Targeted bifunctional degradation agents

Abstract

The present disclosure provides, in one aspect, bifunctional compounds useful for promoting or enhancing degradation of certain circulating proteins. In another aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment and / or management of a disease and / or disorder entails degradation, clearance, or reduction of the concentration of circulating proteins or autoantibodies in a subject. Thus, in certain embodiments, administration of compounds of the present disclosure to a subject clears or reduces the circulating concentration of circulating proteins or autoantibodies, thus treating, ameliorating or preventing diseases and / or disorders. In certain embodiments, the circulating protein is a TNF.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Application No. 17 / 654,990, filed March 15, 2022, which is incorporated herein by reference in its entirety.

[0003] Statement regarding federally funded research or development

[0004] This invention was made with government support under license number GM067543 granted by the National Institutes of Health and license number W81XWH-13-1-0062 granted by the United States Army Medical Research and Material Command. The government holds certain rights to this invention.

[0005] Materials submitted in text files through the office electronic document system are incorporated by reference.

[0006] This disclosure contains one or more sequences in a computer-readable format of an attached text file entitled “047162-7250WO2_sequence_listing”, which is 160.2 KB in size and was created on March 14, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0007] One mechanism regulating the transport of molecules into the cell is receptor-mediated endocytosis. In this process, a receptor on the cell surface binds to a specific ligand (or molecule containing such a ligand) located outside the cell—this ligand can be a small molecule, metabolite, hormone, protein, or even a virus. This binding triggers invagination of the plasma membrane, forming a vesicle containing the receptor-ligand complex. The vesicle becomes an endosome and subsequently fuses with a lysosome, and the receptor, along with the ligand cargo bound to it, is either degraded or reclaimed to the cell surface for further collection of circulating ligands.

[0008] One such receptor is the desialylate glycoprotein receptor (ASGPR). This receptor is a C-type lectin, and its primary biological function is to bind to, internalize, and subsequently clear glycoproteins (desialylglycoproteins) containing terminal galactose or N-acetylgalactosamine residues from circulation. ASGPR clears 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, and is also weakly expressed in glandular cells of the gallbladder and stomach. These receptors are known to be involved in clearing circulating IgG isoforms and other antibody isoforms, eliminating apoptotic cells, clearing low-density lipoprotein (LDL) and chylomicron residues, and processing fibronectin.

[0009] Tumor necrosis factor (TNF, also known as tumor necrosis factor α or TNFα) is a cell signaling protein (cytokine) involved in the acute-phase systemic inflammatory response. It is primarily produced by activated macrophages, but can also be produced by other cell types, such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons. The main function of TNF is to regulate immune cells. TNF is an endogenous pyrogen and can induce fever, apoptotic cell death, cachexia, and inflammation, as well as inhibit tumorigenesis and viral replication. It also responds to sepsis via cells that produce IL-1 and IL-6. Dysregulation of TNF production plays a role in diseases such as Alzheimer's disease, cancer, major depressive disorder, psoriasis, and inflammatory bowel disease (IBD).

[0010] Autoantibodies are antibodies produced by the immune system that react with one or more proteins found in a person's own body. Sometimes, the immune system stops recognizing one or more normal components of the body as "its own," leading to the production of pathological (or disease-related) autoantibodies. These autoantibodies attack the body's own healthy cells, tissues, or organs, causing inflammation and damage. Many autoimmune diseases, such as lupus, are caused by these autoantibodies.

[0011] Pathological autoantibodies may target specific organs or be systemic in nature. Autoantibodies contribute to the development and progression of many diseases, including but not limited to Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, atypical hemolytic uremic syndrome (HUS), catastrophic antiphospholipid syndrome (CAPS), systemic lupus erythematosus (SLE), chronic inflammatory demyelinating polyneuropathy (CIDP), childhood autoimmune neuropsychiatric disorders associated with streptococcal infection, and Sydenham's chorea.

[0012] Clearing disease-associated autoantibodies has been shown to alleviate symptoms and lead to improved clinical outcomes. Currently, strategies for reducing antibody titers include plasmapheresis, where the patient's plasma is separated from whole blood through centrifugation / filtration and replaced with plasma or albumin from a healthy donor; and intravenous immunoglobulin (IVIG), where antibodies are pooled from donor plasma and injected intravenously into the patient. These methods all have limitations and drawbacks. Challenges of plasmapheresis include high cost, inconvenience, and significant health risks and complications (such as stroke, hypotension, infection, and hypocalcemia). Similarly, IVIG also has many disadvantages, including cost, long response time, and side effects (such as allergies).

[0013] There is a need in the art for novel compounds and methods that allow the inhibition, clearance, and / or degradation of TNF in order to treat, improve, and / or prevent certain diseases and / or disorders in subjects. There is also a need in the art for novel compounds and methods that allow the inhibition, clearance, and / or degradation of certain extracellular proteins in order to treat, improve, and / or prevent certain diseases and / or disorders in subjects. Furthermore, there is a need in the art for novel compounds and methods that allow the inhibition, clearance, and / or degradation of certain autoantibodies that mediate diseases and / or disorders in subjects. This disclosure addresses these needs. Summary of the Invention

[0014] This disclosure provides a compound comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0015] [Protein binding agents] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (I),

[0016] Protein binders, CON, linker groups, CRBM, k', h, i, h' and j' are defined elsewhere in this document.

[0017] This disclosure further provides a compound comprising formula (II), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0018] [TNF binding agents] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (II),

[0019] TNF binder, CON, linker group, CRBM, k', h, i, h' and j' are defined elsewhere in this document.

[0020] This disclosure further provides a compound comprising formula (III), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0021] [AATM] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (III),

[0022] AATM, CON, linking group, CRBM, k', h, i, h' and j' are defined elsewhere in this document.

[0023] This disclosure further provides a pharmaceutical composition comprising at least one compound considered herein and at least one pharmaceutically acceptable excipient.

[0024] This disclosure further provides a method for treating a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound considered herein. Attached Figure Description

[0025] The accompanying drawings generally illustrate various embodiments of this application by way of example and not by way of limitation.

[0026] As used herein, the term "REAG" refers to any reagent including -CON, -linker group, -CON-linker group, -linker group-CON, -CON-linker group-CON, -CRBM, -CON-CRBM, -linker group-CRBM, -CON-linker group-CRBM, -linker group-CON-CRBM, and / or -CON-linker group-CON-CRBM. In some embodiments, REAG reacts with a TNF-binding group to incorporate a TNF-binding agent into a compound or fragment thereof, its derivative or intermediate thereof of this disclosure. In some embodiments, REAG reacts with a protein-binding group to incorporate a protein-binding agent into a compound or fragment thereof, its derivative or intermediate thereof of this disclosure. In some embodiments, REAG reacts with an AATM group to incorporate AATM into a compound or fragment thereof, its derivative or intermediate thereof of this disclosure. In some embodiments, the symbol... This indicates a non-restrictive position where REAG and / or protein binders and / or AATM can be covalently linked.

[0027] Figure 1The non-limiting preparation of compounds including folic acid receptor binders of the present disclosure is illustrated.

[0028] Figure 2 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0029] Figure 3 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0030] Figure 4 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0031] Figure 5 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0032] Figure 6 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0033] Figure 7 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0034] Figure 8 The diagram illustrates the non-limiting preparation of compounds including mannose receptor binders of this disclosure.

[0035] Figure 9 The diagram illustrates the non-limiting preparation of polymer compounds including mannose-6-phosphate receptor binders.

[0036] Figure 10 A diagram illustrating R in ASGPRBM 1 and / or R 3 Non-limiting examples of groups.

[0037] Figure 11 A diagram illustrating R in ASGPRBM 2 Non-limiting examples of groups.

[0038] Figure 12 The non-limiting synthesis of the compounds disclosed herein is illustrated.

[0039] Figure 13 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0040] Figure 14 The non-limiting synthesis of the compounds disclosed herein is illustrated.

[0041] Figure 15 The non-limiting synthesis of the compounds disclosed herein is illustrated.

[0042] Figure 16 The non-limiting synthesis of the compounds disclosed herein is illustrated.

[0043] Figure 17 The non-limiting synthesis of the compounds disclosed herein is illustrated.

[0044] Figure 18 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0045] Figure 19 The diagram illustrates a non-limiting synthesis of intermediates for preparing certain compounds of this disclosure (such as, but not limited to, formula (2a)).

[0046] Figure 20 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0047] Figure 21 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0048] Figure 22 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0049] Figure 23 The non-limiting synthesis of the TNF binder considered in this disclosure and its coupling with REAG to generate the compound of this disclosure are illustrated.

[0050] Figures 24A-24B The non-restricted synthesis of the ASGPRBM group is illustrated.

[0051] Figures 25A-25D The non-limiting synthesis of certain ASGPRBM groups is illustrated. Examples disclose non-limiting Cbz protecting groups, but synthesis can also be performed using any other suitable protecting groups known to those skilled in the art. Protecting groups (one or more) in each intermediate and / or final product can be deprotected as appropriate.

[0052] Figure 26A-26LThe non-limiting synthesis of certain ASGPRBM groups is illustrated. Examples disclose non-limiting Cbz protecting groups, but synthesis can also be performed using any other suitable protecting groups known to those skilled in the art. Protecting groups (one or more) in each intermediate and / or final product can be deprotected as appropriate.

[0053] Figure 27A-27O The non-limiting synthesis of certain ASGPRBM groups is illustrated. Examples disclose non-limiting Cbz protecting groups, but synthesis can also be performed using any other suitable protecting groups known to those skilled in the art. Protecting groups (one or more) in each intermediate and / or final product can be deprotected as appropriate.

[0054] Figures 28A-28B The non-limiting compounds of this disclosure, including the PCSK9 binder, and their preparation are illustrated.

[0055] Figure 29 The non-limiting compounds of this disclosure, including the PCSK9 binder, and their preparation are illustrated.

[0056] Figure 30 The non-limiting compounds of this disclosure, including the PCSK9 binder, and their preparation are illustrated.

[0057] Figure 31 The non-limiting compounds of this disclosure, including the PCSK9 binder, and their preparation are illustrated.

[0058] Figure 32 The non-limiting compounds of this disclosure, including VEGF binders, and their preparation are illustrated.

[0059] Figure 33 The non-limiting compounds of this disclosure, including VEGF binders, and their preparation are illustrated.

[0060] Figure 34 The non-limiting compounds of this disclosure, including TGF-β binders, and their preparation are illustrated.

[0061] Figure 35 The non-limiting compounds of this disclosure, including TGF-β binders, and their preparation are illustrated.

[0062] Figure 36 The non-limiting compounds of this disclosure, including the TSP-1 binder, and their preparation are illustrated.

[0063] Figures 37A-38B The non-limiting compounds of this disclosure, including soluble uPAR binders, and their preparation are illustrated.

[0064] Figures 38A-38BThe non-limiting compounds of this disclosure, including PSMA binders, and their preparation are illustrated.

