents (which may be protected with a suitable protecting group): TIFF0007842459000023.tif37128 wherein at least one R is REAG and the remaining Rs are independently H or C1-C6 alkyl.

[0173] Asialoglycoprotein receptor (ASGPR) The present disclosure contemplates the use of an ASGPR binding moiety (ASGPRBM).

[0174] In certain embodiments, the ASGPRBM group is any group described in Huang, et al., 2017, Bioconjugate Chem. 28:283-295, which is hereby incorporated by reference in its entirety.

[0175] In certain embodiments, the ASGPRBM group has the following structure: It includes TIFF0007842459000024.tif24128, wherein X is a linker 1 to 4 atoms in length, and when X is a linker 1 atom in length, X is O, S, N(R N1 ), or C(R N1 )(R N1 ), and when X is a linker 2 atoms in length, no more than 1 atom of X is O, S, or N(R N1 ), and when X is a linker 3 or 4 atoms in length, no more than 2 atoms of X are independently O, S, or N(R N1 ), such that it contains an O, S, N(R N1 ), or C(R N1 )(R N1 ) group.

[0176] In certain embodiments, RN1 Each occurrence of is independently H, or C1-C3 alkyl optionally substituted with one to three independently selected halogens and / or one or two hydroxyl groups.

[0177] In certain embodiments, when X is two atoms in length, X in ASGPRBM is -O-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-, -S-C(R N1 )(R N1 [ )-, -C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 ).

[0178] In certain embodiments, when X is three atoms in length, X in ASGPRBM is -O-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-C(R N1 )(R N1 )-, -O-C(R N1 )(R N1 )-O-, -O-C(R N1 )(R N1 )-S-, -O-C(R N1 )(R N1 )-N(R N1 ), -S-C(R<00001,30>)(R N1 )-C(R N1 )(R N1 ), -C(R N1 )(R N1 )-S-C(R N1 )(R N1 ), -C(RN1 )(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 )

[0179] In certain embodiments, when X is the length of four atoms, X in ASGRBM 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 )-is.

[0180] In certain embodiments, X is OCH2, and R N1 H is H.

[0181] In certain embodiments, X is CH2O, and R N1 H is H.

[0182] In certain embodiments, the ASGRBM has the following structure: Includes TIFF0007842459000025.tif19128.

[0183] In certain embodiments, the ASGRBM has the following structure: Includes TIFF0007842459000026.tif21128.

[0184] In certain aspects, R 1 This is the base shown in Figure 10. In certain embodiments, R 3 This is the base shown in Figure 10. In certain embodiments, R 1 and R 3 These are each independent bases shown in Figure 10.

[0185] In certain aspects, R 1 and R 3 These are H and -(CH2) respectively, independently. K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K (Vinyl), -O(CH2) K (Vinyl), -(CH2) K (Alkinyl), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K The elements are C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens.

[0186] In certain aspects, R 1 and R 3 Each of these is independently Ph(CH2) K - and this may be substituted with 1 to 3 independently selected halogens; C1 to C4 alkyls which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxys which may be substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0187] In certain aspects, R1 and R 3 Each of these has the following independent structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 It is the basis of, and in the formula, R 7 C1-C4 alkoxys may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2

[0188] 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.

[0189] 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 aspects, R N3 Each occurrence is independently H or C1-C3 alkyl. In certain embodiments, R N3 Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0191] In certain aspects, each R N4 Each occurrence is independently H, C1-C3 alkyl, or Ph-(CH2) K -In certain cases, R N4 Each occurrence may be independently substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or C1-C3 alkyl, or Ph-(CH2) K - is

[0192] In certain aspects, R 1 and R3 Each is independently selected from the following group: In formula TIFF0007842459000027.tif27128, CYC is the group consisting of the following: Selected from TIFF0007842459000028.tif111156, in the formula, The join described in TIFF0007842459000029.tif2128 is -(CH2) K This indicates the part of the CYC to which it is connected.

[0193] In certain aspects, L 1 is a linker, -CON-linker, or -CON-linker-CON. In certain embodiments, L 1 L is a combination. In certain aspects, L 1 is a linker. In certain embodiments, L 1 is a -CON-linker. In certain embodiments, L 1 It is the CON linker CON.

[0194] In certain aspects, R C is absent, H, 1-3 optionally substituted halogens and / or 1-2 optionally substituted hydroxyl groups, or C1-C4 alkyl groups, or the following structure: This is the basis of TIFF0007842459000030.tif23128, in the formula, R 4 , R 5 , and R 6 Each of these is independently H, F, Cl, Br, I, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens, C1-C3 alkoxy which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) KThe elements are C(=O)O-(C1~C4 alkyl), OC(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens.

[0195] In certain aspects, R N2 Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0196] In certain aspects, R C teeth The file is TIFF0007842459000031.tif25153.

[0197] In certain aspects, R 1 and R 3 Each of these is independently (C3~C8 saturated carbon ring)-(CH2) K - and here the carbon ring is -L 1 and -R C It is further replaced by [this].

[0198] In certain aspects, R N Each occurrence is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0199] In certain aspects, R 2 This is the base shown in Figure 11.

[0200] In certain aspects, R 2 ha-(CH2) K -N(R N1 )-C(=O)R AM That is the case.

[0201] In certain aspects, R AMC1-C4 alkyl, -(CH2) which may be substituted with H, 1-3 independently selected halogens and / or 1-2 hydroxyl groups. K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), -C(=O)(C1~C4 alkyl), or -(CH2) K -NR N3 R N4 That is the case.

[0202] In certain aspects, R 2 teeth TIFF0007842459000032.tif16128, and in the formula, R TA H, CN, NR N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 independently selected halogens, -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O(C1~C4 alkyl), -OC(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or -C(=O)(C1~C4 alkyl) which may be substituted with 1 to 3 independently selected halogens, or R TA C3~C 10 An aryl group, or a 3-10 membered heteroaryl group containing 1-5 non-carbon ring atoms, where the aryl group or heteroaryl group is designated as CN or NR, respectively. N1 R N2 ,-(CH2) K OH may be replaced by 1 to 3 independently selected halogens - (CH2)K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3 alkoxy), -(CH2) K COOH may be replaced by 1 to 3 independently selected halogens - (CH2) K C(=O)O-(C1~C4 alkyl), which may be substituted with 1 to 3 independently selected halogens-OC(=O)(C1~C4 alkyl), or which may be substituted with 1 to 3 independently selected halogens-(CH2) K It may be substituted with 1 to 3 groups independently selected from C(=O)-(C1~C4 alkyl), or R TA teeth TIFF0007842459000033.tif49128, which may be substituted with 1 to 3 independently selected halogens or 1 to 3 C1-C3 alkyl groups, or R TA teeth TIFF0007842459000034.tif29128, and in the formula, each -(CH2) K The group may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups, or with 1 to 4 C1-C3 alkyl groups.

[0203] In certain embodiments, the ASGRBM group has the following structure: Includes TIFF0007842459000035.tif51158, During the ceremony, R A is a C1-C3 alkyl which may be substituted with 1-5 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 nonexistent, -(CH2) IM -, -C(=O)-(CH2) IM -, or -C(=O)(CH2) IM -NR M -and; R M is a C1-C3 alkyl group which may be substituted with H or 1-2 hydroxyl groups; Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0204] In certain aspects, R A is methyl or ethyl, and both may be substituted with 1 to 3 fluorine atoms.

[0205] In certain aspects, Z A This is a PEG group containing 1 to 4 ethylene glycol residues.

[0206] In certain embodiments, the ASGPRBM group includes one of the following (Mamidyala, et al., 2012, J. Am. Chem. Soc. 134:1978-1981): TIFF0007842459000036.tif181163TIFF0007842459000037.tif228149TIFF0007842459000038.tif127160

[0207] In certain embodiments, the ASGPRBM group includes one of the following (Sanhueza, et al., 2017, J. Am. Chem. Soc. 139:3528-3536): TIFF0007842459000039.tif125157

[0208] Linker and CON In certain embodiments, the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

[0209] In certain embodiments, the linker has the following structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - Alternatively, it may contain a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units. Each R a is independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b Together with other groups, they form a pyrrolidine group or a hydroxypyrroline group; Each R b These are 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 in the range of 1 to 15.

[0210] In certain embodiments, the linker is structured -[N(R ' -(CH2) 1~15 The formula contains -C(=O)]-, where R' is H or a C1-C3 alkyl which may be substituted with 1-2 hydroxyl groups, and m is an integer in the range of 1-100.

[0211] In certain embodiments, the linker has the following structure: -ZD-Z'- Includes, During the ceremony, Z and Z' are joined independently. It is TIFF0007842459000040.tif26154; Each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 These are independently H or C1-C3 alkyl groups; Each Y is independently a bond, O, S, or N(R); Each i is independently 0 to 100; in certain aspects 0 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects 0, 1, 2, 3, 4, or 5; D represents a bond, -(CH2) i -YC(=O)-Y-(CH2) i -,-(CH2) m' -, or -[(CH2) n -X1)] j -However, Z, Z', and D cannot be combined at the same time; X 1 is O, S, or N(R); j is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects an integer in the range of 1, 2, 3, 4, or 5; m' is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; in certain aspects an integer in the range of 1, 2, 3, 4, or 5; n is an integer in the range of 1 to 100; in certain aspects 1 to 75; in certain aspects 1 to 60; in certain aspects 1 to 55; in certain aspects 1 to 50; in certain aspects 1 to 45; in certain aspects 1 to 40; in certain aspects 2 to 35; in certain aspects 3 to 30; in certain aspects 1 to 15; in certain aspects 1 to 10; in certain aspects 1 to 8; in certain aspects 1 to 6; and in certain aspects an integer in the range of 1, 2, 3, 4, or 5.

[0212] In certain embodiments, the linker has the following structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2-, or -(CH2CH2CH2O) n - Includes, In the formula, n and n' are each an integer in the range of 1 to 25, in certain embodiments 1 to 15, in certain embodiments 1 to 12, in certain embodiments 2 to 11, in certain embodiments 2 to 10, in certain embodiments 2 to 8, in certain embodiments 2 to 6, in certain embodiments 2 to 5, in certain embodiments 2 to 4, in certain embodiments 2 or 3, and in certain embodiments 1, 2, 3, 4, 5, 6, 7, or 8.

[0213] In certain embodiments, the linker has the following structure: -PEG-CON-PEG- Includes, In the formula, each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The filename is TIFF0007842459000041.tif14128.

[0214] In certain configurations, CON has the following structure: Includes TIFF0007842459000042.tif85134, In the formula, R' and R'' are independently H, methyl, or a bond.

[0215] 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)- Includes, In the formula, each R 1 n'' is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, in certain embodiments from 1 to 7, and in certain embodiments from 1, 2, 3, 4, 5, or 6.

[0216] In certain configurations, CON has the following structure: Includes TIFF0007842459000043.tif14128, During the ceremony, R 1a , R 2a , and R 3a These are H and -(CH2) respectively, independently. 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)NR4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; 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 either 0 or 1; Each R 4 These are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), however, the same R 1a , R 2a , and R 3a It is not possible for both M2 and M3 within the same variable to be 0 at the same time.

[0217] In certain configurations, CON has the following structure: Includes TIFF0007842459000044.tif46128.