[0065] Figures 39A-39B The non-limiting compounds of this disclosure, including IL-2 binders, and their preparation are illustrated.

[0066] Figures 40A-40B The non-limiting compounds of this disclosure, including the GP120 binder, and their preparation are illustrated.

[0067] Figure 41 The non-limiting compounds of this disclosure, including the GP120 binder, and their preparation are illustrated.

[0068] Figure 42 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0069] Figure 43 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0070] Figure 44 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0071] Figure 45 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0072] Figure 46 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0073] Figure 47 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0074] Figure 48 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0075] Figure 49 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0076] Figure 50 The non-limiting preparation of compounds of this disclosure, including MIF binders, is illustrated.

[0077] Figures 51A-51B The non-restrictive PCSK9 ligand and its schematic synthesis are illustrated.

[0078] Figures 52A-52B The non-restrictive PCSK9 ligand and its schematic synthesis are illustrated.

[0079] Figures 53A-53B The non-restrictive PCSK9 ligand and its schematic synthesis are illustrated.

[0080] Figure 54 The non-restrictive PCSK9 ligand and its schematic synthesis are illustrated.

[0081] Figure 55A-55N The diagram illustrates the non-limiting synthesis of certain ASGPRBM groups and / or compounds of this disclosure using MIF binders as non-limiting protein binders. Any protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0082] Figures 56A-56O The diagram illustrates the non-limiting synthesis of certain ASGPRBM groups and / or compounds of this disclosure using MIF binders as non-limiting protein binders. Any protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0083] Figure 57A-57M The diagram illustrates the non-limiting synthesis of the TNF binders considered in this disclosure and their coupling with REAG to generate compounds of this disclosure, such as, but not limited to, formula (2b).

[0084] Figure 58 Some compounds of formula (2b) are illustrated, wherein in the non-limiting embodiments R represents R 3b .

[0085] Figure 59 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0086] Figure 60 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0087] Figure 61 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0088] Figure 62 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0089] Figure 63 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0090] Figure 64 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0091] Figure 65The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0092] Figure 66 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0093] Figure 67 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0094] Figure 68 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0095] Figure 69 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2b).

[0096] Figures 70A-70C The diagram illustrates what can be used for preparation (2b) (providing R) 3 ) or formula (2c) (providing R 2 Non-restricted synthesis of certain intermediates of compounds.

[0097] Figure 71 The non-limiting synthesis of some compounds of this disclosure is illustrated, such as, but not limited to, formula (2c).

[0098] Figure 72 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2c).

[0099] Figure 73 The diagram illustrates the non-restricted synthesis of intermediates that can be used to prepare compounds of formula (2c).

[0100] Figure 74 The non-restricted synthesis of the compound of formula (2c) is illustrated.

[0101] Figure 75 The structure of GalNAc-NH2 is illustrated.

[0102] Figure 76 The diagram illustrates the unrestricted synthesis of indole-GN3, a bifunctional molecule that targets the degradation of human IgG / IgE / IgM.

[0103] Figure 77 The diagram illustrates the unrestricted synthesis of AMD-GN3, a bifunctional molecule that targets the selective degradation of human IgG.

[0104] Figure 78The diagram illustrates the unrestricted synthesis of FcIII-GN3, a bifunctional molecule that targets the selective degradation of human IgG.

[0105] Figures 79A-79B The figure illustrates in vivo data demonstrating that DNP-GN3 mediates the cleavage of anti-DNP IgG in mouse serum. Figure 79A Mouse experiments showed that the bifunctional molecule DNP-GN3 induced the degradation of anti-DNP IgG antibodies injected into mouse serum, while the negative control molecule or mediator control did not show this effect. Purple arrow: Intraperitoneal injection of anti-DNP IgG antibody into mice; Green arrow: Intraperitoneal injection of PBS (mediator), DNP-(OH)3 (negative control), or DNP-GN3 into mice. Figure 79B The structure of DNP-GN3.

[0106] Figures 80-84 The non-limiting synthesis of some of the bifunctional compounds disclosed herein is illustrated.

[0107] Figure 85 The synthesis of DNP-OH3 is illustrated.

[0108] Figures 86A-86C The formation of the DNP-GN3-mediated ternary complex is illustrated. Figure 86A DNP-GN3 mediates the formation of a ternary complex between hepatocytes and α-DNP antibodies. Figure 86B The formation of the DNP-GN3-mediated ternary complex is inhibited by competitive binding agents of ASGPR or α-DNP antibodies. Figure 86C The formation of the DNP-GN3-mediated ternary complex was inhibited by the reported ASGPR-binding proteins desialylated fetoglobulin and asialylated serum mucin.

[0109] Figures 87A-87B The diagram illustrates that the endocytosis of α-DNP antibody depends on the concentrations of α-DNP antibody and DNP-GN3. Figure 87A : Enthalation of α-DNP antibody six hours later. Figure 87B : Internalization of α-DNP antibody after 12 hours.

[0110] Figure 88The graph illustrates how competitive binding agents of ASGPR or α-DNP antibodies reduce DNP-GN3-mediated endocytosis. Controls are shown in gray, compounds expected to inhibit the proposed mode of action of DNP-GN3 are shown in blue, and compounds not expected to inhibit it are shown in red. Data are expressed as mean ± SD of nine replicates across four experiments. Statistical differences were determined by the Kruskall-Wallace test and post-hoc comparisons between each inhibitor group and the non-inhibitor group (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, “ns”P>0.9999).

[0111] Figure 89 The figure illustrates how clathrin-dependent endocytosis inhibitors reduce DNP-GN3-mediated α-DNP antibody uptake. Data are expressed as mean ± SD of nine replicates across four experiments. Statistical analysis is as follows: Figure 88 As outlined in the document.

[0112] Figure 90 The diagram illustrates that the accumulation of α-DNP antibody-derived fluorescence in cells depends on the presence of α-DNP antibody and DNP-GN3.

[0113] Figures 91A-91B The diagram illustrates how endocytosed α-DNP antibodies are transported to lysosomes 12 hours later. Figure 91A The endocytic α-DNP antibody does not colocalize with the early endosome marker EEA1. Figure 91B The endocytic α-DNP antibody co-localizes with the late endosome and lysosomal protein LAMP2 in cells.

[0114] Figures 92A-92B This diagram illustrates the accumulation of protein fragments derived from α-DNP antibodies. Figure 92A α-DNP antibody-derived protein fragments accumulate over time in cell lysates. Figure 92B Over time, α-DNP antibody fragments will not accumulate in the cell supernatant.

[0115] Figures 93A-93C The diagram illustrates that DNP-GN3 and DNP-OH3 were non-toxic to mice at all tested concentrations. Figure 93A Body weight of mice after treatment with DNP-GN3 or DNP-OH3. Statistical differences were analyzed using a t-test. Figure 93B : Aspartate aminotransferase (AST) levels in mice after treatment. Dashed lines represent the normal range. Figure 93C : Alanine aminotransferase (ALT) levels in mice after treatment. Dashed lines represent the normal range.

[0116] Figure 94The figure illustrates that serum α-DNP antibody levels decreased more rapidly after repeated DNP-GN3 treatment. Serum antibody levels were measured using an ELISA assay. Each experimental group contained three mice. In experiments involving in vivo consumption of α-DNP antibodies, statistical differences were assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparisons of simple effects between each treatment group and PBS.

[0117] Figure 95 The figure illustrates that serum α-DNP antibody levels decreased significantly after treatment with DNP-GN3, but not with DNP-OH3. Each experimental group contained at least five mice.

[0118] Figure 96 The decrease in serum α-DNP antibody levels mediated by a single dose of DNP-GN3 was illustrated. Each experimental group contained at least eight mice. Statistical differences were assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparisons of simple effects between each treatment group and PBS.

[0119] Figure 97 The diagram illustrates how DNP-GN3 treatment accelerates the consumption of polyclonal α-DNP antibodies in serum. The PBS-treated group contained two mice, while the DNP-GN3 group contained three mice.

[0120] Figure 98 The graph illustrates that the binding of α-DNP antibody to HepG2 cells depends on the concentration of DNP-AF3. Error bars represent three biological replicates (SD).

[0121] Figure 99 The figure illustrates that the binding of DNP-AF3-mediated antibody to HepG2 cells is inhibited by an increase in the concentration of α-DNP antibody binding to the control DNP-OH3. Error bars represent the standard deviation of three biological replicates.

[0122] Figure 100 The figure illustrates that the binding of DNP-AF3-mediated α-DNP antibody to HepG2 cells is inhibited by an increase in the concentration of ASGPR-bound control monomeric sugar AF. Error bars represent the standard deviation of three biological replicates.

[0123] Figure 101 The figure illustrates that the binding of DNP-AF3-mediated α-DNP antibody to HepG2 cells is inhibited by increased concentrations of the ASGPR-binding protein ASOR, but not by ORM. Error bars represent the standard deviation of three biological replicates.

[0124] Figure 102The figure illustrates that the binding of DNP-AF3-mediated α-DNP antibody to HepG2 cells is not inhibited by increased concentrations of the ASGPR-binding protein ASF or the protein fetoglobulin. Data points represent single flow cytometry experiments at each concentration. Data are expressed as mean fluorescence intensity of the cell population because internal controls with 100% and 0% ternary complex formation were not included in this experiment.

[0125] Figure 103A-103C The diagram illustrates that DNP-AF3-mediated alpha-DNP antibody endocytosis depends on the concentrations of both the alpha-DNP antibody and DNP-AF3. Each data point represents a single biological experiment. Figure 103A Six hours later, DNP-AF3 mediated α-DNP antibody endocytosis occurred. Figure 103B : DNP-AF3-mediated α-DNP antibody endocytosis occurred 12 hours later. Figure 103C DNP-AF3-mediated α-DNP antibody endocytosis occurred 24 hours later.

[0126] Figure 104 The graph illustrates the increase in intracellular fluorescence over time resulting from DNP-AF3-mediated endocytosis of α-DNP antibodies. The α-DNP antibody was present at a concentration of 100 nM. Each data point represents a single biological experiment.

[0127] Figure 105 The figure illustrates that DNP-AF3-mediated endocytosis of antibodies in HepG2 cells is inhibited by competitive binding agents of ASGPR and α-DNP antibody. Antibody was 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 replicates. Significance was analyzed using one-way ANOVA with multiple comparisons to a control without additives. P-values ​​are as follows: ASOR p = 0.0040 (**); ORM p = 0.8879 (ns); ASF p = 0.0032 (**); fetoglobulin p = 0.7709 (ns); DNP-OH3 p = 0.0073 (**); GalNAc p = 0.0054 (**); AF p = 0.0069 (**).