[0218] Protein binder Any protein binder that binds to the protein of interest (which in certain embodiments is a circulating protein) is useful in formulas (I) and (Ia) of this 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.

[0219] Protein binders can be incorporated into compounds of formula (I) and / or formula (Ia) using any method known in the art and / or any technique described or illustrated herein. For example, protein binders can be attached 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 site of the protein binder should be such that the attached protein binder in formula (I) or formula (Ia) can still bind to the protein of interest. Assuming the mode of binding of the protein binder to the protein of interest, identifying potential binding sites on the protein binder, and / or attaching the protein binder to the CON and / or linker to determine whether this attachment interferes with the binding of the protein binder to the protein of interest is within the scope of standard experimental methods expected and / or known to those skilled in the art.

[0220] In certain embodiments, the protein binder is an antibody, such as a monoclonal antibody, but is not limited thereto. An antibody of interest can be incorporated into a compound of formula (I) or formula (Ia) using any method known in the art and / or any technique described or illustrated herein. For example, an antibody can be linked to a linker and / or CON via a carboxylic acid group on the surface of the antibody, for example, using an amide or esterification reaction. For example, an antibody can be linked to a linker and / or CON via an amine group on the surface of the antibody, for example, using an amide formation reaction. For example, an antibody can be linked to a linker and / or CON via a thiol group on the surface of the antibody, for example, using a nucleophilic substitution reaction. In this case, the surface cysteine ​​residue may be present in the wild type of the antibody and / or may be introduced by a mutation using, for example, site-directed mutagenesis. A linker and / or CON useful within the scope of this disclosure can be any linker known in the art, as long as the presence of the linker does not significantly impede the ability of the antibody to bind to the protein of interest.

[0221] In certain embodiments, the protein binder is a polypeptide. A polypeptide of interest can be incorporated into a compound of formula (I) or formula (Ia) using any method known in the art and / or any technique described or illustrated herein. For example, a polypeptide can be linked to a linker and / or CON through its C-terminus and / or N-terminus, for example, using an amide or esterification reaction. For example, a polypeptide can be linked to a linker and / or CON through any intermediate residue, for example, using an amide or esterification reaction and / or a nucleophilic substitution reaction (e.g., if the polypeptide has thiol residues). Polypeptides 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 to enable simple linking to a targeting domain.

[0222] Protein-based protein binders, such as antibodies and polypeptides, can be synthesized by various methods well known in this field, for example, by the expression of binders that do not require post-translational modification (PTM) in E. coli, or by the expression of binders that do not require PTM in mammalian cultures. These binding proteins can be made into bifunctional proteins by introducing non-natural amino acid tags for linking (N3, alkynes, etc.) and then reacting them with the corresponding targeting domain, or by many other well known bioorthogonal reactions for specific protein tagging.

[0223] As those skilled in the art will understand, any protein binder capable of recognizing and specifically binding to a protein of interest is useful in this disclosure. This disclosure should not be construed as being limited to any single protein binder, whether publicly known or previously unknown, provided that such protein binder specifically binds to the protein of interest and can prevent or minimize the biological activity of the protein of interest.

[0224] In certain embodiments, the protein of interest is CD40L. In certain embodiments, the protein binder that binds to CD40L includes the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG within the assumed compound of this disclosure): TIFF0007842459000045.tif81128

[0225] In certain embodiments, the protein of interest is PCSK9. In certain embodiments, the protein binder that binds to PCSK9 includes the following (wherein the peptide C-terminus may be amidated, and the dashed line indicates a potential and non-limiting binding site to REAG within the assumed compound of this disclosure): TIFF0007842459000046.tif100128, TIFF0007842459000047.tif4128 (where X = OH or NH2).

[0226] In certain embodiments, the protein of interest is PCSK9. In certain embodiments, the protein binder that binds to PCSK9 includes any binder described in WO2018 / 057409. In certain embodiments, the protein binder includes any of the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG in the compound assumed in this disclosure): TIFF0007842459000048.tif82145TIFF0007842459000049.tif220153

[0227] In certain embodiments, the protein of interest is VEGF. In certain embodiments, the protein binder that binds to VEGF includes the following (wherein the peptide C-terminus may be amidated, and the dashed line indicates a potential and non-limiting binding site to REAG in the assumed compound of this disclosure): TIFF0007842459000050.tif4128 (where X = OH or NH2), TIFF0007842459000051.tif53128.

[0228] In certain embodiments, the protein of interest is TGF-β. In certain embodiments, the protein binder that binds to TGF-β includes the following (wherein the peptide C-terminus may be amidated, and the dashed line indicates a potential and non-limiting binding site to REAG within the assumed compound of this disclosure): TIFF0007842459000052.tif4128 (where X = OH or NH2), TIFF0007842459000053.tif74128.

[0229] In certain embodiments, the protein of interest is TSP-1. In certain embodiments, the protein binder that binds to TSP-1 includes the following (wherein the peptide C-terminus may be amidated, and the dashed line indicates a potential and non-limiting binding site to REAG within the assumed compound of this disclosure): TIFF0007842459000054.tif4128 (where X = OH or NH2).

[0230] In certain embodiments, the protein of interest is a soluble uPAR. In certain embodiments, the protein binder that binds to the uPAR includes the following (wherein the wavy lines indicate potential and non-limiting binding sites to REAG within the assumed compound of this disclosure): TIFF0007842459000055.tif91128

[0231] In certain embodiments, the protein of interest is soluble PSMA. In certain embodiments, the protein binder that binds to PSMA includes the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG in the assumed compound of this disclosure): TIFF0007842459000056.tif38128

[0232] In certain embodiments, the protein of interest is IL-2. In certain embodiments, the protein binder that binds to IL-2 includes the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG in the compound envisioned in this disclosure): TIFF0007842459000057.tif37128

[0233] In certain embodiments, the protein of interest is GP120. In certain embodiments, the protein binder that binds to GP120 includes the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG in the compound envisioned in this disclosure): TIFF0007842459000058.tif194121

[0234] In certain embodiments, the protein of interest is MIF. In certain embodiments, the protein binder that binds to MIF includes the following (wherein the formula, the dashed line indicates a potential and non-limiting binding site to REAG in the compound assumed in this disclosure): TIFF0007842459000059.tif81128

[0235] In certain embodiments, the protein of interest is IgA, which is known in the art or described elsewhere in this specification. In certain embodiments, the protein binder that binds to MIF includes, but is not limited to, any peptide described in Hatanaka, et al., 2012, J. Biol. Chem. 287:43126-43136. TIFF0007842459000060.tif48128TIFF0007842459000061.tif20287

[0236] These peptides may be acyclic (as free thiols) or cyclized as oxidized thiols (disulfide bonds). Furthermore, this disclosure envisions incorporating these peptides into the compounds of this disclosure via N-terminal and / or C-terminal bonds.

[0237] In certain embodiments, the protein binder that binds to IgA is any Fc-α receptor peptide mimetic described in Heineke, et al., 2017, Eur. J. Immunol. 47:1835-1845, including, but not limited to, the following. Linear peptides: TIFF0007842459000062.tif19128 Cyclic peptide: CLIPS TIFF0007842459000063.tif48128 Cyclic peptide: Oxidation TIFF0007842459000064.tif26128

[0238] These peptides may be acyclic (as free thiols) or cyclized as oxidized thiols (disulfide bonds). Furthermore, this disclosure envisions incorporating these peptides into the compounds of this disclosure via N-terminal and / or C-terminal bonds.

[0239] CLIPS exhibits cyclization of linear peptides through the reaction of a cysteine ​​thiol functional group with a small, robust entity. This anchor reacts only with thiols and binds to the peptide by covalent bonds. Non-limiting examples of CLIPS crosslinkers envisioned in this disclosure include the following: TIFF0007842459000065.tif94128

[0240] TNF Binder Any TNF binder that binds to TNF is useful in formulas (II) and (IIa) of this 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.

[0241] TNF binders can be incorporated into the compounds of formulas (II) and (IIa) by any method known in the art and / or any technique described or illustrated herein. For example, TNF binders can be bonded to the linker and / or CON by amide coupling, ester coupling, nucleophilic substitution, electrophilic substitution, radical coupling, or any other synthetic method known in the art. The binding site of the TNF binder should be such that the bonded TNF binder in formulas (II) and (IIa) can still bind to TNF. Assuming the mode of binding of the TNF binder to TNF, identifying potential binding sites on the TNF binder, and / or bonding the TNF binder to the CON and / or linker to determine whether this bond interferes with the binding of the TNF binder to TNF are within the scope of standard experimental methods expected and / or known to those skilled in the art.

[0242] In certain embodiments, the TNF binder is an antibody such as, but not limited to, a monoclonal antibody. An antibody of interest can be incorporated into the compounds of formulas (II) and (IIa) using any method known in the art and / or any technique described or illustrated herein. For example, an antibody can be conjugated to the linker and / or CON via a carboxylic acid group on the surface of the antibody, for example, using an amide or esterification reaction. For example, an antibody can be conjugated to the linker and / or CON via an amine group on the surface of the antibody, for example, using an amide formation reaction. For example, an antibody can be conjugated to the linker and / or CON via a thiol group on the surface of the antibody, for example, using a nucleophilic substitution reaction. In this case, the surface cysteine ​​residue may be present in the wild type of the antibody and / or may be introduced by a mutation using, for example, site-directed mutagenesis. A linker and / or CON useful within the scope of this disclosure can be any linker known in the art, provided that the presence of the linker does not significantly impede the antibody's ability to bind to TNF.

[0243] In certain embodiments, the TNF binder is a polypeptide. The polypeptide of interest can be incorporated into the compounds of formulas (II) and (IIa) by any method known in the art and / or any technique described or illustrated herein. For example, the polypeptide can be linked to the linker and / or CON through its C-terminus and / or N-terminus, for example, by amide or esterification reactions. For example, the polypeptide can be linked to the linker and / or CON through any intermediate residue, for example, by amide or esterification reactions and / or nucleophilic substitution reactions (e.g., if the polypeptide has thiol residues). The polypeptide can be synthesized by standard Fmoc-SPPS. In certain embodiments, the C-terminus of the peptide is amidated. After introducing a linker at the N-terminus or C-terminus, a functional handle (N3, alkyne, etc.) can be introduced to enable simple linking to the ASGPR targeting domain. In non-limiting examples... The filename is TIFF0007842459000066.tif30150.

[0244] Protein-based TNF binders, such as antibodies and polypeptides, can be synthesized by various methods well known in this field, for example, by the expression of binders that do not require post-translational modification in E. coli, or by the expression of binders that do not require PTM in mammalian cultures. These binding proteins can be made into bifunctional proteins that target TNF-ASGPR by introducing non-natural amino acid tags for linking (N3, alkynes, etc.) and then reacting them with the corresponding ASGPR targeting domain, or by many other well known bioorthogonal reactions for specific protein tagging.

[0245] As those skilled in the art will understand, any TNF binder capable of recognizing and specifically binding to TNF is useful in this disclosure. If a TNF binder specifically binds to TNF and can prevent or minimize the biological activity of TNF, this disclosure should not be construed as being limited to any one type of TNF binder, whether known or previously unknown.

[0246] In certain embodiments, the TNF binder contains the polypeptide STPTRYS (SEQ ID NO: 120) (Guangdong Yixue 2008, 29(1):55-57).