[0128] Figure 106The figure illustrates how DNP-AF3-mediated antibody endocytosis in 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 a single biological experiment. Black bars represent control conditions, red represents metabolites, green represents phagocytosis and macropinocytosis inhibitors, blue represents caveolin-dependent endocytosis inhibitors, and gray represents clathrin-dependent endocytosis inhibitors. Significance was analyzed using one-way ANOVA with multiple comparisons to a control without additives. The p-values ​​are as follows: NaN3 / DOG p = 0.0001 (****); CytD p = 0.0710 (ns); EIPA p = 0.9994 (ns); ammonia-pyrazinamide p = 0.4812 (ns); nystatin p = 0.9997 (ns); indomethacin p = 0.6682 (ns); genistein p = 0.8406 (ns); NH4Cl p = 0.0001 (****); monensin p = 0.0001 (****); primaquine p = 0.0001 (****); chloroquine p = 0.0001 (****); bafloxacin p = 0.0001 (****).

[0129] Figure 107 The diagram illustrates the accumulation of endocytosed α-DNP antibodies in puncta within HepG2 cells over time. The antibody was present at a concentration of 100 nM, and DNP-AF3 at a concentration of 40 nM. The number and intensity of the puncta increased over time.

[0130] Figure 108 The diagram illustrates that both DNP-AF3 and α-DNP antibodies are essential for observing fluorophore-containing cleavage marks in HepG2 cells. No cleavage marks were observed in the absence of either DNP-AF3 or α-DNP antibody.

[0131] Figure 109 The diagram illustrates that the fluorescent signal generated by the endocytic α-DNP antibody does not colocalize with the early endosome protein EEA1.

[0132] Figure 110 The diagram illustrates the colocalization of the fluorescent signal generated by the endocytic α-DNP antibody with the late endosome and lysosomal protein LAMP2.

[0133] Figure 111 The figure illustrates direct fluorescence imaging of the α-DNP antibody protein fragment in a sample collected from cell culture supernatant. The α-DNP antibody was present at a concentration of 100 nM, and DNP-AF3 was present at a concentration of 40 nM.

[0134] Figure 112 The figure illustrates direct fluorescence imaging of α-DNP antibodies in samples collected from cell culture lysates. Low accumulation of α-DNP antibodies was observed in untreated samples in the cell lysates. In contrast, DNP-AF3-treated cells showed an increase in α-DNP antibody-derived Alexa 488 signal over time.

[0135] Figure 113 The image illustrates the ratiometric imaging of fluorescence intensity generated by the α-DNP antibody fragment. Density determination was performed using Photoshop image analysis.

[0136] Figure 114 The graph illustrates the change in fluorescence intensity over time produced by proteins of different molecular weights in cell lysates. Error bars represent the standard deviation (SD) of three biological replicates.

[0137] Figure 115 The graph illustrates the ratio of accumulation of low molecular weight Alexa 488 modified protein fragments in cell lysates. After 12 hours, the 25 kDa band became brighter than the 50 kDa band. Error bars represent the standard deviation (SD) of three biological replicates.

[0138] Figure 116 The effect of different protease inhibitors on the degradation of endocytic α-DNP antibodies is illustrated graphically. A lower ratio indicates more degradation, while a higher ratio indicates less degradation. Data points represent single biological replicates.

[0139] Figure 117 The effect of protease inhibitors on the degradation of endocytic α-DNP antibodies in HepG2 cells is illustrated graphically. A lower ratio indicates greater degradation. Error bars represent the standard deviation (SD) of three biological replicates.

[0140] Figure 118 The effect of selected protease inhibitors on the degradation of endocytosed α-DNP antibodies in HepG2 cells is illustrated. A lower ratio indicates greater degradation. Error bars represent the standard deviation (SD) of three biological replicates. One-way ANOVA was used for multiple comparisons with a control without protease inhibitors to analyze significance. P-values ​​are as follows: Leucopeptide p = .0504 (ns); E64 p = .0461 (*); Pepstatin p = .9419 (ns); Antiprotease p = .0252 (*); ALLN 100 p = .0418 (*); ALLN 10 p = .0267 (*).

[0141] Figure 119A-119B The synthesis of the bifunctional molecule MIF-GN3 is illustrated.

[0142] Figure 120 The synthesis of the MIF inhibitor 3w is illustrated.

[0143] Figure 121 The synthesis of MIF combined with the bifunctional molecule MIF-PEG2-GN3 is illustrated.

[0144] Figure 122 The synthesis of MIF combined with the bifunctional molecule MIF-PEG4-GN3 is illustrated.

[0145] Figure 123 The synthesis of MIF combined with the bifunctional molecule MIF-NVS-PEG3 is illustrated.

[0146] Figure 124 The synthesis of MIF-binding bifunctional molecule MIF-AF1 is illustrated.

[0147] Figure 125 The synthesis of MIF-binding bifunctional molecule MIF-AF2 is illustrated.

[0148] Figure 126 The synthesis of MIF-binding bifunctional molecule MIF-AF3 is illustrated.

[0149] Figure 127 The structure of a small molecule that inhibits the activity of mouse MIF enzyme is illustrated.

[0150] Figure 128A-128B The figure illustrates the study on the consumption of MIF in cell culture supernatant. Figure 128A Bifunctional MIF-binding molecules mediated the consumption of huMIF from cell culture supernatant. Figure 128B The MIF inhibitor 3w did not mediate the consumption of MIF from cell culture supernatant.

[0151] Figure 129 The figure illustrates the consumption of MIF by a bifunctional MIF-binding molecule with an optimized ASGPR-binding motif from cell culture supernatant. Error bars represent the standard deviation of nine biological replicates. Human MIF protein was present at a concentration of 100 nM.

[0152] Figure 130 The graph illustrates the endocytosis of fluorescently labeled human MIF protein mediated by MIF-GN3. Each data point represents the mean of three biological replicates. Error bars represent the standard deviation.

[0153] Figure 131 The graph illustrates the uptake of fluorescently labeled MIF proteins mediated by MIF-GN3 across a wide range of target protein concentrations. Each value represents a single biological replicate.

[0154] Figure 132The figure illustrates the inhibition of MIF-GN3-mediated endocytosis of MIFs in HepG2 cells by clathrin-mediated inhibitors. Antibodies were present at a concentration of 100 nM, and MIF-GN3 at a concentration of 200 nM. Each data point represents a single biological experiment. Black bars represent control conditions, red represents metabolotoxins, green represents phagocytosis and macropinocytosis inhibitors, blue represents caveolin-dependent endocytosis inhibitors, and gray represents clathrin-dependent endocytosis inhibitors. Values ​​represent the mean of three biological replicates. Error bars represent standard deviations. Statistical differences were determined by the Kruskall-Wallace test and post-hoc comparisons between each inhibitor and the no-inhibitor group (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, “ns”P>0.9999).

[0155] Figure 133 The figure illustrates the accumulation of MIF nicks in cells treated with MIF-GN3 and exogenous MIF. MIF signaling showed strong co-localization with LAMP2 but not with EEA1. MIF was present at a concentration of 100 nM, while MIF-GN3 was present at a concentration of 200 nM.

[0156] Figure 134 The figure illustrates that cells treated with MIF-GN3 showed faster clearance of human MIF from the mouse bloodstream four hours after treatment. Each data point represents the mean and SD of three mice in each arm. T-test analysis at the four-hour time point did not show significant differences (p = .1525).

[0157] Figure 135 The figure illustrates how cells treated with MIF-GN3 showed faster clearance of human MIF from the mouse bloodstream. Each data point represents the average of two (MIF ipPBS arm) or three serum sample readings (all other arms).

[0158] Figure 136 The figure illustrates the rapid clearance of human MIF from the bloodstream in mice treated with MIF-GN3 at early time points. Each data point represents the mean MIF concentration in serum collected from four or five mice. Statistical differences were assessed by repeated measures two-way ANOVA and Tukey's test for post-hoc comparisons of simple effects between treatment groups and PBS.

[0159] Figure 137 The figure illustrates that treatment with MIF-GN3 did not reduce serum MIF levels in mice. Each point represents the mean of 10 serum samples, and the error bars are SD. Animals received a single dose of MIF-GN3 immediately after the zero-hour time point.

[0160] Figure 138 The diagram illustrates how administration of MIF-GN3 and α-MIF antibodies slowed the growth of PC3 human prostate cancer cells in mice. Each arm consisted of five mice (except for the DNP-GN3 arm, which had four mice).

[0161] Figure 139 The figure illustrates how administration of MIF-GN3 and α-MIF antibodies reduced circulating human MIF protein levels in mice injected with PC3 prostate cancer cells. Each arm consisted of five mice (except for the DNP-GN3 arm, which had four mice).

[0162] Figure 140 The illustration shows that administration of MIF-GN3 and α-MIF antibodies improved the survival rate of mice injected with human prostate cancer PC3 cells. Each arm consists of five mice (except for DNP-GN3, which has four mice).

[0163] Figure 141 The synthesis of the bifunctional molecule FcIII-BCN-GN3 is illustrated.

[0164] Figure 142 The figure illustrates FcIII-GN3-mediated endocytosis of human IgG within a certain concentration range. Fluorescence of cell populations treated with human IgG but not with the compound was subtracted from these samples to account for autofluorescence and non-small molecule-mediated endocytosis. Each data point represents the mean of three biological replicates. Error bars represent standard deviations.

[0165] Figure 143 The graph illustrates the effects of FcIII-BCN-GN3 on IgG endocytosis over time and within a certain concentration range. Each data point represents a single biological replicate.

[0166] Figure 144 The figure illustrates the increase in intracellular human IgG-derived fluorescence in the presence of FcIII-GN3. IgG was present at a concentration of 100 nM; FcIII-GN3 was present at a concentration of 200 nM.

[0167] Figure 145 The diagram illustrates the lysosomal transport of human IgG mediated by FcIII-GN3. IgG is present at a concentration of 100 nM; FcIII-GN3 is present at a concentration of 200 nM. The blue channel represents Hoechst nuclear staining.

[0168] Figures 146A-146B The diagram illustrates a bifunctional molecular fragment that binds to TNF. Figure 146A TNF binder. Figure 146B The molecule of formula (II) has -[CON] h -[Linking group] i -[CON] h'-[CRBM] j' Fragment synthesis.

[0169] Figures 147A-147B The characteristics of TNF binders in Figure 159A are illustrated. Figure 147A Mass spectrometry of TNF binders. Figure 147B HPLC purification of TNF binders. Detailed Implementation

[0170] This disclosure provides, in one aspect, bifunctional compounds that can be used to promote and / or enhance the degradation of extracellular proteins (or “proteins,” which, in non-limiting instances, may be circulating proteins and / or cell surface proteins that may attach to or embed in cell membranes) in a subject. In some embodiments, the treatment or management of the disease and / or disorder contemplated by this disclosure requires the degradation, clearance, and / or reduction of the concentration of extracellular proteins in a subject. Therefore, in some embodiments, administration of the compounds of this disclosure to a subject can clear extracellular proteins and / or reduce the circulating concentration of extracellular proteins, thereby treating, improving, and / or preventing the subject's disease and / or disorder. In some embodiments, the extracellular protein includes TNF. In some embodiments, the extracellular protein is TNF.