[0247] In certain embodiments, the TNF binder includes polypeptide CALWHWWHC (SEQ ID NO:121) or C(T / S)WLHWWAC (SEQ ID NO:122) (Diyi Daxue Xuebao 2002, 22(7):597-599).

[0248] In certain embodiments, the TNF binder comprises any Tbab protein as described in Zhu, et al., 2016, Protein Sci. 25:2066-2075.

[0249] In certain embodiments, the TNF binder contains polypeptide (L / M)HEL(Y / F)(L / M)X(W / Y / F)(SEQ ID NO:123) as described in Zhang, et al., 2003, Biochem. Biophys. Res. Commun. 310:1181-1187.

[0250] In certain embodiments, the TNF binder comprises one of the following polypeptides: TIFF0007842459000067.tif12140(Yang, et al., 2019, FEBS Lett. 593:1292-1302).

[0251] In certain embodiments, the TNF binder includes TNFR1 or TNFR2 (Yang & Yang, 2013, Fenxi Huaxue / Chinese J. Anal. Chem. 41:664-669).

[0252] In certain embodiments, the TNF binder contains anti-kakexin C1 and / or C2 (Lian, et al., 2013, J. Am. Chem. Soc. 135:11990-11995). TIFF0007842459000068.tif63128

[0253] In certain embodiments, the TNF binder includes adalimumab, infliximab, etanercept, golimumab, and / or certolizumab.

[0254] In certain embodiments, the TNF binder contains 29.2 kDa scFv, as identified in Safarpour, et al., 2018, Iran. J. Pharm. Res. 17:743-752.

[0255] In certain embodiments, TNF binders This includes TIFF0007842459000069.tif4128 (in non-limiting examples, this may be a sulfur-linked tris-bromomethylmesitylene core; Luzi, et al., 2015, Protein Eng. Des. Sel. 28:45-52).

[0256] In certain embodiments, the TNF binder contains any aphibodies (approximately 60 amino acids) identified in Lofdahl, et al., 2009, N. Biotechnol. 26:251-259.

[0257] In certain embodiments, the TNF binder contains any affibodies identified in Kronqvist, et al., 2008, Protein Eng. Des. Sel. 21:247-255.

[0258] In certain embodiments, the TNF binder contains any affibo as identified in Jonsson, et al., 2009, Biotechnol. Appl. Biochem. 54:93-103.

[0259] In certain embodiments, the TNF binder includes a bispecific albumin / TNF-binding polypeptide identified in Nilvebrant, et al., 2011, PLoS One 6.

[0260] In certain embodiments, the TNF binder includes a ubiquitin-based artificial binding protein identified in Hoffmann, et al., 2012, PLoS One 7:2-11.

[0261] In certain embodiments, the TNF binder contains the HIHDDLLRYYGW linear peptide (SEQ ID NO:127) or the tetrabranched peptide (SEQ ID NO:128) identified in Brunetti, et al., 2014, Molecules 19:7255-7268.

[0262] In certain embodiments, the TNF binder contains any TNF-α binding peptide (P51 and P52) identified in Alizadeh, et al., 2017, Eur. J. Pharm. Sci. 96:490-498. TIFF0007842459000070.tif74151

[0263] In certain embodiments, the TNF binder contains the scFv antibody identified in Alizadeh, et al., 2015, Adv. Pharm. Bull. 5:661-666.

[0264] In certain embodiments, the TNF binder comprises any TNF-binding peptide described in WO 2006 / 053568, which is incorporated herein in whole by reference (such as, but not limited to, KRWSRYF (SEQ ID NO: 129), which may be polyvalent in certain embodiments).

[0265] In certain embodiments, the TNF binder may be any TNF-binding peptide described in WO 2015 / 055597, which is incorporated herein in whole by reference (in certain embodiments, it may be polyvalent). This includes, but is not limited to, TIFF0007842459000071.tif4128.

[0266] In certain embodiments, the TNF binder contains YCWSQYLCY (SEQ ID NO: 130), which was identified in Arthritis & Rheumatism 2007, 56(4):1164-74.

[0267] In certain aspects, the TNF binder was identified in Chirinos-Rojas, et al., 1998, J. Immunol. 161:5621-5626. Includes TIFF0007842459000072.tif4128.

[0268] In certain embodiments, the TNF binder contains 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 non-limiting examples.

[0269] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000073.tif121157(Zaka, et al., 2019, J. Biomol. Struct. Dyn. 37:2464-2476).

[0270] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000074.tif95156 (Shen, et al., 2014, Eur. J. Med. Chem. 85:119-126). See Figures 13 and 14 for non-limiting examples.

[0271] In certain embodiments, the TNF binder includes the following: For a non-limiting example, see Figure 15. TIFF0007842459000075.tif55128

[0272] In certain embodiments, the TNF binder includes the following: For a non-limiting example, see Figure 16. TIFF0007842459000076.tif50128

[0273] In certain embodiments, the TNF binder includes the following: For a non-limiting example, see Figure 17. TIFF0007842459000077.tif52128

[0274] In certain embodiments, the TNF binder includes one of the following (Saddala & Huang, 2019, J. Transl. Med. 17:1-16): TIFF0007842459000078.tif190128

[0275] In certain embodiments, the TNF binder includes SPD-304 and its analogues (He, et al., 2005, Science 310:1022-1025; Papaneophytou, et al., 2015, Medchemcomm 6:1196-1209). TIFF0007842459000079.tif31128TIFF0007842459000080.tif188128

[0276] Non-limiting chemical schemes for preparing and derivatizing these compounds are shown herein. TIFF0007842459000081.tif97135 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. TIFF0007842459000082.tif173165 Structures of 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-restrictive example.

[0277] In certain embodiments, the TNF binder comprises a compound of formula (2a): TIFF0007842459000083.tif21128In formula, A 1 and A 2 is independently a substituted or unsubstituted phenyl group, where the substituent comprises at least one of the following heterocycles which may be 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 CF3 but not limited thereto), C1-C4 alkoxy, C1-C4 haloalkoxy, benzyloxy, and F, Cl, Br, I, OH, C1-C4 alkyl, C1-C4 alkyl substituted with at least one OH, C1-C4 fluoroalkyl (such as CF3 but not limited thereto), C1-C4 alkoxy, and C1-C4 haloalkoxy (dotted lines indicate bonding points): TIFF0007842459000084.tif71131; Each R 5 is independently a hydrogen atom or a C1-C4 alkyl group which may be substituted; R 1 and R 2is independently a hydrogen atom or a C1-C4 alkyl group which may be substituted; X 1 and X 2 These are independently carbonyl or CH2; n is 2, 3, or 4; R 3 and R 4 R is independently a hydrogen atom or a C1-C4 alkyl group which may be substituted, or R 3 and R 4 These may combine to form a heterocyclyl ring. See Figure 19 for a non-restrictive example.

[0278] For example, A 1 and A 2 These are 1-(3-(trifluoromethyl)phenyl)-1H-indole and 6,7-dimethyl-4H-chromen-4-one, respectively, X 1 and X 2 If both are CH2, then R 3 and R 4 These rings form heterocyclyl rings, such as but not limited to piperazinyl rings.

[0279] In certain embodiments, the TNF binder contains the small molecule IA-14069.

[0280] In certain embodiments, TNF binders This includes TIFF0007842459000085.tif29128 (Mouhsine, et al., 2017, Sci. Rep. 7:1-10 (2017)). In certain embodiments, the linker and / or Con may be bonded to the sulfonamide phenyl ring. See Figure 20 for a non-limiting example.

[0281] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000086.tif25128(Melagraki, et al., 2017, PLoS Comput. Biol. 13:1-27).

[0282] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000087.tif69135(Melagraki, et al., 2018, Front. Pharmacol. 9:1-12).

[0283] In certain embodiments, TNF binders This includes TIFF0007842459000088.tif35128 (Ma, et al., 2014, J. Biol. Chem. 289:12457-12466). In certain embodiments, the linker and / or CON may be bonded to the phenyl group indicated by the arrow. See Figure 21 for a non-limiting example.

[0284] In certain embodiments, the TNF binder includes one of the following: In formula TIFF0007842459000089.tif25128, R represents a non-restrictive derivatization site (Kumar, et al., 2011, Chem. Commun. 47:5010-5012). See Figure 22 for an example of non-restrictive derivatization.

[0285] In certain embodiments, TNF binders Includes TIFF0007842459000090.tif19128 (Jiajiu & Shaw, 2013, Cancer Chemother Pharmacol 72:1-7 (2013)).

[0286] In certain embodiments, the TNF binder comprises any dihydro-benzo[cd]indole-6-sulfonamide or analogue as shown herein (non-limiting binding sites to REAG include the naphthyl-containing R1 or hydrophobic R group on the right-hand side of the molecule). TIFF0007842459000091.tif60153TIFF0007842459000092.tif198114

[0287] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000093.tif160128(Shiu-Hin Chan, 2010, Angew Chem Int Ed Engl. 49:2860-4).

[0288] In certain embodiments, the TNF binder includes any of the following: TIFF0007842459000094.tif130148

[0289] In certain embodiments, the TNF binder includes one of the following: TIFF0007842459000095.tif70147(Chen, et al., 2017, J. Chem. Inf. Model. 57:1101-1111).

[0290] In certain embodiments, the TNF binder includes any compound disclosed in U.S. Patent No. 10,266,532, which is incorporated herein in whole by reference.

[0291] In certain embodiments, the TNF binder includes any compound disclosed in U.S. Patent No. 9,879,016, which is incorporated herein in whole by reference.

[0292] In certain embodiments, the TNF binder includes any compound disclosed in WO 2008 / 142623, which is incorporated herein in whole by reference.

[0293] In certain embodiments, the TNF binder includes the following: In certain embodiments, the linker and / or CON may be bonded to the compound via a piperidinyl group (Blevitt, et al., 2017, J. Med. Chem. 60:3511-3517). See Figure 23 for a non-limiting example.

[0294] In certain embodiments, the TNF binder includes a compound of formula (2b), or a pharmaceutically acceptable salt thereof, tautomer, geometric isomer, or stereoisomer: TIFF0007842459000097.tif27128In formula, R 1 is H, OH, F, or an optionally substituted (C1-C3) alkyl group; R 2 is an optionally substituted aryl, optionally substituted (C3-C8) cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or, R 1 and R 2 They may together form a saturated or partially saturated carbocyclic ring, or a saturated or partially saturated heterocyclic ring, which may be substituted; A 1 , A 2 , and A 3 Of these, up to two are N, and the rest are independently C(R) A2 ) and; X is N, Y is C, and here Z 1 is -C(R z )2- and Z 2 is -C(R z )2-, -N(R z1 ) - , or -O-; or, Z 1 is -CH2-, Z 2 Ha-Z 2a -Z 2b -and, Here's Z 2a is Z 1 Combine with Z 2b is C(R 1 )(R 2 ) joins; Z 2a and Z 2b -C(R z )2-, -C(R z )2C(R z )2-, -O-, or -N(R z1 )-However, 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, however R 1 It is neither -OH nor -F, here Z 1 is -C(R z )2- and Z 2 is -C(R z )2- is; or, Z 1 is -C(R z )2- and Z 2 Ha-Z 2a -Z 2b -and, Here's Z 2a is Z 1 Combine with Z 2b is C(R 1 )(R 2 ) joins to Z 2a is -C(R z )2-, -C(R z )2C(R z )2-, -O-, or -N(R z1 ) and Z 2b is -C(R z )2- or -Z 2a -Z 2b -ha-N(R z1 )C(O)- or -C(O)N(R z1 )-form; R 3 ha-R 3a -R 3b And here R 3a is an optionally substituted aryl, an optionally substituted saturated or partially saturated heterocyclyl, or an optionally substituted heteroaryl; R 3bH, -CF3, -CN, -C(O)OH, -N(R a )(R b ), -C(O)N(R a )(R b ), -C(O)- may be 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 (C1-C5) alkyl, -(CH2) may be substituted. p -May be substituted (C3~C6) cycloalkyl, -(CH2) p -Optionally substituted heteroaryl, or -(CH2) p -A saturated, unsaturated, or partially saturated heterocyclyl which may be substituted; however, R 2 If R is a phenyl that may be substituted, 3b It is neither H nor methoxy; R a and R b These are independently H, optionally substituted (C1-C5) alkyl, -C(O)- optionally substituted (C1-C5) alkyl, and optionally substituted -(CH2). p -(C3~C6) cycloalkyl and -(CH2) p -Selected from heterocyclyls which may be substituted; R c and R d These are independently H, optionally substituted (C1-C5) alkyl, and optionally substituted -(CH2). p -(C3~C6) cycloalkyl and -(CH2) p -Selected from heterocyclyls which may be substituted; R A2 These are independently H, CF3, halo, or (C1-C3) alkyl; R z These are independently H, F, CF3, -OH, or (C1-C3) alkyl; R z1 is independently H or (C1-C3) alkyl; p is independently 0, 1, or 2.

[0295] In certain aspects, R 2 This is not a phenyl substituted with -OCHF2.

[0296] In certain embodiments, the compound is 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidine-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidine-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]benzimidazole-7-yl]-2-pyridyl]methanol; tert-butyl 4-[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-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; not (1R or S)-1-phenyl-7-[6-(piperazine-1-yl)pyridine-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0297] In certain embodiments, the compound is 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidine-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidine-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]benzimidazole-7-yl]-2-pyridyl]methanol; tert-butyl 4-[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-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; (1R or S)-1-phenyl-7-[6-(piperazine-1-yl)pyridine-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0298] In certain embodiments, the compound of formula (2a) comprises one of the following: TIFF0007842459000098.tif51128In 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 It is either CH2 or O.

[0299] In certain aspects, R 3a The following group was selected: TIFF0007842459000099.tif18128

[0300] In certain aspects, R 3b The following group was selected: TIFF0007842459000100.tif195149TIFF0007842459000101.tif61128In certain aspects, R 3a or R 3b The TNF linker can be used to link the compounds of this disclosure. This is done using the R listed herein. 3a Or R 3b This can be done using any hydroxyl group, amino group, amide group, thiyl group, or carboxylic acid group that is present in or can be introduced therein, for example. In any of these cases, as is known to those skilled in the art, R 3a or R 3b For example, the hydroxyl group inside can be used to form an ester bond, R 3a or R 3b The carboxylic acid group in the middle can be used, for example, to form an ester bond or an amide bond, R 3a or R 3b The amino group inside can be used, for example, to form an amide group and an imine group, R 3a or R 3b The amino, amide, or thiyl groups within the compound can be used, for example, to form chemical bonds through alkylation or nucleophilic substitution.

[0301] In certain aspects, R 1 The element is selected from the group consisting of H, methyl, and hydroxyl.

[0302] In certain aspects, R 1 and R 2 They come together to form one of the following: TIFF0007842459000102.tif24128

[0303] In certain aspects, R 4The following group was selected: TIFF0007842459000103.tif68128

[0304] In certain embodiments, the compound is selected from the group consisting of the following: 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; 4-(3-fluorophenyl)-7-(2-morpholinopyrimidine-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)pyridine-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (S)-2-(2-Molfolinopyrimidine-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)pyrimidine-2-yl)propan-2-ol; 2-(5-(1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; (S)-7-(2-((1R,6S)-3,10-diazabicyclo[4.3.1]decane-10-yl)pyrimidine-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)pyrimidine-2-yl)-7-azaspiro[3.5]nonane-2-amine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-cyclopenta[4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 1-(5-(8-phenyl-7,8-dihydro-6H-cyclopenta[4,5]imidazo[1,2-b]pyridazine-2-yl)pyrimidine-2-yl)piperidine-4-ol; 2-(5-(4-(2-methoxyphenyl)-3,4-dihydro-1H-pyran[3',4':4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 2-(5-(8-(pyridine-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyrimidine-2-yl)propan-2-ol; 2-(5-(1-(pyridine-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-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)pyrimidine-2-yl)-1,4-oxazepane; 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)-4-methylpiperidine-4-ol; (4-Fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)piperidine-4-yl)methanol; (4-Fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)piperidine-4-yl)methanol; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)azepan-4-ol; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)piperidine-4-ol; 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-4-ol; 7-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-((R)-8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(4-(3-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(4-(2-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 4-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-7-(5-((R)-4-phenyl-3,4-dihydro-1H-pyrano[3',4':4,5]imidazo[1,2-a]pyridine-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 1-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (S)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-3-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)oxetan-3-ol; (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)cyclobutanol; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)tetrahydro-2H-pyran-4-ol; (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 2-(5-(4-(2,6-dichlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-7-yl)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(4-(2-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-indene]-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; (R)-1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)piperidine-4-ol; (R)-4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)morpholine; (S)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; (R)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; (S)-4-(3-fluorophenyl)-7-(2-morpholinopyrimidine-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; Compound of 7-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one and ethane (1:1); 7-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)piperidine-4-ol; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 3,3-difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)piperidine-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)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)morpholine; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)morpholine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)piperazine-2-one; 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-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)pyrimidine-2-yl)morpholine; (S)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)piperidine-4-ol; 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)morpholine; 2-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)propan-2-ol; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzenesulfonamide; 1-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)piperidine-4-ol; 7-(4-(ethylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (S)-7-(2-morpholinopyrimidine-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)pyrimidine-2-yl)morpholine; 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; (S)-7-(2-(1,4-oxazepan-4-yl)pyrimidine-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]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; (1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)piperidine-3-yl)methanol; 1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-7-yl)pyrimidine-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)pyrimidine-2-yl)piperazine-1-sulfonamide; N-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzyl)methanesulfonamide; 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidine-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)pyrimidine-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]imidazole-7-yl)benzenesulfonamide; (4-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-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)pyrimidine-2-yl)thiomorpholine 1,1-dioxide; 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)morpholine; (R)-4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidine-2-yl)morpholine; 2-(5-(1-(3-fluorophenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-yl)methanol; 4-(5-(9-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)morpholine; (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidine-2-yl)propan-2-ol; (S)-7-(2-(1'-methyl-[4,4'-bipiperidine]-1-yl)pyrimidine-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']dipyridine-2-yl)pyrimidine-2-yl)propan-2-ol; 7-(2-morpholinopyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(2-methylmorpholino)pyrimidine-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]oxazine-7-yl)pyrimidine-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)pyrimidine-2-yl)morpholine; Ethyl 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazole-2-yl]pyrimidine-2-yl]amino]acetate; (S)-7-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (S)-7-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)phenyl)acetonitrile; 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-2-yl)piperazine-2-one; 7-(2-cyclopropylpyrimidine-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)pyrimidine-2-yl)piperazin-2-one; 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-2-yl)pyridine-2-yl)oxy)acetic acid; 7-(6-(ethylsulfonyl)pyridine-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)pyrimidine-2-yl)piperazine-2-one; 10-(3-fluorophenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)piperazine-2-one; (S)-6-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-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]imidazole-7-yl)benzamide; N-ethyl-N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 7-(6-morpholinopyridine-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)pyrimidine-2-yl)propan-2-ol; 2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; (S)-7-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-3-yl)acetic acid; 7-(5-methyl-6-morpholinopyridine-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(2-methyl-1H-imidazole-1-yl)pyrazine-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]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; 2-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-4-yl)ethanol; (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)-1,4-diazepan-2-one; 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-4-yl)propanoic acid; 4-phenyl-7-(6-(trifluoromethyl)pyridine-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)pyrimidine-2-yl)piperazine-2-one; 7-(5-fluoro-6-methoxypyridine-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]imidazole-7-yl)pyridine-2-amine; 7-(2-methylpyridine-4-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (4S)-4-phenyl-7-(2-(2-(trifluoromethyl)morpholino)pyrimidine-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)pyrimidine-2-yl)-2,7-diazaspiro[4,4]nonane-1-one; N-cyclopentyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-amine; 7-(2-(1H-pyrazole-1-yl)pyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(2,6-dimethylmorpholino)pyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(6-methylpyridine-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(5-ethoxypyridine-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 2-(2-morpholinopyrimidine-5-yl)-9-(m-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 7-(6-(methylthio)pyridine-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)pyrimidine-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)pyrimidine-2-yl)piperazin-1-yl)propan-1-ol; 9-(3-fluorophenyl)-2-(2-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 2-(2-morpholinopyrimidine-5-yl)-9-phenyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 4-(2,5-difluorophenyl)-7-(2-morpholinopyrimidine-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-Phenyl-7-(6-(piperazin-1-yl)pyridine-3-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 9-(2-methoxyphenyl)-2-(2-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; (S)-7-(2-(2-oxa-6-azapiro[3,4]octan-6-yl)pyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(1H-imidazole-1-yl)pyrazine-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(Flo[3,2-b]pyridine-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(3-chlorophenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; N-ethyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)phenoxy)acetonitrile; 2-(2-morpholinopyrimidine-5-yl)-10-(m-tolyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 2-((5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)amino)acetic acid; N-cyclopropyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 1-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridine-2-yl)piperazin-1-yl)ethanone; 7-(6-(4-methylpiperazin-1-yl)pyridine-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-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 8-phenyl-2-(4-(pyrimidine-2-yl)piperazin-1-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; 9-(4-fluorophenyl)-2-(2-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazine-3(5H)-one; 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)amino)acetic acid; 10-(4-fluorophenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 9-(3-chlorophenyl)-2-(2-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; N-cyclopropyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-amine; 9-(3-chloro-5-fluorophenyl)-2-(2-morpholinopyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; N,N-dimethyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-amine; 1-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidine-2-yl)piperidine-4-carboxylic acid; 7-(6-isopropoxypyridine-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(6-isopropoxypyridine-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)pyrimidine-2-yl)morpholine; 1-phenyl-7-(1-(pyridine-3-ylmethyl)-1H-pyrazole-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]oxazin; 2-(2-morpholinopyrimidine-5-yl)-9-(p-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol; 7-(6-(methylsulfonyl)pyridine-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]imidazole-7-yl)benzamide; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 4-phenyl-7-(6-(2,2,2-trifluoroethoxy)pyridine-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]oxazine-7-yl)pyrimidine-2-yl)piperidine-4-carboxylic acid; 7-(5-methyl-6-(4-methylpiperazine-1-yl)pyridine-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]pyridine-2-yl)thiophene-2-carboxylic acid; 7-(6-(4-methylpiperazine-1-yl)pyridine-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'-bipiperidine]-1-yl)pyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(2-methoxypyrimidine-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-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-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)pyrimidine-2-yl)pyrrolidine-3-ol; 4-(5-(9-(2-methoxyphenyl)-6,7-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)morpholine; 10-(4-methoxyphenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 7-(5-(1H-pyrazole-1-yl)pyrazine-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-Phenyl-7-(pyridine-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]imidazole-7-yl)pyrimidine-2-amine; 2-(2-morpholinopyrimidine-5-yl)-10-(p-tolyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-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)pyrimidine-2-yl)propan-2-ol; (S)-7-(2-((R)-3-(methylsulfonyl)pyrrolidine-1-yl)pyrimidine-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]pyridine-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)pyrimidine-2-yl)propan-2-ol; 7-(2-methylpyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 1-Phenyl-7-(pyrimidine-5-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; 7-(6-methoxy-5-methylpyridine-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(4-chlorophenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)phenyl)acetonitrile; N-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzyl)methanesulfonamide; 7-(6-methylpyridine-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)pyrimidine-2-yl)propan-2-ol; (S)-7-(2-(4-(1-methylpiperidine-4-yl)piperazine-1-yl)pyrimidine-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)pyridine-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; (4S)-7-(2-(3-(methylsulfonyl)pyrrolidine-1-yl)pyrimidine-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)pyrimidine-2-yl)-1,3,8-triazaspiro[4.5]decane-4-one; 7-(6-isopropoxy-5-methylpyridine-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-methylpyridine-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]imidazole-7-yl)benzamide; 4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)morpholine; N-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridine-2-yl)acetamide; N-ethyl-N-methyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyridine-2-amine; 7-(3-methyl-3H-imidazo[4,5-b]pyridine-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 10-(3,5-dimethoxyphenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-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)pyridine-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)pyrimidine-2-yl)pyrrolidine-3,4-diol; N-(2-(dimethylamino)ethyl)-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzamide; 10-(3-methoxyphenyl)-2-(2-morpholinopyrimidine-5-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridine-10-ol; 7-(1,5-dimethyl-1H-pyrazole-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]imidazole-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]pyrazine-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]imidazole-7-yl)pyridine-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)pyrimidine-2-yl)pyrrolidine-3,4-diol; 4-phenyl-7-(pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (S)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)propan-2-ol; 2-(2-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-yl)phenol; 4-(5-(6-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:4,5-b']dipyridine-3-yl)pyrimidine-2-yl)piperazine-2-one; (S)-7-(2-(3-morpholinoazetidine-1-yl)pyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(5-(methylsulfonyl)pyridine-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; (R)-7-(2-morpholinopyrimidine-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine; 7-(2-methylpyridine-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)pyrimidine-2-yl)azetidine-3-carboxylic acid; 7-(1-methyl-1H-pyrrole-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)pyridine-2-amine.