[0171] In some embodiments, the compounds of this disclosure include a group that binds to an extracellular protein. In other embodiments, the compounds of this disclosure further include another group (such as, but not limited to, a small molecule) that binds to a cell receptor, thereby causing endocytosis of the compound (and / or the extracellular protein-compound complex). The receptor binder and the extracellular protein binder may be linked via a linker group such as polyethylene glycol (PEG), any other length-tunable linker group described herein, or other linker groups described herein that include one or more linker molecules (hereinafter referred to as CON). Once the extracellular protein-compound complex has undergone endocytosis, the extracellular protein is eventually degraded, and the compound may be degraded or recycled outside the cell. In some embodiments, the extracellular protein is TNF, and the compounds of this disclosure are TNF binders.

[0172] This disclosure, in another aspect, provides bifunctional compounds that can be used to promote or enhance the degradation of certain autoantibodies of interest. In some embodiments, autoantibodies mediate diseases and / or disorders in a subject, and the treatment or management of the diseases and / or disorders requires the degradation, clearance, or reduction of the concentration of autoantibodies in the subject. Therefore, in some embodiments, administration of the compounds of this disclosure to a subject can clear autoantibodies and / or reduce the circulating concentration of autoantibodies, thereby treating, improving, or preventing the subject's diseases and / or disorders.

[0173] In some embodiments, the compounds of this disclosure include another group (such as, but not limited to, a small molecule) that binds to a cell receptor, thereby causing endocytosis of the compound (and / or the extracellular protein-compound complex). Furthermore, in some embodiments, the compounds of this disclosure include an autoantibody targeting moiety (AATM), such as, but not limited to, an autoantibody ligand, such as, but not limited to, a small molecule, peptide, and / or nucleic acid aptamer, which can bind to the autoantibody of interest. The receptor binder and the AATM may be linked via a linker group such as polyethylene glycol (PEG), any other adjustable-length linker group described herein, or other linker groups described herein that include one or more linker molecules (hereinafter referred to as CON). Once the autoantibody-compound complex has undergone endocytosis, the autoantibody is eventually degraded, while the compound may be degraded or recycled extracellularly.

[0174] Without wishing to be limited by any theory, the bifunctional compounds of this disclosure, which can be used to promote or enhance the degradation of certain autoantibodies of interest, offer unique advantages compared to existing methods for eliminating autoantibodies in subjects. AATMs provide specificity for bifunctional compounds. By using ATMs, one can target specific groups of autoantibodies. As shown elsewhere herein, compounds of this disclosure comprising anti-DNP IgG as a model autoantibody successfully induced the degradation of anti-DNP IgG injected into mice.

[0175] This disclosure provides a molecular method for achieving similar goals to plasma exchange in diseases caused by autoantibodies. Unlike plasma exchange, this technique can be easily performed by a variety of medical professionals, not just transfusion medicine professionals. Because this method is based on small molecules derived from synthetic methods, this disclosure avoids the need for expensive equipment and materials, as well as complex manufacturing practices. Compared to plasma exchange and IVIG, this method is more economical, safer, and more readily accepted by patients.

[0176] Furthermore, this disclosure offers a less invasive and safer route of administration compared to in vitro procedures that may cause additional complications. The compounds described herein are modular and versatile. Targeting motifs (CRBM and AATM) at either end of the linker can be modified to bind with a wide variety of autoantibodies of interest with extremely high specificity. Moreover, the well-defined composition of these compounds simplifies and standardizes manufacturing practices, reducing batch-to-batch variability. The predictable binding of AATM to autoantibodies allows for the prediction of treatment outcomes, drug-drug interactions, and potential side effects.

[0177] In some embodiments, the receptor is the hepatocyte desialylate glycoprotein receptor (ASGPR). In this case, the binding portion is referred to herein as the ASGPR binding portion or ASGPRBM. This disclosure is not limited to this receptor, but rather the use of other receptors described herein or any other endocytic receptor known in the art is contemplated.

[0178] Furthermore, this disclosure is not limited to degradation occurring in hepatocytes. Rather, this disclosure considers that non-hepatocytes in the body also exhibit certain degradation receptors, and those receptors are also within the scope of this disclosure.

[0179] In one aspect, the compounds of this disclosure bind to extracellular proteins and / or autoantibodies, causing them to be cleared from circulation (and from the body) via the liver. In some embodiments, the extracellular protein is extracellular TNF. Thus, the compounds of this disclosure utilize the body's own mechanisms for degrading proteins and / or autoantibodies. Without wishing to be limited by any theory, the compounds of this disclosure bind to certain receptors located in certain cells (e.g., but not limited to hepatocytes), such as, but not limited to, ASGPR. This binding triggers the degradation of the protein target via lysosomal proteolysis. Due to this mechanism, the circulating levels of extracellular protein targets and / or extracellular autoantibodies are reduced. In some embodiments, the extracellular protein target is TNF. Therefore, corresponding disease symptoms are alleviated and / or eliminated in subjects administering the compounds.

[0180] ASPGR is capable of clearing desialylated glycoproteins capped with exposed non-reducing D-galactose (Gal) or N-acetylgalactosamine (GalNac). ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is present in very small amounts elsewhere in the body. ASGPR has a half-life of approximately 3 minutes for the internalization of target glycoproteins. The disclosed bifunctional compound selectively binds to extracellular proteins via its extracellular protein-binding portion, thus forming a protein complex. When this protein complex reaches the liver, the desialylated glycoprotein receptor-binding portion (ASGPRBM) in the molecule binds to the terminal lysosomal pathway of hepatocytes via ASGPR. Endosomally bound ASPGR releases the extracellular protein ligand at pH 5.4, and the ligand is expelled from the bloodstream by hepatocytes. However, ASPGR remains available for circulation; it avoids lysosomal degradation and enters the circulating endosomes. In fact, depending on the cell line, it can be recirculated up to approximately 200 times, with a recirculation rate of approximately 15–20 minutes. ASPGR has very flexible requirements for ligand size, with diameters potentially reaching approximately 70 nm. In contrast, the diameter of the IgM pentamer is approximately 20 nm, and therefore meets the ligand size requirements of ASPGR.

[0181] The disclosures of International Patent Application No. PCT / US2019 / 026260, filed on April 8, 2019 (and published as WO2019 / 199634 on October 17, 2019) and International Patent Application No. PCT / US2019 / 026239, filed on April 8, 2019 (and published as WO 2019 / 199621 on October 17, 2019), are incorporated herein by reference in their entirety.

[0182] Based on this disclosure, conventional chemical synthesis and pharmaceutical formulation methods within the scope of the art, as well as pharmacological, molecular biological, microbiological, and recombinant DNA technologies, can be employed. These technologies are well known and have been extensively described in the literature.

[0183] Reference will now be made in detail to certain embodiments of the disclosed subject matter, some of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the listed claims, it is to be understood that the illustrative subject matter is not intended to limit the claims to the disclosed subject matter.

[0184] Values ​​expressed in range format throughout this document should be interpreted flexibly to include not only the values ​​explicitly stated as range boundaries, but also all individual values ​​or subranges included within that range, as if each value and subrange were explicitly stated. For example, the range “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges within the specified range (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise stated, the statement “about X to Y” has the same meaning as “about X to about Y”. Similarly, unless otherwise stated, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z”.

[0185] In the methods described herein, actions may be performed in any order unless the timing or sequence of operations is explicitly stated. Furthermore, specified actions may be performed simultaneously unless the language of the claim specifies that they should be performed separately. For example, the claimed action of performing X and the claimed action of performing Y may be performed simultaneously in a single step, and the resulting method will fall within the literal scope of the claimed method.

[0186] definition

[0187] The term “about” as used herein may allow for a degree of variation in the value or range, for example, within 10%, 5%, or 1% of the specified limit of the specified value or range, and includes the exact specified value or range.

[0188] In this document, unless the context clearly specifies otherwise, the terms “a,” “an,” or “the” include one or more. Unless otherwise stated, “or” means non-exclusive “or.” The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” Furthermore, it should be understood that, unless otherwise defined, the phrases or terms used herein are for descriptive purposes only and not for limitation. The use of any section headings is intended to aid in reading this document and should not be construed as limiting; information relating to a section heading may appear within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety as if individually incorporated by reference.

[0189] The term "abnormal," when used in the context of an organism, tissue, cell, or component thereof, refers to an organism, tissue, cell, or component thereof that differs from an organism, tissue, cell, or component thereof in at least one observable or detectable characteristic (such as age, treatment, time, etc.) that displays a "normal" (expected) characteristic. A characteristic that is normal or expected for one cell or tissue type may be abnormal for different cell or tissue types.

[0190] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bonded via a carbonyl carbon atom. The carbonyl carbon atom bonds with hydrogen to form a "formyl" group, or bonds with another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic, heteroaryl, heteroaryl, or heteroarylalkyl group. An acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group may include double or triple bonds as defined herein. Acryloyl is an example of an acyl group. An acyl group may also include heteroatoms as defined herein. Nicotinyl (pyridyl-3-carbonyl) is an example of an acyl group as defined herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridinylacetyl, cinnamoyl, and acryloyl. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. The example is trifluoroacetyl.

[0191] As used herein, the term "alkyl" refers to straight-chain and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl, and anteisoalkyl, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted once or multiple times with any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups.

[0192] As used herein, the term "alkenyl" refers to straight-chain, branched, and cyclic alkyl groups as defined herein, distinguished by the presence of at least one double bond between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to approximately 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, etc.

[0193] As used herein, the term "alkoxy" refers to an oxygen atom bonded to an alkyl group (including cycloalkyl groups) as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. An alkoxy group may include 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 include double or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups within the meaning of this document, as is methylenedioxy when two adjacent atoms of the structure are substituted with it.

[0194] As used herein, the term "alkynyl" refers to both straight-chain and branched alkyl groups, distinguished by the presence of at least one triple bond between two carbon atoms. Thus, an alkynyl group has 2 to 40 carbon atoms, 2 to approximately 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).

[0195] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group)3, where each group may be independently H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, and alkylarylamines; R2NH, where each R is independently chosen, such as dialkylamines, diarylamines, arylamines, heterocyclic amines, etc.; and R3N, where each R is independently chosen, such as trialkylamines, dialkylarylamines, alkyldiarylamines, and triarylamines, etc. The term "amine" also includes, as used herein, the ammonium ion.

[0196] The term "amino acid sequence variant" refers to a polypeptide that has an amino acid sequence that differs from the native polypeptide sequence in a certain degree. Typically, amino acid sequence variants share at least about 70%, at least about 80%, at least about 90%, or at least about 95% homology with the native polypeptide. Amino acid sequence variants have substitutions, deletions, and / or insertions at certain positions in the amino acid sequence of the native polypeptide.