[0305] In certain embodiments, the compound is selected from the group consisting of the following: 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 3,3-difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)piperidine-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)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidine-2-yl)morpholine; (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-2-yl)morpholine; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)piperazine-2-one; 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-4-ol; 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)morpholine; (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidine-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)pyrimidine-2-yl)morpholine; 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; N-methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)benzenesulfonamide; (S)-7-(2-morpholinopyrimidine-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)pyrimidine-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)pyrimidine-2-yl)propan-2-ol; (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidine-2-yl)propan-2-ol; Ethyl 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazole-2-yl]pyrimidine-2-yl]amino]acetate; or 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-2-yl)pyridine-2-yl)oxy)acetic acid.

[0306] In certain embodiments, the compound is selected from the group consisting of the following: (8aR)-7-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)amino)cyclobutanol; 5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-2-amine; 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-3-ol; 2'-(2-(4-methylpiperazine-1-yl)pyrimidine-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-morpholinopyrimidine-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]oxazine-4,1'-indene]-7-yl)pyrimidine-2-yl)piperidine-4-ol; (1-(5-(2,3,6',8'-tetrahydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-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]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 2'-(2-(1,4-oxazepan-4-yl)pyrimidine-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[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-ol; 2-Hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)piperazine-1-yl)ethanone; (4-Fluoro-1-(5-(2,3,6',8'-Tetrahydrospiro[inden-1,9'-Pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-yl)methanol; 2'-(2-morpholinopyrimidine-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[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-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]oxazine]-2'-yl)pyrimidine-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]oxazine]-2'-yl)pyrimidine-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]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)amino)cyclobutanol; 5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-2-amine; 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-3-ol; 2'-(2-(4-methylpiperazine-1-yl)pyrimidine-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-morpholinopyrimidine-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]oxazine-4,1'-indene]-7-yl)pyrimidine-2-yl)piperidine-4-ol; (1-(5-(2,3,6',8'-tetrahydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-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]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 2'-(2-(1,4-oxazepan-4-yl)pyrimidine-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[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-ol; 2-Hydroxy-1-(4-(5-(2,3,6',8'-tetrahydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)piperazine-1-yl)ethanone; (4-Fluoro-1-(5-(2,3,6',8'-Tetrahydrospiro[inden-1,9'-Pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-yl)methanol; 2'-(2-morpholinopyrimidine-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[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-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]pyridine-2-yl)pyridine-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]oxazine]-2'-yl)pyridine-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]oxazine]-2'-yl)pyridine-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]oxazine]-2'-yl)pyridine-2-yl)oxy)cyclopentanol; 2'-(2-morpholinopyrimidine-5-yl)-6',7'-dihydrospiro[cyclohexane-1,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine]; 2'-(2-morpholinopyrimidine-5-yl)-6',7'-dihydrospiro[chroman-4,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine]; 2'-(2-(piperazine-1-yl)pyrimidine-5-yl)-6'H,8'H-spiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-methoxypyrimidine-5-yl)-6',8'-dihydrospiro[chroman-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-ethoxypyrimidine-5-yl)-6',8-dihydrospiro[chroman-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-(methylsulfonyl)pyrimidine-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)pyrimidine-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]oxazine]-2'-yl)-N-isopropylpyrimidine-2-amine; 2'-(2-morpholinopyrimidine-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]oxazine]-2'-yl)pyrimidine-2-yl)propan-2-ol; 2'-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-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]oxazine]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-2-amine; (8aR)-7-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-3-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)azetidine-3-ol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)pyrroridine-3-ol; 3-((5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)amino)cyclobutanol; 1-(5-(6',8'-dihydrospiro[chroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)-3-methylazetidine-3-ol; 2'-(2-(4-methylpiperazine-1-yl)pyrimidine-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-pyrrole-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-pyrrole-3-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-(piperazine-1-yl)pyrimidine-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)pyridine-4-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]; 2'-(2-methoxypyrimidine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-3-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-3-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-1-yl)-2-hydroxyethane-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]oxazine]-2'-yl)pyrimidine-2-yl)-3-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-3-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-1-yl)-2-hydroxyethanone; 2-(5-(2,3-dihydro-6'H,8'H-spiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)propan-2-ol; 2'-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-6',8'-dihydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-3(2H)-one; 2'-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-6'H,8'H-spiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-6'-ol; 2'-(1-(pyrimidine-4-yl)-1,2,3,6-tetrahydropyridine-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]oxazine]-2'-yl)-5,6-dihydropyridine-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]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-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]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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]oxazine]-2'-yl)pyridine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-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]oxazine]-2'-yl)pyrimidine-2-yl)-2-methylpiperazine-1-yl)-2-hydroxyethanone; 1-(5-(6',8'-dihydrospiro[isochroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-ol; (8aR)-7-(5-(6',8'-dihydrospiro[isochroman-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one; 2'-(2-morpholinopyrimidine-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[idene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidine-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]oxazine]-2'-yl)pyrimidine-2-yl)propan-2-amine; or 2'-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3,6',8'-tetrahydrospiro[inden-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-3-ol.

[0307] In certain embodiments, the compound is selected from the group consisting of the following: ((R)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyrimidine-2-yl)pyrrolidine-2-yl)methanol; ((S)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyrimidine-2-yl)pyrrolidine-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]pyridine-2-yl)pyridine-2(1H)-one; 1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-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)pyrimidine-2-yl)ethanol; (5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidine-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)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)piperazine-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)pyrimidine-2-yl)piperazine-1-yl)ethanone; (1R,3R)-3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine-2-yl)pyridin-2-yl)oxy)cyclopentanecarbonitride; (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyridine-2(1H)-one; 2-(5-(8-(pyridine-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyrimidine-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)pyrimidine-2-yl)piperazine-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)pyrimidine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)-2-methylpiperazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)-2-methylpiperazine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)-2-methylpiperazine-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)pyrimidine-2-yl)-2-methylpiperazine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-4-yl phosphate dihydrogen hydrochloride; (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)cyclopentanol; (R)-4-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridine-2-yl)pyridine-2-yl)oxy)cyclohexanol; (R)-2-(2-(oxetan-3-yloxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)cyclohexanol; (R)-2-(2-(oxetan-3-ylmethoxy)pyridine-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(((R)-1-methylpyrrolidine-3-yl)oxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)ethanol; (R)-2-(2-(((S)-1-methylpyrrolidine-3-yl)oxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)cyclohexanol; (8R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-3-yl)oxy)pyridine-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)pyridine-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(cyclopentyloxy)pyridine-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(cyclohexyloxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)cyclohexanecarboxylate; Methyl 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridine-2-yl)pyridine-2-yl)oxy)cyclopentanecarboxylate; (R)-2-(2-butoxypyridine-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]pyrrolidine-2-yl)pyridin-2-yl)oxy)cyclopentanecarbonitride; (R)-8-phenyl-2-(2-((S)-pyrrolidin-3-yloxy)pyridine-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-8-phenyl-2-(2-(piperidine-3-yloxy)pyridine-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-8-phenyl-2-(2-((R)-pyrroridine-3-yloxy)pyridine-4-yl)-7,8-dihydro-6H-pyrroro[2',1':2,3]imidazo[4,5-b]pyridine; (8R)-2-(2-(6-azaspiro[3,4]octan-1-yloxy)pyridine-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)pyridine-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]nonane-1-yloxy)pyridine-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]oxazine]-2'-yl)pyrimidine-2-yl)piperidine-4-ol; (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyridine-2(1H)-one; (R)-1-(2-methoxyethyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)pyridine-2(1H)-one; (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2(1H)-one; 4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)-1-(tetrahydrofuran-3-yl)pyridine-2(1H)-one; (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine-2-yl)-1-(tetrahydro-2H-pyran-4-yl)pyridine-2(1H)-one; (R)-8-phenyl-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-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]oxazine]-2'-yl)pyridine-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)pyrimidine-2-yl)piperidine-4-ol; 2-(2-morpholinopyrimidine-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]pyridine-7-yl)pyridine-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)pyrimidine-2-yl)hexahydroimidazo[1,5-a]pyrazine-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)pyrimidine-2-yl)piperidine-4-ol; 1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidine-2-yl)piperidine-4-ol; 2-(2-(1,4-oxazepan-4-yl)pyrimidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-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)pyrimidine-2-yl)piperazin-1-yl)ethanone; (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine; (R)-2-(2-(2-methoxyethoxy)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)propan-2-ol; (R)-8-phenyl-2-(1,2,3,6-tetrahydropyridine-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]pyridine-2-yl)pyridine-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]pyridine-2-yl)pyridine-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]pyridine-2-yl)pyridine-2-yl)oxy)methyl)cyclohexyl)methanol; (R)-8-phenyl-2-(1-(pyrimidine-4-yl)-1,2,3,6-tetrahydropyridine-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]pyridine-2-yl)cyclohexa-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-2-yl)piperidine-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)pyrimidine-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)pyrimidine-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)pyrimidine-2-yl)propan-2-amine; 2-(2-(4,4-difluoropiperidine-1-yl)pyrimidine-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]pyridine-2-yl)pyridine-2-yl)oxy)cyclohexanol.