[0197] As used in this article, the term "amino group" refers to -NH2, -NHR, -NR2, and -NR3. + (where each R is independently chosen) form, and except -NR3 + The protonated form of each substituent other than (which cannot be protonated). Therefore, any compound substituted with an amino group can be considered an amine. "Amino" as used herein can refer to primary, secondary, tertiary, or quaternary amino groups. "Alkylamino" includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0198] As used herein, the term "aminoalkyl" refers to an amine linked to an alkyl group as defined herein. The amino group can appear at any suitable position in the alkyl chain, such as at the end of the alkyl chain or at any position within the alkyl chain.

[0199] As used herein, the term "aralkyl" means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to an aryl group as defined herein. Representative aralkyl groups include benzyl, phenethyl, and fused (cycloalkylaryl) alkyl groups, such as 4-ethylindenyl. Arylene is an alkenyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to an aryl group as defined herein.

[0200] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in its ring. Therefore, aryl includes, but is not limited to, phenyl, azulel, hepta-enyl, biphenyl, indole-3-yl, fluorenyl, phenanthrene, triphenylene, pyrene, and naphthacenyl. The aryl group can be chrysenyl, biphenyl, anthraceneyl, or naphthyl. In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. As defined herein, the aryl group can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or polysubstituted, such as, but not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the benzene ring, or naphthyl groups substituted at any one or more of the 2- to 8-positions of the benzene ring.

[0201] As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to an antigen. Antibodies can be complete immunoglobulins derived from natural or recombinant sources and can be the immunologically active portion of a complete immunoglobulin. Antibodies are typically tetramers of immunoglobulin molecules. Antibodies in this disclosure can exist in a variety of 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, New York; 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).

[0202] The term "antibody fragment" refers to a portion of a complete antibody and specifically to the antigenic determination variable region of the complete antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, scFv antibodies, single-domain antibodies such as sdAb (VL or VH) (e.g., camelid antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38), camelid VHH domains consisting of VL or VH domains with sufficient affinity for the target), and multispecific antibodies formed from antibody fragments (e.g., bivalent fragments comprising two Fab fragments connected by a hinge region disulfide bridge) and isolated complementarity-determining regions (CDRs) or other epitope-binding fragments of the antibody. Antigen-binding fragments can also be incorporated into single-domain antibodies, macrobodies, microbodies, nanobodies, intracellular antibodies, di-antibodies, tri-antibodies, tetra-antibodies, v-NARs, and bi-scFvs (see, for example, Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments can also be grafted onto peptide-based scaffolds, such as fibronectin type III (Fn3) (US Patent No. 6,703,199, which describes a fibronectin peptide microantibody). Antibody fragments may also include portions of human antibodies or humanized antibodies.

[0203] As used herein, the term "antigen" or "Ag" is defined as a molecule that elicits an immune response. This immune response may involve the production of antibodies, or the activation of specific immune cells, or both. Those skilled in the art will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can also be derived from recombinant DNA or genomic DNA. Those skilled in the art will understand that any DNA, including nucleotide sequences or partial nucleotide sequences encoding proteins that elicit an immune response, therefore encodes what is referred to herein as an "antigen." Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded solely by the full-length nucleotide sequence of a gene. It is readily apparent that this disclosure includes, but is not limited to, the use of partial nucleotide sequences of more than one gene, and that these nucleotide sequences are arranged in different combinations to elicit the desired immune response. Furthermore, those skilled in the art will understand that an antigen does not necessarily need to be encoded by a "gene." It is readily apparent that antigens can be synthetically produced or can be derived from biological samples. Such biological samples can include, but are not limited to, tissue samples, tumor samples, cells, or biological fluids.

[0204] As used in this article, an "aptamer" refers to a small molecule that can specifically bind to another molecule. Aptamers are typically based on polynucleotides or peptides. A polynucleotide aptamer is a DNA or RNA molecule, usually composed of multiple nucleic acid chains, designed with a highly specific three-dimensional conformation to have appropriate binding affinity and specificity to specific target molecules (such as peptides, proteins, drugs, vitamins, and other organic and inorganic molecules). Such polynucleotide aptamers can be screened from a large number of random sequences through systematic evolution of exponentially enriched ligands. Peptide aptamers are typically loops of about 10 to about 20 amino acids attached to a protein scaffold that binds to a specific ligand. Peptide aptamers can be identified and isolated from combinatorial libraries using methods such as the yeast two-hybrid system.

[0205] As used herein, the term "desialylglycoprotein receptor-binding moiety" or "ASGPRBM" refers to a group capable of binding to at least one hepatocyte desialylglycoprotein receptor on the surface of a cell (such as, but not limited to, hepatocytes). Once the ASGPRBM and any other attached moiety bind to the receptor on the surface of the hepatocyte, molecules including the ASGPRBM are carried into the hepatocyte via phagocytosis, where the molecules are at least partially degraded by lysosomal degradation.

[0206] As used in this article, the term "(C)" 6-10 -C 6-10 "Lianfangji" refers to C 6-10 The aryl moiety binds to another C via a single bond. 6-10 The aryl group is covalently bonded. C 6-10 The aryl moiety can be any suitable aryl group as described herein. C 6-10 -C 6-10 Non-limiting examples of biaryl groups include biphenyl and binaphthyl.

[0207] As used herein, the term "coding sequence" refers to a sequence or portion thereof of a nucleic acid or its complement that can be transcribed and / or translated to produce mRNA and / or peptides or fragments thereof. Coding sequences include exons in genomic DNA or immature primary RNA transcripts that link together through cellular biochemical mechanisms to form mature mRNA. The antisense strand is the complement of this nucleic acid, and the coding sequence can be deduced from it. Conversely, as used herein, the term "non-coding sequence" refers to a sequence or portion thereof of a nucleic acid or its complement that is not translated into amino acids in vivo or that does not interact with tRNA to substitute for or attempt to substitute for amino acids. Non-coding sequences include both intron sequences in genomic DNA or immature primary RNA transcripts and gene-related sequences (such as promoters, enhancers, silencers, etc.).

[0208] As used herein, the terms "complementary" or "complementarity" refer to polynucleotides (i.e., nucleotide sequences) related by base pairing rules. For example, the sequence "AGT" is complementary to the sequence "TCA". Complementarity can be "partial," where only some nucleic acid bases match according to base pairing rules. Alternatively, there can be "complete" or "total" complementarity between nucleic acids. The degree of complementarity between nucleic acid chains has a significant impact on the efficiency and strength of hybridization between nucleic acid chains. This is particularly important in amplification reactions and detection methods that rely on nucleic acid binding.

[0209] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous injection, oral administration, aerosol, parenteral administration, ocular, pulmonary, and topical administration.

[0210] As used herein, the terms “conservative variation” or “conservative substitution” refer to the substitution of one amino acid residue for another that is biologically similar. Conservative variations or substitutions are unlikely to alter the shape of the peptide chain. Examples of conservative changes or substitutions include the substitution of one hydrophobic residue (such as isoleucine, valine, leucine, or methionine) for another hydrophobic residue, or the substitution of one polar residue for another polar residue, such as lysine for arginine, aspartic acid for glutamic acid, or asparagine for glutamine.

[0211] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight-chain or branched alkyl groups as defined herein. Representative substituted cycloalkyl groups can be monosubstituted or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono, di, or trisubstituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination refers to cyclic alkenyl groups.

[0212] "Disease" refers to a state of health in an animal in which the animal is unable to maintain homeostasis, and if the disease is not treated, the animal's health will continue to deteriorate.

[0213] In contrast, an animal's "disorder" is a state of health in which the animal is able to maintain homeostasis, but its health is worse than when it is not in a disorder. Without treatment, a disorder does not necessarily lead to further deterioration of the animal's health.

[0214] The disease or disorder is "alleviated" if the severity of the symptoms, the frequency with which the patient experiences such symptoms, or both decrease.

[0215] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient quantity of a drug to provide the desired biological outcome. This outcome may be a reduction and / or alleviation of the symptoms, signs, or cause of a disease, or any other desired alteration of a biological system. Those skilled in the art can determine the appropriate therapeutic amount for any individual case through routine laboratory testing.

[0216] As used in this article, the term "efficacy" refers to the maximum effect (E) achieved in a trial. max ).

[0217] "Encoding" refers to the inherent property of a specific nucleotide sequence in a polynucleotide (such as a gene, cDNA, or mRNA) to serve as a template for the synthesis of other polymers and macromolecules in biological processes. These polymers and macromolecules have defined nucleotide sequences (i.e., rRNA, tRNA, and mRNA) or defined amino acid sequences, and the resulting biological properties. Therefore, if the transcription and translation of the mRNA corresponding to a gene produces a protein in a cell or other biological system, then that gene encodes that protein. Both the coding strand (whose nucleotide sequence is identical to the mRNA sequence and is usually provided in the sequence listing) and the non-coding strand (which serves as a transcription template for a gene or cDNA) can be referred to as encoding a protein or other product of that gene or cDNA.

[0218] As used herein, the term "fragment" when applied to nucleic acids refers to a subsequence of a larger nucleic acid. The length of a nucleic acid "fragment" can be at least about 15 nucleotides; for example, at least about 50 nucleotides to about 100 nucleotides; at least about 100 nucleotides to about 500 nucleotides; at least about 500 nucleotides to about 1000 nucleotides; at least about 1000 nucleotides to about 1500 nucleotides; about 1500 nucleotides to about 2500 nucleotides; or about 2500 nucleotides (and any integer value between the two). As used herein, the term "fragment" when applied to proteins or peptides refers to a subsequence of a larger protein or peptide. The length of a protein or peptide "fragment" can be 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 between the two).

[0219] As used herein, the term "GN3" refers to the following groups:

[0220]

[0221] As used herein, unless otherwise stated, the terms “halo,” “halogen,” or “halide” refer to a fluorine, chlorine, bromine, or iodine atom, either on its own or as part of another substituent.

[0222] As used herein, the term "haloalkyl" includes monohaloalkyl, polyhaloalkyl (where all halogen atoms may be the same or different), and perhaloalkyl (where all hydrogen atoms are replaced by halogen atoms, such as fluorine atoms). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, etc.

[0223] 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 8-12 ring members. Heteroaryls are various heterocyclic groups having aromatic electronic structures. A heteroaryl named C2-heteroaryl can be a pentaneous ring with two carbon atoms and three heteroatoms, a hexaaneous ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl can be a pentaneous ring with one heteroatom, a hexaaneous ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, the following groups: for example, pyrrole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, phenylthio, benzo[benzylthio], benzo[furan], indolyl, azaindolyl, indolyl, benzimidazolyl, azabenzimidazolyl, benzo[oxazolyl], benzo[thiazolyl], benzo[thiadiazolyl], imidazo[pyridinyl], isoxazolylpyridinyl, thianaphthyl, purine, xanthine, adenine, guanidinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups may be unsubstituted or substituted with groups discussed herein. Representative substituted heteroaryl groups may be substituted once or multiple times with groups listed herein.