[0308] In certain embodiments, the compound is selected from the group consisting of the following: 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)propan-2-ol; 9-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-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']dipyridine-2-yl)pyrimidine-2-yl)morpholine; 1-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-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']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)propan-2-ol; 9-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-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']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol; 4-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-methanoimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-2-yl)morpholine; 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridine-2-yl)pyrimidine-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']dipyridine-2-yl)pyrimidine-2-yl)piperidine-4-ol.

[0309] The disclosures of U.S. Patent Nos. 10,266,532 B2 and 9,856,253 B2, and U.S. Patent Application Publications 20160304517A1 and 2018 / 0179198 A1 are incorporated herein by reference in their entirety.

[0310] In certain embodiments, the TNF binder includes a compound of formula (2c), or a pharmaceutically acceptable salt thereof, tautomer, geometric isomer, or stereoisomer: TIFF0007842459000104.tif31128In formula, X, Y, and Z are independently CR 4 Or it is N; However, Y and Z are not both N; A is -C(R z )2-; E is CH2 or O and G is CH; or E is CH2 and G is CH or N; R 1 is an optionally substituted aryl or optionally substituted heteroaryl; R 2 ha-R 2a -R 2b And here R 2a is a saturated, unsaturated, or partially saturated heterocyclyl, or a heteroaryl, which may be substituted; R 2b is -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 -A heterocyclyl which may be substituted; here R a and R b These are independently H, an optionally substituted (C1-C5) alkyl, and -(CH2) n -Selected from heterocyclyls which may be substituted; R 4 These are independently H, halo, CF3, or (C1-C3) alkyl; R z These are independently H, halo, CF3, or (C1-C3) alkyl; n is either 0 or 1; p is either 0 or 1.

[0311] In certain embodiments, compounds of formula (2c) include the following: In formula TIFF0007842459000105.tif30128, G is N or CH; Z is CH or CF.

[0312] In certain embodiments of the compound of formula (2c), R 1 The following group was selected: TIFF0007842459000106.tif37128

[0313] In certain embodiments of the compound of formula (2c), R 2 The following group was selected: TIFF0007842459000107.tif67156

[0314] In certain aspects, R 2 The TNF linker can be used to link the compounds of this disclosure. This is done using the R listed herein. 2 This can be done using any hydroxyl group, amino group, amide group, thiyl group, or carboxylic acid group that is present in or can be introduced therein, for example. In any of these cases, as is known to those skilled in the art, R 2 For example, the hydroxyl group inside can be used to form an ester bond, R 2 The carboxylic acid group in the middle can be used, for example, to form an ester bond or an amide bond, R 2 The amino group inside can be used, for example, to form an amide group and an imine group, R 2 The amino, amide, or thiyl groups within the compound can be used, for example, to form chemical bonds through alkylation or nucleophilic substitution.

[0315] In certain embodiments, the compound is selected from the group consisting of the following: 3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 1-(5-(3-(2-(difluoromethoxy)phenyl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-6-yl)pyrimidine-2-yl)piperidine-4-carboxylic acid; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidine-1-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidine-1-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 3-(2-(difluoromethoxy)phenyl)-6-(2-(4-hydroxypiperidine-1-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2((((S)-5-oxopyrrolidine-3-yl)methyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2((((S)-5-oxopyrrolidine-3-yl)methyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2((((R)-5-oxopyrrolidine-3-yl)methyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2((((R)-5-oxopyrrolidine-3-yl)methyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azapiro[3.5]nonan-7-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azapiro[3.5]nonan-7-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-6-(2-(4-acetylpiperazine-1-yl)pyrimidine-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-6-(2-(4-acetylpiperazine-1-yl)pyrimidine-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-morpholinopyrimidine-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazole-11(7H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-(4-hydroxypiperidine-1-yl)pyrimidine-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazole-11(7H)-one; 6-(2-(difluoromethoxy)phenyl)-3-(2-(1,1-dioxidethiomorpholino)pyrimidine-5-yl)-8,9-dihydro-6H-pyridazino[1,2-a]indazole-11(7H)-one; 3-(2-methoxyphenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 2-Methyl-6-(6-(2-morpholinopyrimidine-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile; 6-(2-morpholinopyrimidine-5-yl)-3-phenyl-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 4-Methoxy-3-(6-(2-morpholinopyrimidine-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile; 2-Methoxy-3-(6-(2-morpholinopyrimidine-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile; 3-(1-isopropyl-1H-pyrazole-5-yl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 2-Methyl-6-(6-(2-morpholinopyrimidine-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzamide; rac-(1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; rac-(1R,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; rac-(1R,10bR)-1-(2-(difluoromethoxy)phenyl)-9-(2-morpholinopyrimidine-5-yl)-3,4-dihydro-1H-[1,4]oxazino[3,4-a]isoindole-6(10bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrroridine-1-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrroridine-1-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (1R)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropan-2-yl)-4-methylpyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; (R)-6-(2-((R)-4-acetyl-2-methylpiperazine-1-yl)pyrimidine-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-6-(2-((R)-4-acetyl-3-methylpiperazine-1-yl)pyrimidine-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-4-(2-hydroxyacetyl)-3-methylpiperazine-1-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (S)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidine-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one; (R)-6-(2-((R)-4-acetyl-3-methylpiperazine-1-yl)pyrimidine-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one; 9b-(2-methoxyphenyl)-8-(2-morpholinopyrimidine-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; or 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinopyrimidine-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one.

[0316] 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 assumed to be within the scope of this disclosure.

[0317] In certain embodiments, AATM is any peptide and / or small molecule that binds to FcRn, which is known in the art or described elsewhere in this specification.

[0318] In certain embodiments, AATM includes FcRn antagonists such as, but not limited to, rozanolixizumab (see, for example, Kiessling, et al., 2017, Sci. Transl. Med. 9:eaan1208).

[0319] In certain embodiments, AATM includes FcRn antagonists such as, but not limited to, efgartigimod (see, for example, Ulrichts, et al., 2018, J. Clin. Invest. 128(10):4372).

[0320] In certain embodiments, AATM comprises 2,4-dinitrobenzene or any derivative or analog thereof (which may be substituted with a phenyl ring). TIFF0007842459000108.tif20128

[0321] In certain embodiments, 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). The chemical groups indicated by * are non-limiting linker or CON binding sites in the compounds of this disclosure. TIFF0007842459000109.tif96128, It is also represented as TIFF0007842459000110.tif11128 (SEQ ID NO: 139, internal cystine form with C-terminus amidated).

[0322] In certain embodiments, 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). The chemical groups indicated by * are non-limiting linker or CON binding sites in the compounds of this disclosure. TIFF0007842459000111.tif107128, It is also represented as TIFF0007842459000112.tif13128 (SEQ ID NO: 140, internal cystine form with C-terminus amidated).

[0323] In certain embodiments, AATM comprises a compound of formula (3a) or (3b): TIFF0007842459000113.tif28128In formula, R 1 Each occurrence of R 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 bonded, substituted, or otherwise C1-C6 alkyl group, or a substituted, or otherwise C1-C6 heteroalkyl group; R 2Each occurrence of R 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 bonded, substituted, or otherwise C1-C6 alkyl group, or a substituted, or otherwise C1-C6 heteroalkyl group; R 3 is H, R, -OH, -NH2, -NHR, -C(=O)OH, or -SH, where each instance of R is a C1-C6 alkyl or C3-C8 cycloalkyl; R 4 is a cycloalkyl group containing a polycyclic cycloalkyl group, which may be substituted with 1 to 4 groups independently substituted from the group consisting of 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; Here, AATM is R 3 Through, or at least one R 1 Or R 2 It is connected to the linker or CON through this.

[0324] In certain embodiments, AATM comprises one of the following compounds (see WO 2006 / 024175 A1). Each chemical group indicated by * represents a non-limiting linker or CON bond position in the compounds of this disclosure. TIFF0007842459000114.tif150128

[0325] In certain embodiments, AATM comprises the following compounds, where The chemical bond shown in TIFF0007842459000115.tif1128 represents a non-limiting bonding position of linker or CON in the compounds of this disclosure (see Chemistry & Biology 18:1179-1188). TIFF0007842459000116.tif20128In formula, R 1 Each occurrence of R 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 Each occurrence of R is independently H, 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.

[0326] 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 entirety.

[0327] The compounds described herein may have one or more stereocenters, each stereocenter independently existing in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic compounds. It should be understood that the compounds described herein encompass racemic compounds, optically active compounds, positional isomers, and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein. Preparation of optically active compounds is achieved in any preferred manner, including, but not limited to, recrystallization techniques for racemic separation, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0328] The methods and formulations described herein involve the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound described herein, as well as metabolites and active metabolites of these compounds exhibiting similar activity. Examples of solvates include solvates of water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol), and acetic acid esters. In certain embodiments, the compounds described herein exist in solvated forms with water and pharmaceutically acceptable solvents such as ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0329] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0330] In certain embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” means an agent that is converted to the parent drug in vivo. In certain embodiments, at in vivo administration, the prodrug is chemically converted to a biological, pharmaceutical, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical, or therapeutically active form of the compound by one or more steps or processes.

[0331] In certain embodiments, a portion of the compounds described herein, such as an aromatic ring, is susceptible to various metabolic reactions. By incorporating appropriate substituents onto the aromatic ring structure, these metabolic pathways can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents to reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, to name just a few, deuterium, halogens, or alkyl groups.

[0332] The compounds described herein also include isotope-labeled compounds in which one or more atoms are replaced by atoms having the same number of atoms but with atomic masses or atomic mass numbers different from those commonly found in nature. Examples of isotopes suitably included in the compounds described herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S is one example, but is not limited to it. In certain embodiments, isotope-labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium results in increased metabolic stability (e.g., increased in vivo half-life or reduced required dose). In yet another embodiment, 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 1N is useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds are prepared by any suitable method or by a process that uses a suitable isotope-labeled reagent instead of a separately used unlabeled reagent.

[0333] In certain embodiments, the compounds described herein are labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0334] The compounds described herein, and other related compounds having different substituents, can be synthesized using the techniques and materials described herein, and refer to Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), and March, Advanced Organic Chemistry 4. th The compounds are synthesized as described, for example, in Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference). The general methods for preparing the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various parts found in the formulas shown herein.

[0335] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources, or prepared using the procedures described herein.

[0336] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxyl groups are protected to avoid their undesirable involvement in the reaction. Protecting groups are used to block some or all of the reactive parts, preventing the group from participating in the chemical reaction until the protecting group is removed. In other embodiments, each protecting group can be removed by different means. The need for differential removal is satisfied by protecting groups that cleave under completely different reaction conditions.

[0337] In certain embodiments, protecting groups are removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetals, and t-butyldimethylsilyl are acid-unstable and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected with Cbz groups, which are also removable by hydrolysis, and amino groups protected with base-unstable Fmoc groups. Carboxylic acid and hydroxyl reactive moieties are blocked with base-unstable groups such as methyl, ethyl, and acetyl in the presence of amines blocked with acid-unstable groups such as t-butylcarbamates, or with carbamates that are both acid-stable and base-stable but removable by hydrolysis.

[0338] In certain embodiments, the carboxylic acid-reactive and hydroxyl-reactive moieties are blocked by hydrolytically removable protecting groups such as benzyl groups, while the amine group capable of hydrogen bonding with acids is blocked by a base-unstable group such as Fmoc. The carboxylic acid-reactive moiety is protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or blocked by oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while the simultaneously present amino group is blocked by a fluoride-unstable silylcarbamate.

[0339] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups, because the former are stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl blocking carboxylic acids are deprotected by palladium-catalyzed reactions in the presence of acid-unstable t-butylcarbamate or base-unstable acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate binds. As long as the residue is bound to the resin, its functional group is blocked and does not react. When released from the resin, the functional group becomes available for reaction.

[0340] Typically, blocking / protecting groups can be selected from the following: TIFF0007842459000117.tif79136

[0341] Other protecting groups are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference, along with a detailed description of the techniques applicable to the preparation and removal of protecting groups.

[0342] composition A composition comprising the compounds described herein comprises a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for oral or parenteral administration, for example, through routes of administration such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal), urethral (transurethral), intravaginal (e.g., transvaginal and perivaginal), transnasal (intranasal), and rectal (transrectal), intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0343] Treatment method The compounds of this disclosure can be used to treat certain diseases and / or disorders, including but not limited to autoimmune diseases (e.g., IgA nephropathy), cancer, inflammation, and any other diseases or disorders intended herein.

[0344] The methods described herein include a step of administering a therapeutically effective amount of at least one compound described herein, which may be formulated in a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further includes a step of administering an additional therapeutic agent that treats a disease or disorder.

[0345] In certain embodiments, administering the compounds described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of that additional therapeutic agent alone required to achieve similar results in treating a disease or disorder in that subject. For example, in certain embodiments, the compounds described herein reduce the dose of the additional therapeutic agent required to achieve the same effect by enhancing the activity of the additional therapeutic agent.

[0346] In certain embodiments, the compounds and therapeutic agents described herein are administered simultaneously to the subject. In other embodiments, the compounds and therapeutic agents described herein are formulated simultaneously and administered simultaneously to the subject.

[0347] In certain aspects, the subject is a mammal. In other aspects, the mammal is a human.

[0348] Combination therapy Compounds useful within the scope of the methods described herein may be used in combination with one or more additional therapeutic agents useful for treating a disease or disorder, and / or additional therapeutic agents that reduce or alleviate the symptoms of the disease or disorder, and / or the side effects of therapeutic agents used in treating the disease or disorder. These additional therapeutic agents may include compounds that are commercially available or available to those skilled in the art by synthesis. When additional therapeutic agents useful for treating a disease or disorder are used, these additional therapeutic agents are known to treat the disease or disorder or reduce its symptoms.

[0349] In various embodiments, synergistic effects are observed when the compounds described herein are administered together with one or more additional therapeutic agents or therapeutic compounds. These synergistic effects include, for example, sigmoid-E max The effects can be calculated using, for example, preferred methods such as the equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453), the Loewe additive equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326), and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). By applying each of the equations mentioned above to experimental data, corresponding graphs useful for evaluating the effects of drug combinations can be created. The corresponding graphs associated with the equations mentioned above are the concentration-effect curve, the isobologram curve, and the combination exponential curve, respectively.

[0350] Dosage / Prescription The administration regimen may influence what constitutes an effective dose. Therapeutic formulations may be administered before or after the onset of disease or disability. Furthermore, several divided and staggered doses may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. In addition, the dose of the therapeutic formulation may be increased or decreased proportionally as needed depending on the treatment or preventive situation.

[0351] The administration of the compositions described herein to patients, preferably mammals, more preferably humans, can be carried out using known procedures in doses and for durations effective in treating the disease or disorder in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the current state of the disease or disorder in the patient; the patient's age, sex, and weight; and the therapeutic compound's ability to treat the disease or disorder in the patient. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as needed depending on the treatment situation. Non-limiting examples of the effective dose range of the therapeutic compounds described herein are about 1 to 5,000 mg / kg body weight / day. Those skilled in the art will be able to determine the effective dose of the therapeutic compound without excessive experimentation by considering the relevant factors.

[0352] The actual dose level of the active ingredient in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without causing toxicity to the patient.

[0353] In particular, the selected dosage level depends on a variety of factors, including the activity of the specific compound used, the time of administration, the rate of elimination of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, physical condition, overall health, and medical history of the patient being treated, as well as similar factors well known in the medical field.

[0354] A physician with ordinary skills in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian can start with a dose of the compound described herein used in the pharmaceutical composition at a level lower than the level required to obtain the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0355] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage forms to facilitate administration and ensure uniformity of dosage. As used herein, a unit dosage form means a physically separate unit suitable as a unit dosage form for a patient being treated, each unit containing a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical medium. The unit dosage forms of the compounds described herein are determined and directly depend on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding / formulating the therapeutic compound.

[0356] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0357] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by the use of a surfactant. Inhibition of microbial activity can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol and sorbitol, in the composition. Long-term absorption of the injectable composition can be achieved by incorporating absorption-delaying agents, such as aluminum monostearate or gelatin, into the composition.

[0358] In certain embodiments, the compositions described herein are administered to a patient at a frequency ranging from one to five times or more per day. In other embodiments, the compositions described herein are administered to a patient at a frequency ranging from once daily, once every two days, once every three days to once a week, and once every two weeks, but not limited to these. It will be obvious to those skilled in the art that the administration frequency of the various combination compositions described herein will vary from individual to individual depending on many factors, including but not limited to age, the disease or disorder being treated, sex, general health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular administration regime, and the exact administration frequency and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors concerning the patient.

[0359] The compounds described herein for administration are approximately 1 μg to 10,000 mg, approximately 20 μg to 9,500 mg, approximately 40 μg to 9,000 mg, approximately 75 μg to 8,500 mg, approximately 150 μg to 7,500 mg, approximately 200 μg to 7,000 mg, approximately 350 μg to 6,000 mg, approximately 500 μg to 5,000 mg, approximately 750 μg to 4,000 mg, and approximately 1 mg to 3,000 mg. The ranges are mg, approximately 10 mg to 2,500 mg, approximately 20 mg to 2,000 mg, approximately 25 mg to 1,500 mg, approximately 30 mg to 1,000 mg, approximately 40 mg to 900 mg, approximately 50 mg to 800 mg, approximately 60 mg to 750 mg, approximately 70 mg to 600 mg, and approximately 80 mg to 500 mg, as well as any and all integer or decimal increments between them.

[0360] In some embodiments, the dose of the compound described herein is about 1 mg to about 2,500 mg. In some embodiments, the dose of the compound described herein used in the composition described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, as well as any and all of these in integer or decimal increments.

[0361] In certain embodiments, the composition described herein is a packaged pharmaceutical composition comprising a container for holding a therapeutically effective amount of the compound described herein, either alone or in combination with a second agent, and instructions for using the compound in a patient to treat a disease or disorder or to reduce one or more of its symptoms.

[0362] The formulations can be used as mixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carriers, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. The pharmaceutical formulations may be sterile and, if desired, may be mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic agents. If desired, they may be combined with other effective agents, such as other analgesics.

[0363] Routes of administration for any composition described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical administration. Compounds used in the compositions described herein can be formulated for administration by any preferred route, for example, oral or parenteral administration, percutaneous, transmucosal (e.g., sublingual, intralingual, buccal, urethral (transurethral), vaginal (e.g., transvaginal and perivaginal), nasal (intranasal, and rectal (transrectal)), intravesical, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0364] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, licks, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions described herein are not limited to the specific preparations and compositions described herein.

[0365] Oral administration For oral administration, tablets, sugars, solutions, drops, suppositories, or capsules, caplets, and gel capsules are particularly preferred. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Examples of these excipients include inert diluents such as lactose; granulators and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or coated by known techniques for aesthetic purposes or to delay the release of the active ingredient. Oral formulations may also be presented as hard gelatin capsules containing a mixture of the active ingredient and an inert diluent.

[0366] For oral administration, the compounds described herein may be in the form of tablets or capsules, prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, crystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets may be coated using suitable methods and coating materials, such as the OPADRY® film coating system available from Colorcon, West Point, Pennsylvania (e.g., OPADRY® OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY® White, 32K18400). Liquid formulations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid formulations can be prepared by conventional means with suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (e.g., lecithin or gum arabic); non-aqueous media (e.g., almond oil, oily esters, or ethyl alcohol); and pharmaceutically acceptable additives such as preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid).

[0367] Parenteral administration For parenteral administration, the compounds described herein can be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses and / or for continuous infusion. Suspensions, solutions, or emulsions in an oily or aqueous medium may be used, which may contain other formulation agents such as suspending agents, stabilizers, and / or dispersants.

[0368] The sterile injectable formulations of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile non-volatile oils are commonly used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as pharmaceutically acceptable natural oils such as olive oil or castor oil, particularly their polyoxyethylated derivatives, are useful in the preparation of injectable formulations. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0369] Further forms of administration Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Further dosage forms suitable for use with the compounds and compositions described herein include those described in PCT applications WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0370] Controlled-release formulations and drug delivery systems In certain embodiments, the formulations described herein may, but are not limited to, short-release formulations, rapid-release formulations, and controlled-release formulations, such as sustained-release formulations, delayed-release formulations, and pulsed-release formulations.

[0371] The term "sustained-release," as it is commonly used, refers to a drug formulation that releases the drug gradually over a long period, and can, if not necessarily, maintain a substantially constant level of the drug in the blood over that period. The duration can be longer than one month and should be longer than the release of the same amount of drug administered in bolus form.

[0372] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that imparts sustained release properties to the compound. Therefore, the compound used in the method described herein can be administered, for example, by injection in the form of a microparticle, or by embedding in the form of an edible film or disc.

[0373] In some cases, the dosage form used can be realized as a slow or controlled release of one or more active ingredients in the dosage form, for example, by using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof in various proportions to achieve a desired release profile. Suitable controlled-release formulations known to those skilled in the art, including those described herein, are readily selectable for use in the pharmaceutical compositions described herein. Accordingly, single unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, adapted for controlled release, are included in the compositions and dosage forms described herein.

[0374] Most controlled-release formulations share the common goal of improving drug therapy compared to the corresponding uncontrolled formulati...