[0224] Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indole, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazole, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracene (1-anthrayl, 2-anthrayl, 3-anthrayl), phenylthio (2-phenylthio, 3-phenylthio), furanyl (2-furanyl, 3-furanyl), indole, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthyl, isoindanyl, diphenylmethyl, acridineyl, thiazolyl, pyrrole (2-pyrrole), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl ( 1,2,3-Triazol-1-yl, 1,2,3-Triazol-2-yl, 1,2,3-Triazol-4-yl, 1,2,4-Triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridinyl (2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl), isoquinolinyl (1... -Isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), Hydrogen-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]phenylthio (2-benzo[b]phenylthio, 3-benzo[b]phenylthio, 4-benzo[b]phenylthio, 5-benzo[b]phenylthio, 6-benzo[b]phenylthio, 7-benzo[b]phenylthio), 2,3-dihydro-benzo[b]phenylthio, (2-(2,3-dihydro-benzo[b]phenylthio), 3-(2,3-dihydro-benzo[b]phenylthio), 4-(2,3-dihydro-benzo[b]phenylthio), 5-(2,3-dihydro-benzo[b]phenylthio), 6-(2,3-dihydro-benzo[b]phenylthio), 7-(2,3-Dihydro-benzo[b]phenylthio), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazole, 3-indazole, 4-indazole, 5-indazole, 6-indazole, 7-indazole), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) (e.g., imidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazole (1-carbazole, 2-carbazole, 3-carbazole, 4-carbazole), 5H-dibenzo[b,f]aza, (5H-dibenzo[b,f]aza) -1-yl,5H-dibenzo[b,f]aza -2-yl,5H-dibenzo[b,f]aza -3-yl,5H-dibenzo[b,f]aza -4-yl,5H-dibenzo[b,f]aza -5-yl), 10,11-dihydro-5H-dibenzo[b,f]aza (10,11-dihydro-5H-dibenzo[b,f]aza) -1-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -2-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -3-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -4-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -5-base, etc.

[0225] As used herein, the term “heteroarylalkyl” means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to the heteroaryl group as defined herein.

[0226] The term "C" used in this article 6-10 "-5-6-membered heteroaryl" refers to a C-terminal bond covalently bonded to a 5- or 6-membered heteroaryl group via a single bond. 6-10 Aryl. C 6-10 The aryl and 5-6-membered heteroaryl groups can be any suitable aryl and heteroaryl group described herein. 6-10 Non-limiting examples of -5-6 molecular heteroaryl groups include: When C 6-10When a -5-6 membered heteroaryl group is listed as a substituent (e.g., an "R" group), C 6-10 -5-6 hydroxylated aryl groups via C 6-10 Part of it is bonded to the rest of the molecule.

[0227] As used in this article, the term "5-6 yuan-C" 6-10 "Hybrid aryl" and C 6-10 -5-6 grade heteroaryl groups are the same, the difference being that when 5-6 grade -C 6-10 When a heteroaryl group is listed as a substituent (e.g., as an "R" group), the 5-6 member -C 6-10 Heteroaryl groups are bonded to the rest of the molecule through a 5-6 member heteroaryl moiety.

[0228] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cyclic compound containing three or more ring members, wherein one or more of the ring members are heteroatoms, such as, but not limited to, N, O, and S. Therefore, a heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or, if polycyclic, any combination thereof. In some embodiments, a heterocyclyl group comprises 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. A heterocyclyl group named C2-heterocyclyl can be a pentaneous ring having two carbon atoms and three heteroatoms, a hexane ring having two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl group can be a pentaneous ring having one heteroatom, a hexane ring having two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. The heterocyclyl ring may also include one or more double bonds. Heteroaryl rings are an embodiment of heterocyclyl groups. The phrase "heterocyclyl" includes fused cyclic substances, including those fused with aromatic and non-aromatic groups. For example, both dioxolane and benzodioxolane systems (methylenedioxanone systems) are heterocyclic groups within the meaning of this document. This phrase also includes polycyclic systems containing heteroatoms, such as, but not limited to, quinuclidyl groups. Heterocyclic groups may be unsubstituted or substituted as discussed herein. Heterocyclic groups include, but are not limited to, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, phenylthio, benzobenzylthio, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolylpyridinyl, thianaphthyl, purine, xanthine, adenine, guanidine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclic groups can be monosubstituted or multiple substituted, such as, but not limited to, piperidinyl or quinolinyl, which are 2-, 3-, 4-, 5- or 6-substituted, or disubstituted as those listed herein.

[0229] As used herein, the term "heterocyclylalkyl" means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group as defined herein are replaced by bonds attached to a heterocyclic group as defined herein. Representative heterocyclyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0230] Unless the context clearly indicates otherwise, the term "independently selected from" as used herein means that the mentioned groups are the same, different, or a mixture thereof. Therefore, according to this definition, the phrase "X"1 X 2 and X 3 "Independently selected from inert gases" will include, for example, X. 1 X 2 and X 3 All are the same, among which X 1 X 2 and X 3 All are different, among which X 1 and X 2 Same but X 3 Unlike other similar arrangements.

[0231] As used in this article, the term "immunoglobulin" or "Ig" refers to a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes called BCRs (B cell receptors) or antigen receptors. Five members of this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is the main antibody found in human secretions such as saliva, tears, breast milk, gastrointestinal secretions, and respiratory and genitourinary tract mucus. IgG is the most common circulating antibody. IgM is the main immunoglobulin produced in most subjects during the primary immune response. It is the most effective immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in fighting bacteria and viruses. IgD is an immunoglobulin that does not have a known antibody function but can act as an antigen receptor. IgE is an immunoglobulin that mediates an immediate hypersensitivity response after exposure to an allergen by inducing the release of mediators from mast cells and basophils.

[0232] "Isolated" means altered or removed from its native state. For example, nucleic acids or polypeptides naturally present in living animals are not "isolated," but the same nucleic acids or polypeptides that are partially or completely separated from their native state are "isolated." Isolated nucleic acids or proteins can exist in a substantially purified form or in non-native environments, such as, for example, host cells.

[0233] As used herein, the term "modulating" refers to a detectable increase or decrease in the activity and / or level of mRNA, peptide, or response in a subject compared to the activity and / or level of mRNA, peptide, or response in a subject who is otherwise identical but untreated. This term includes activating, inhibiting, and / or otherwise influencing native signals or responses to mediate a beneficial therapeutic response in a subject (preferably a human).

[0234] As used in this article, the term "monovalent" refers to a substituent that is bonded to the substituted molecule via a single bond. When a substituent is monovalent, such as F or Cl, it is bonded to the substituted atom via a single bond.

[0235] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include oxygen-containing groups, such as alkoxy, aryloxy, aralkyloxy, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic esters; sulfur-containing groups, such as alkyl and aryl thioether 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, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, and (CH2). 0-2 N(R)C(O)R、(CH2) 0-2 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, C(=NOR)R and substituted or unsubstituted (C1-C 100 R can be a hydrocarbon group, wherein R can be hydrogen (in instances including other carbon atoms) or a carbonyl moiety, and wherein the carbonyl moiety can be substituted or unsubstituted.

[0236] The terms “patient,” “subject,” or “individual” are used interchangeably herein and refer to any animal or its in vitro or in situ cells to which the methods described herein are applicable. In a non-limiting embodiment, the patient, subject, or individual is a human being.

[0237] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not diminish the biological activity or properties of a compound and is relatively non-toxic, i.e., that the material can be administered to an individual without causing adverse biological effects or interacting with any component contained in the composition in a harmful manner.

[0238] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of an applied compound prepared from a pharmaceutically acceptable, non-toxic acid or base (including inorganic acids or bases, organic acids or bases, their solutions, hydrates, or inclusion complexes).

[0239] 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 hydrogen sulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acid organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharinic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid.

[0240] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-meglumine), and procaine. All these salts can be prepared from the respective compounds by reacting them with, for example, a suitable acid or base.

[0241] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to 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 participates in carrying or transporting the compound described herein into or to a patient so that it can perform its intended function. Typically, such a compound is carried or transported from one organ or site of the body to another organ or site of the body. Each carrier must be "acceptable" in the sense that it is compatible with other components of the formulation, including one or more of the compounds described herein, and will not cause harm to the patient. Examples of materials that can be used 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; ethylene glycols such as propylene glycol; polyols such as glycerol, 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; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. The term "pharmaceutically acceptable carrier" as used herein also includes any and all coatings, antibacterial and antifungal agents, absorption delay agents, etc., that are compatible with the activity of one or more compounds described herein and are physiologically acceptable to patients. Additional active compounds may also be added to the composition. "Pharmaceutically acceptable carrier" may also include pharmaceutically acceptable salts of one or more of the compounds described herein. Other additional ingredients that may be included in the pharmaceutical composition and used with the methods or compounds described herein are known in the art and have been described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0242] As used herein, the term "polypeptide" refers to a polymer consisting of amino acid residues, related naturally occurring structural variants, and synthetic, non-natural analogs linked by peptide bonds. Synthetic polypeptides can be synthesized using, for example, an automated polypeptide synthesizer. As used herein, the term "protein" generally refers to a large polypeptide. As used herein, the term "peptide" generally refers to a short polypeptide. Polypeptide sequences are represented using conventional notation: the left end of the polypeptide sequence is the amino terminus, and the right end is the carboxyl terminus.

[0243] As used in this article, the term "potency" refers to the ability to produce the maximum response (ED). 50 (half the required dose)

[0244] As used in this article, the term "protein" refers to the extracellular protein of interest.

[0245] As used herein, the term "REAG" refers to any reagent including -CON, -linker group, -CON-linker group, -linker group-CON, -CON-linker group-CON, -CRBM, -CON-CRBM, -linker group-CRBM, -CON-linker group-CRBM, -linker group-CON-CRBM, and / or -CON-linker group-CON-CRBM. In some embodiments, REAG reacts with TNF-binding groups to incorporate TNF-binding agents into compounds or fragments thereof, derivatives thereof, or intermediates of this disclosure.

[0246] The term "room temperature" as used in this article refers to a temperature of approximately 15°C to 28°C.

[0247] The term "specifically bind" as used in this article refers to an antibody that recognizes a specific antigen but does not substantially 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 antigens from one or more species. However, this cross-species reactivity itself does not change the antibody's specific classification. In another instance, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, this cross-reactivity itself does not change the antibody's specific classification. In some cases, the term "specific bind" or "specifically bind" can be used to refer to the interaction of an antibody, protein, or peptide with a second chemical substance, meaning that this interaction depends on the presence of a specific structure on the chemical substance (e.g., an antigenic determinant or epitope); for example, the antibody recognizes and binds to a specific protein structure, rather than a protein in general. If an antibody is specific for epitope "A," then in a reaction containing labeled "A" and an antibody, the presence of a molecule containing epitope "A" (or free, unlabeled "A") will reduce the amount of labeled "A" binding to the antibody.

[0248] As used herein, the term "solvent" refers to a liquid that can dissolve solids, liquids, or gases. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0249] The term "standard temperature and pressure" as used in this article refers to 20°C and 101 kPa.

[0250] As used herein, the term "substantially" means the majority or the vast majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term "substantially free of" may mean that it contains no or only a very small amount of material such that the amount of material present does not affect the material properties of the composition comprising the material, such that the material in the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to or greater than about 4.5 wt%, 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 wt% or less. The term "substantially free" can mean having a negligible amount such that the material in the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to or greater than about 4.5 wt%, 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 wt% or less, or about 0 wt%.

[0251] The term “substituted” as used herein in conjunction with the molecule or organic group as defined herein means a state in which one or more hydrogen atoms are replaced by one or more non-hydrogen atoms. The terms “functional group” or “substituent” as used herein refer to a group that can be or is substituted onto a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in the following groups: hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, carboxyl groups (including carboxylic acids, carboxylates, and carboxyl esters); sulfur atoms in the following groups: thiols, alkyl and aryl thioether groups, sulfoxides, sulfones, sulfonyl groups, and sulfonamides; nitrogen atoms in the following groups: 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 bond with substituted carbon (or other) atoms include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O (oxo), S (thiocarbonyl), 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, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R、(CH2) 0-2 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 moiety; for example, R can be hydrogen, (C1-C 100 ) hydrocarbon group, alkyl group, acyl group, cycloalkyl group, aryl group, aralkyl group, heterocyclic group, heteroaryl group or heteroaryl group; or two R groups bonded to a nitrogen atom or an adjacent nitrogen atom may together with one or more nitrogen atoms to form a heterocyclic group.

[0252] As used herein, the term "synthetic antibody" refers to an antibody generated using recombinant DNA technology, such as the phage-expressed antibody described herein. The term should also be interpreted as an antibody produced by synthesizing a DNA molecule encoding an antibody, and that the DNA molecule expresses an antibody protein or an amino acid sequence specifying an antibody, wherein the DNA or amino acid sequence is obtained using synthetic DNA or amino acid sequencing technology that is available and well known in the art.

[0253] "Therapeutic" treatment refers to treatment administered to subjects exhibiting pathological symptoms in order to alleviate or eliminate those symptoms.

[0254] As used herein, the term "thioalkyl" refers to a sulfur atom bonded to an alkyl group as defined herein. The alkyl group in a thioalkyl group can be straight-chain or branched. Examples of straight-chain 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, secondary thiobutyl, tertiary thiobutyl, isothiopentyl, and isothiohexyl. The sulfur atom can appear at any suitable position in the alkyl chain, such as at the end of the alkyl chain or at any position within the alkyl chain.

[0255] As used in this article, the terms “treat,” “treating,” and “treatment” refer to the reduction of the frequency or severity of a disease or symptom experienced by a subject by administering a reagent or compound to the subject.

[0256] As used herein, the term "wild-type" refers to a gene or gene product isolated from a natural source. A wild-type gene is the gene most commonly observed in a population and is therefore arbitrarily engineered to be in its "normal" or "wild-type" form. Conversely, the term "modified" or "mutant" refers to a gene or gene product that exhibits modifications in sequence and / or functional characteristics (i.e., altered traits) compared to a wild-type gene or gene product. It is important to note that naturally occurring mutants can be isolated; they are identified by the fact that they possess altered characteristics (including altered nucleic acid sequences) compared to wild-type genes or gene products.

[0257] The term "autoimmune disease" refers to diseases that occur when the body's tissues are attacked by its own immune system. Examples of autoimmune diseases include, for example, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis.

[0258] A more complete list of autoimmune diseases that can be treated by the compounds and pharmaceutical compositions disclosed herein 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, Sjogren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, and autophospholipid syndrome. Aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed-type cryoagglutininemia, Evans syndrome, pernicious anemia, pure red cell dysplasia, thrombocytopenia, adiposis dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry-Romberg syndrome. Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndromeSystemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonopathies, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eatonmyasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, and streptococcal-associated pediatric autoimmune neuropsychiatric disorder. Streptococcus (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Syndenhamchorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate teuveitis, ligneous conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmia.ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Méniére's disease, Bechet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica Rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, and pyoderma gangrenosum, etc.

[0259] The terms “cancer” or “neoplasia” are used throughout this specification to refer to the pathological process that leads to the formation and growth of cancer or malignant tumors, namely, abnormal tissue that grows through cell proliferation, typically growing faster than normal tissue and continuing to grow after the stimulus that initiated new growth has ceased. Malignant tumors exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to multiple sites, are likely to recur after attempted resection, and will lead to patient death unless properly treated. As used herein, the term tumor is used to describe the disease state of all cancers and encompasses or includes the pathological processes associated with malignant hematogenous tumors, ascites tumors, and solid tumors. Tumors include, but are not limited to, abnormal morphology of cells in the subject's or host's tissues compared to normal proliferation in similar tissues, and pathological proliferation of cells in the subject's tissues. Furthermore, tumors include benign tumors and invasive or non-invasive malignant tumors (such as colon tumors). Malignant tumors (cancer) are distinguished from benign tumors by exhibiting a higher degree of anaplasia, or loss of cell differentiation and orientation, and by having invasive and metastatic characteristics. Examples of growths or tumors from which the target cells of this disclosure may be derived include, but are not limited to, cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, particularly Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myoma, peripheral neuroepithelial tumor, and synovial sarcoma; and tumors of the central nervous system (e.g., glioma, etc.). Astrocytoma, oligodendroglioma, epithelioma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; reproductive system tumors (e.g., colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, and melanoma); mixed tumors, especially carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17. sup. th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991).All of these tumors can be treated using compounds according to this disclosure.

[0260] Representative common cancers treatable with compounds according to 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, laryngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, and lymphoma, which can be treated with one or more compounds according to this disclosure. Due to the activity of the compounds of this invention, this disclosure has universal applicability to the treatment of virtually any cancer in any tissue. Therefore, the compounds, compositions and methods disclosed herein are generally applicable to the treatment of cancer and to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0261] In certain specific aspects of this disclosure, the cancer treated is metastatic, recurrent, or drug-resistant, with a particular emphasis on drug-resistant cancer. Specifically, metastatic cancer can be found in virtually any tissue in patients with advanced-stage cancer; typically, it can be found in the lymphatic system / nodules (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and virtually any tissue, including the brain (brain cancer / tumor). Therefore, this disclosure is universally applicable and can be used to treat any cancer in any tissue, regardless of its etiology.

[0262] The term "anticancer agent" or "additional anticanceragent" refers to a compound other than the chimeric compounds according to this disclosure, which can be used in combination with compounds according to this disclosure for the treatment of cancer. Exemplary anticancer agents that can be co-administered in combination with one or more chimeric compounds according to this disclosure include, for example, antimetabolites, inhibitors of topoisomerases I and II, alkylating agents, and microtubule inhibitors (e.g., paclitaxel). Exemplary anticancer compounds used in this disclosure may include everolimus, trabettetidine, albumin-bound paclitaxel (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, enzatolin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR inhibitors. TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CdK inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, lesion adhesion kinase inhibitors, Map kinase kinase (MEK) inhibitors, VEGF capture antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, dicarboxinib, panitumumab, amrubicin, oligomab, lep-etu, noratrexed, azd2171, batabulin, ofatum Arzerra (umab), Zanolimumab, Eotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gematometacon, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7- Dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylhexylestradiol), estradiol, estrogen, estrogen conjugate, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(Bu t)6,Azgly 10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 Oi4-(C2H4O2) X[where x = 1 to 2.4], Goserelin acetate, Leuprorelin acetate, Triptorelin dihydroxynaphthyl acetate, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Raloxifene, Bicalutamide, Flutamide, Nilutamide, Medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Tipifafenib; Amifostine, NVP-LAQ824, Suberoyl Analide Hydroxamic Acidvalproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, daunomycin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone udrocortisone), fluoromethyltestosterone, flutamide, gemcitabine, glievac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, dichloromethyldiethylamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, procalcimycin, porfimer, procarbazine, raltitrexed, rituximab, streptozoline, teniposide, testosterone, thalidomide Thalidomide, Thioguanine, Thiotepa, Retinoic acid, Vinpocetine, 13-cis-retinoic acid, Phenylalanine mustard, Uramustine, Estrustine, Hexamethylmelamine, Fluorouracil, 5-Deooxyuridine, Cytosine arabinoside, 6-Mecaptopurine, Deoxycoformycin, Calcitriol, Pentorubicin, Mitramycin, Vincristine, Vinorelbine, Topotecan, Razoxin, Marimasta ( Marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukinDiftitox, Gefitinib, Bortezomib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody), Erbitux, Cremophor-free Paclitaxel, Epihilone B, BMS-247550, BMS-310705, Droloxifen ), 4-hydroxytamoxifen, piperfen, ERA-923, azoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, PEG-Fibraserin, Dabepoetin, Erythropoietin Gastrointestinal motility factor (GMP), zoledronic acid, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histamine, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxan, alemtuzumab, cremophor-free paclitaxel, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomabTiuxetan), androgens, decitabine, hexamethylmelamine, bexarotene, tosimomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal donomycin, Edwina-asparaginase, strontium-89, caspopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim This includes immunotherapy agents such as IDO inhibitors (inhibitors of the indoleamine 2,3-dioxygenase (IDO) pathway), such as Indoximod (NLG-8187), Navoximod (GDC-0919), and NLG802; PDL1 inhibitors (inhibitors of programmed death-ligand 1), including nivolumab, durvalumab, and atezolizumab; PD1 inhibitors, such as pembrolizumab (Merck); and CTLA-4 inhibitors (inhibitors of cytotoxic T-lymphocyte-associated protein 4 / differentiation cluster 152), including ipilimumab and tremelimumab, etc.

[0263] In addition to anticancer agents, a wide range of other agents may be used in combination with the chimeric compounds according to this disclosure when treating cancer. These include activators, minerals, vitamins, and nutritional supplements that have shown some efficacy in inhibiting cancerous tissue or its growth, or are otherwise used to treat cancer. For example, one or more of dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and phytoestrogens (including β-sitosterol) may be used in combination with the compounds of this invention to treat cancer.