Claims

1. Compounds of formula (III), or pharmaceutically acceptable salts thereof: [AATM] k' -[CON] h -[リンカー] i -[CON] h' -[CRBM] j' (III) During the ceremony, AATM is as follows: The autoantibody binding site is selected from the group consisting of the following, where * indicates a binding site to a linker or CON; CRBM has the following structure: (In the formula, Z B is absent, -(CH 2 ) IM -, -C(=O)-(CH 2 ) IM -, or -C(=O)(CH 2 ) IM -NR M -, where any carbonyl in Z B is bonded to NH, R M C may be substituted with H or 1-2 hydroxyl groups. 1 ~C 3 It is alkyl, Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6. Having; CON is independently selected in each occurrence from the following group: (a) A group selected from the following group: (In the formula, one of R'' and R' is a bond, and the other is H or methyl.) (b) The basis of the following structure: (In the formula, R 1a , R 2a , and R 3a H and -(CH) are independent of each other. 2 ) M1 -,-(CH 2 ) M2 C(=O) M3 (NR 4 ) M3 -(CH 2 ) M2 -,-(CH 2 ) M2 (NR 4 ) M3 C(O) M3 -(CH 2 ) M2 -, or -(CH 2 ) M2 O-(CH 2 ) M1 -C(O)NR 4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; Each occurrence of M1 is independently 1, 2, 3, or 4; Each occurrence of M2 is independently 0, 1, 2, 3, or 4; Each occurrence of M3 is independently either 0 or 1; and R 4 Each occurrence of H and C is independent. 1 ~C 3 Alkyl, C 1 ~C 6 Alkanol, or -C(=O)(C 1 ~C 3 Alkyl) However, the same R 1a , R 2a , and R 3a (M2 and M3 within it cannot be 0 at the same time); The linker is independently selected in each occurrence from the following group: (i) Polyethylene glycol linker having 2 to 12 ethylene glycol residues, (ii) Polypropylene glycol or polypropylene-co-polyethylene glycol linker containing 1 to 100 alkylene glycol units, (iii) The basis of the following structure: -CH 2 CH 2 (OCH 2 CH 2 ) m OCH 2 -、-(CH 2 ) m CH 2 -、または-[N(R a )-CH(R b )(C=O)] m - (In the formula, Each occurrence of m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. R a H and C are independent of each other. 1 ~C 3 Alkyl, or C 1 ~C 6 Alkanol, R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH 3 )CH 2 CH 3 -, -CH 2 CH(CH 3 ) 2 -, -(CH 2 ) 3 -guanidine, -CH 2 C(=O)NH 2 -, -CH 2 C(=O)OH, -CH 2 SH, -(CH 2 ) 2 C(=O)NH 2 -, -(CH 2 ) 2 C(=O)OH, -(CH[[ID=�7]] 2 )imidazole, -(CH 2 ) 4 NH 2 -, -CH 2 CH 2 SCH 3 -, benzyl, -CH 2 OH, -CH(OH)CH 3 -, and -(CH 2 )phenol, or Or R a R a Together with the nitrogen atom to which it is bonded, R b (It combines with other elements to form a pyrrolidine group or a hydroxypyrroline group); (iv) The basis of the following formula: (In the formula, Z and Z' are independent of each other, bonded, -(CH 2 ) i -O-, -(CH 2 ) i -S-, -(CH 2 ) i -N(R)-, and; R 2 Each occurrence of H or C is independent. 1 ~C 3 It is alkyl; Each occurrence of Y is independently a combination, -O-, -S-, or -N(R)-; D is a bond, -(CH 2 ) i -YC(=O)-Y-(CH 2 ) i -,-(CH 2 ) m' -, or -[(CH 2 ) n -X 1 ] j -However, Z, Z', and D cannot be combined at the same time; X 1 Each occurrence of -O-, -S-, or -N(R)- is independent; Each occurrence of R is independent of H and C. 1 ~C 3 Alkyl, or C 1 ~C 6 It is alkanor; Each occurrence of i is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of m' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; (v) The basis of the following structure: -CH 2 -(OH 2 CH 2 ) n -CH 2 -、-(CH 2 CH 2 ABOUT) n' CH 2 CH 2 -、または-(CH 2 CH 2 CH 2 ABOUT) n - (In the formula, Each occurrence of n is an independent integer between 1 and 25; n' is an integer between 1 and 25); (vi) Formula: -PEG-[CON]-PEG- base During the ceremony, Each PEG independently consists of 1 to 12 ethylene glycol residues in each occurrence. [CON] is (is); and (vii) Formula: Base of -ZD-Z'-[CON]-ZD-Z'- (In the formula, [CON] is and; During the ceremony, Each occurrence of Z and Z' is independently combined or -(CH 2 ) i -O- is; D is a bond, -(CH 2 ) m' -, or -[(CH 2 ) n -X 1 ] j -and; X 1 is -O-; However, Z, Z', and D cannot be combined simultaneously; i is 2; n is 2; Each occurrence of m' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; In equation (III), k' is 1, 2, or 3; In equation (III), h is 0, 1, 2, 3, 4, 5, or 6; In equation (III), i is 1, 2, 3, 4, or 5; In equation (III), h' is 0, 1, 2, 3, 4, 5, or 6; In equation (III), j' is 1, 2, or 3; However, the sum of h and h' in equation (III) is greater than 0.

2. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound according to claim 1.

3. The pharmaceutical composition according to claim 2, further comprising another therapeutically active agent for treating, relieving, and / or preventing a disease or disorder.

4. A pharmaceutical composition for treating, relieving, and / or preventing an autoimmune disease in a subject, comprising a therapeutically effective amount of at least one compound of formula (III) or a pharmaceutically acceptable salt thereof; [AATM] k' -[CON] h -[リンカー] i -[CON] h' -[CRBM] j' (III) During the ceremony, AATM is as follows: The autoantibody binding site is selected from the group consisting of the following, where * indicates a binding site to a linker or CON; CRBM has the following structure: (In the formula, Z B is nonexistent, -(CH 2 ) IM -, -C(=O)-(CH 2 ) IM -, or -C(=O)(CH 2 ) IM -NR M -and here Z B Each of the carbonyl groups inside is bound to NH, R M C may be substituted with H or 1-2 hydroxyl groups. 1 ~C 3 It is alkyl, Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6. Having; CON is independently selected in each occurrence from the following group: (a) A group selected from the following group: (In the formula, one of R'' and R' is a bond, and the other is H or methyl.) (b) The basis of the following structure: (In the formula, R 1a , R 2a , and R 3a H and -(CH) are independent of each other. 2 ) M1 -,-(CH 2 ) M2 C(=O) M3 (NR 4 ) M3 -(CH 2 ) M2 -,-(CH 2 ) M2 (NR 4 ) M3 C(O) M3 -(CH 2 ) M2 -, or -(CH 2 ) M2 O-(CH 2 ) M1 -C(O)NR 4 -However, R 1a , R 2a , and R 3a It is not possible for both to be H at the same time; Each occurrence of M1 is independently 1, 2, 3, or 4; Each occurrence of M2 is independently 0, 1, 2, 3, or 4; Each occurrence of M3 is independently either 0 or 1; and R 4 Each occurrence of H and C is independent. 1 ~C 3 Alkyl, C 1 ~C 6 Alkanol, or -C(=O)(C 1 ~C 3 Alkyl) However, the same R 1a , R 2a , and R 3a (M2 and M3 within it cannot be 0 at the same time); The linker is independently selected in each occurrence from the following group: (i) Polyethylene glycol linker having 2 to 12 ethylene glycol residues, (ii) Polypropylene glycol or polypropylene-co-polyethylene glycol linker containing 1 to 100 alkylene glycol units, (iii) The basis of the following structure: -CH 2 CH 2 (OCH 2 CH 2 ) m OCH 2 -、-(CH 2 ) m CH 2 -、または-[N(R a )-CH(R b )(C=O)] m - (In the formula, Each occurrence of m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. R a H and C are independent of each other. 1 ~C 3 Alkyl, or C 1 ~C 6 Alkanol, R b These are independently hydrogen, methyl, isopropyl, and -CH(CH 3 )CH 2 CH 3 ,-CH 2 CH(CH 3 ) 2 ,-(CH 2 ) 3 -Guanidine, -CH 2 C(=O)NH 2 ,-CH 2 C(=O)OH, -CH 2 SH, -(CH 2 ) 2 C(=O)NH 2 ,-(CH 2 ) 2 C(=O)OH, -(CH 2 ) Imidazole, -(CH 2 ) 4 NH 2 ,-CH 2 CH 2 SCH 3 , benzyl, -CH 2 OH, -CH(OH)CH 3 , and -(CH 2 ) Selected from the group consisting of phenols, Or R a R a Together with the nitrogen atom to which it is bonded, R b (It combines with other elements to form a pyrrolidine group or a hydroxypyrroline group); (iv) The basis of the following formula: (In the formula, Z and Z' are independent of each other, bonded, -(CH 2 ) i -O-, -(CH 2 ) i -S-, -(CH 2 ) i -N(R)-, and; R 2 Each occurrence of H or C is independent. 1 ~C 3 It is alkyl; Each occurrence of Y is independently a combination, -O-, -S-, or -N(R)-; D is a bond, -(CH 2 ) i -YC(=O)-Y-(CH 2 ) i -,-(CH 2 ) m' -, or -[(CH 2 ) n -X 1 ] j -However, Z, Z', and D cannot be conjugated simultaneously; X 1 Each occurrence of -O-, -S-, or -N(R)- is independent; Each occurrence of R is independent of H and C. 1 ~C 3 Alkyl, or C 1 ~C 6 It is alkanor; Each occurrence of i is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of m' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; (v) The basis of the following structure: -CH 2 -(OH 2 CH 2 ) n -CH 2 -、-(CH 2 CH 2 ABOUT) n' CH 2 CH 2 -、または-(CH 2 CH 2 CH 2 ABOUT) n - (In the formula, Each occurrence of n is an independent integer between 1 and 25; n' is an integer between 1 and 25); (vi) Formula: -PEG-[CON]-PEG- base During the ceremony, Each PEG independently consists of 1 to 12 ethylene glycol residues in each occurrence. [CON] is (is); and (vii) Formula: Base of -ZD-Z'-[CON]-ZD-Z'- (In the formula, [CON] is and; During the ceremony, Each occurrence of Z and Z' is independently combined or -(CH 2 ) i -O- is; D is a bond, -(CH 2 ) m' -, or -[(CH 2 ) n -X 1 ] j -and; X 1 is -O-; However, Z, Z', and D cannot be combined simultaneously; i is 2; n is 2; Each occurrence of m' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; In equation (III), k' is 1, 2, or 3; In equation (III), h is 0, 1, 2, 3, 4, 5, or 6; In equation (III), i is 1, 2, 3, 4, or 5; In equation (III), h' is 0, 1, 2, 3, 4, 5, or 6; In equation (III), j' is 1, 2, or 3; However, the sum of h and h' in equation (III) is greater than 0.

5. 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 purpura. Oglobulinemia, 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 dysthenia syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, pediatric autoimmune streptococcal-associated neuropsychiatric disorders (PANDA). S) Progressive inflammatory neuropathy, restless legs syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mohlen'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 4, 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.

6. The pharmaceutical composition according to claim 4, administered to a subject in combination with at least one additional therapeutic agent for treating, relieving, and / or preventing an autoimmune disease.

7. The pharmaceutical composition according to claim 4, wherein the target is a mammal.

8. The pharmaceutical composition according to claim 4, wherein the target is human.

9. The linker is -ZD-Z'-[CON]-ZD-Z'-, During the ceremony, [CON] and; During the ceremony, Each occurrence of Z and Z' is independently combined or -(CH 2 ) i -O- is; D is bonded, -(CH 2 ) m' -, or -[(CH 2 ) n -X 1 ] j -and; X 1 is -O-; However, Z, Z', and D cannot be combined simultaneously; i is 2; n is 2; Each occurrence of m' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound according to claim 1.

Images