[0264] The term "inflammatory disease" is used to describe diseases or conditions that are characterized primarily by acute inflammation, but more commonly, they are characterized primarily by chronic inflammation. Inflammatory diseases include neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias); diseases that cause inflammation due to impaired immune responses (e.g., T cell maturation, B cell and T cell imbalance, anti-destructive inflammation); chronic inflammatory diseases, such as inflammatory bowel disease including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjögren's disease; hyperglycemia, diabetes (type I and type II), which affects islet function and / or structure, islet β cell death, and associated hyperglycemia, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall's syndrome, Werner's syndrome). Syndrome, leprechaunism, and lipoatrophic diabetes, as well as dyslipidemia (such as hyperlipidemia as seen in obesity, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein (HDL), elevated triglycerides, and metabolic syndrome), liver disease, kidney disease (plaque apoptosis, glomerular disease), cardiovascular disease (especially including infarction, ischemia, stroke, stress overload, and complications during reperfusion), muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions such as cardiac and neurological (central and peripheral) manifestations, including stroke, Alzheimer's disease and sporadic Alzheimer's disease, and mental illnesses including depression), stroke and spinal cord injury, arteriosclerosis, etc. Elevated MIF is frequently observed in these diseases, enabling these disease states and / or conditions to respond to treatment with the compounds and / or pharmaceutical compositions disclosed herein. It is noteworthy that there is some overlap between certain autoimmune diseases and the inflammatory diseases described herein.

[0265] Throughout this disclosure, all aspects of this disclosure may be expressed in range format. It should be understood that the use of range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this disclosure. Therefore, a description of a range should be considered as specifically disclosing all possible subranges within that range, as well as individual numerical values. For example, a description of a range such as 1 to 6 should be considered as specifically disclosing subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual values ​​within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0266] compound

[0267] In one aspect, this disclosure provides a compound of formula (I) or a salt thereof, a geometric isomer, a stereoisomer, or a solvate thereof:

[0268] [Protein binding agents] k' —[CON] h —[Linking group] i —[CON] h' —[CRBM] j' (I).

[0269] In some embodiments, the compound comprises formula (Ia), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0270] [Protein binding agent]—[CON] 0-1 —[Linking group]—[CON] 0-1 —[CRBM](Ia).

[0271] In (I) and / or (Ia), a protein binder is a molecule that binds to an extracellular protein of interest (“protein”), such as, but not limited to, small molecules and / or peptides. In some embodiments, the treatment or management of a disease and / or disorder requires degradation, clearance, and / or reduction of the concentration of extracellular proteins in a subject. In some embodiments, the extracellular protein binders in (I) and / or (Ia) are capable of binding to circulating extracellular proteins in the subject's plasma with the same or substantially similar affinity as the extracellular protein binder itself.

[0272] 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 degrading cells in the subject, thereby causing endocytosis and degradation of (I) and / or (Ia) and / or extracellular proteins. In some embodiments, the CRBM is an ASGPRBM, which is a cell receptor-binding moiety that binds to at least one desialylate glycoprotein receptor on the surface of hepatocytes or other degrading cells in the subject.

[0273] In (I) and / or (Ia), each CON is independently a bond or group that covalently links the protein binder to the CRBM, the protein binder to a linking group, and / or the linking group to the CRBM.

[0274] In (I) and / or (Ia), the linker group is a group having a valence in the range of 1 to 15. In some embodiments, the linker group has a valence of 1 to 10. In some embodiments, the linker group has a valence of 1 to 5. In some embodiments, the linker group has a valence of 1, 2, or 3. In some embodiments, the linker group is covalently linked to one or more CRBM and / or protein binding groups, optionally via CON, wherein the linker group itself optionally comprises one or more CON groups.

[0275] In some implementations, k' is an integer in the range of 1 to 15. In some implementations, k' is an integer in the range of 1 to 10. In some implementations, k' is an integer in the range of 1 to 5. In some implementations, k' is an integer in the range of 1 to 3. In some implementations, k' is 1, 2, or 3.

[0276] In some implementations, j is an integer in the range of 1 to 15. In some implementations, j is an integer in the range of 1 to 10. In some implementations, j is an integer in the range of 1 to 5. In some implementations, j is an integer in the range of 1 to 3. In some implementations, j is 1, 2, or 3.

[0277] In some implementations, h is an integer in the range of 0 to 15. In some implementations, h is an integer in the range of 1 to 15. In some implementations, h is an integer in the range of 1 to 10. In some implementations, h is an integer in the range of 1 to 5. In some implementations, h is an integer in the range of 1 to 3. In some implementations, h is 1, 2, or 3.

[0278] In some implementations, h' is an integer in the range of 0 to 15. In some implementations, h' is an integer in the range of 1 to 15. In some implementations, h' is an integer in the range of 1 to 10. In some implementations, h' is an integer in the range of 1 to 5. In some implementations, h' is an integer in the range of 1 to 3. In some implementations, h' is 1, 2, or 3.

[0279] In some implementations, i is an integer in the range of 0 to 15. In some implementations, i is an integer in the range of 1 to 15. In some implementations, i is an integer in the range of 1 to 10. In some implementations, i is an integer in the range of 1 to 5. In some implementations, i is an integer in the range of 1 to 3. In some implementations, i is 1, 2, or 3.

[0280] In some implementations, at least one of h, h', and i is at least 1.

[0281] In some implementations, k', j', h, h' and i are each independently 1, 2 or 3.

[0282] In some implementations, k' is 1, and j' is 1, 2, or 3.

[0283] In another aspect, this disclosure provides a compound comprising formula (II), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0284] [TNF binding agents] k' —[CON] h —[Linking group] i —[CON] h' —[CRBM] j' (II).

[0285] In some embodiments, the compound comprises formula (IIa), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0286] [TNF binders]—[CON] 0-1 —[Linking group]—[CON] 0-1 —[CRBM] ' (IIa).

[0287] In (II) and / or (IIa), the TNF binder is a molecule that binds to TNF, such as, but not limited to, small molecules and / or peptides. In some embodiments, the treatment or management of a disease and / or disorder requires degradation, clearance, and / or reduction of the concentration of TNF in the subject. In some embodiments, the TNF binder in (II) and / or (IIa) is capable of binding to circulating TNF in the subject's plasma with the same or substantially similar affinity to the TNF binder itself.

[0288] In (II) and / or (IIa), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of a subject's hepatocytes or other degrading cells, thereby leading to the internalization and degradation of (II) and / or (IIa) and / or TNF. In some embodiments, the CRBM is an ASGPRBM, which is a cell receptor-binding moiety that binds to at least one desialylate glycoprotein receptor on the surface of a subject's hepatocytes or other degrading cells.

[0289] In (II) and / or (IIa), each CON is independently a bond or group that covalently links the TNF binder to the CRBM, the TNF binder to a linking group, and / or the linking group to the CRBM.

[0290] In (II) and / or (IIa), the linking group is a group having a valence in the range of 1 to 15. In some embodiments, the linking group has a valence of 1 to 10. In some embodiments, the linking group has a valence of 1 to 5. In some embodiments, the linking group has a valence of 1, 2, or 3. In some embodiments, the linking group is optionally covalently linked to one or more CRBM and / or TNF binding groups via CON, wherein the linking group itself optionally comprises one or more CON groups.

[0291] In some implementations, k' is an integer in the range of 1 to 15. In some implementations, k' is an integer in the range of 1 to 10. In some implementations, k' is an integer in the range of 1 to 5. In some implementations, k' is an integer in the range of 1 to 3. In some implementations, k' is 1, 2, or 3.

[0292] In some implementations, j is an integer in the range of 1 to 15. In some implementations, j is an integer in the range of 1 to 10. In some implementations, j is an integer in the range of 1 to 5. In some implementations, j is an integer in the range of 1 to 3. In some implementations, j is 1, 2, or 3.

[0293] In some implementations, h is an integer in the range of 0 to 15. In some implementations, h is an integer in the range of 1 to 15. In some implementations, h is an integer in the range of 1 to 10. In some implementations, h is an integer in the range of 1 to 5. In some implementations, h is an integer in the range of 1 to 3. In some implementations, h is 1, 2, or 3.

[0294] In some implementations, h' is an integer in the range of 0 to 15. In some implementations, h' is an integer in the range of 1 to 15. In some implementations, h' is an integer in the range of 1 to 10. In some implementations, h' is an integer in the range of 1 to 5. In some implementations, h' is an integer in the range of 1 to 3. In some implementations, h' is 1, 2, or 3.

[0295] In some implementations, i is an integer in the range of 0 to 15. In some implementations, i is an integer in the range of 1 to 15. In some implementations, i is an integer in the range of 1 to 10. In some implementations, i is an integer in the range of 1 to 5. In some implementations, i is an integer in the range of 1 to 3. In some implementations, i is 1, 2, or 3.

[0296] In some implementations, at least one of h, h', and i is at least 1.

[0297] In some implementations, k', j', h, h' and i are each independently 1, 2 or 3.

[0298] In some implementations, k' is 1, and j' is 1, 2, or 3.

[0299] In another aspect, this disclosure provides a compound comprising formula (III), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0300] [AATM] k' —[CON] h —[Linking group] i —[CON] h' —[CRBM] j' (III).

[0301] In some embodiments, the compound comprises formula (IIIa), or a salt, geometric isomer, stereoisomer, or solvate thereof:

[0302] [AATM]—[CON] 0-1 —[Linking group]—[CON] 0-1 —[CRBM] '(IIIa).

[0303] In (III) or (IIIa), the AATM is a ligand for the autoantibody. For example, the ligand may be a small molecule, peptide, and / or nucleic acid aptamer. In some embodiments, the autoantibody mediates a disease and / or disorder in the subject, and treatment or management of the disease and / or disorder requires degradation, clearance, or reduction of the concentration of the autoantibody in the subject. In some embodiments, the AATM in (III) or (IIIa) is capable of binding to the autoantibody in the subject's plasma with the same or substantially similar affinity as the AATM itself.

[0304] In (III) or (IIIa), the CRBM is a cell receptor-binding moiety that binds to at least one receptor on the surface of a subject's hepatocytes or other degrading cells, thereby leading to the endocytosis and degradation of (III) and / or (IIIa) and / or autoantibodies. In some embodiments, the CRBM is an ASGPRBM, which is a cell receptor-binding moiety that binds to at least one desialylate glycoprotein receptor on the surface of a subject's hepatocytes or other degrading cells.

[0305] In (III) or (IIIa), each CON is independently a bond or group that covalently links AATM to CRBM, AATM to a linking group, and / or the linking group to CRBM.

[0306] In (III) or (IIIa), the linking group is a group having a valence in the range of 1 to 15. In some embodiments, the valence of the linking group is 1 to 10. In some embodiments, the valence of the linking group is 1 to 5. In some embodiments, the valence of the linking group is 1, 2, or 3. In some embodiments, the linking group is optionally covalently linked to one or more CRBM and / or AATM groups via CON, wherein the linking group itself optionally comprises one or more CON groups.

[0307] In some implementations, k' is an integer in the range of 1 to 15. In some implementations, k' is an integer in the range of 1 to 10. In some implementations, k' is an integer in the range of 1 to 5. In some implementations, k' is an integer in the range of 1 to 3. In some implementations, k' is 1, 2, or 3.

[0308] In some implementations, j is an integer in the range of 1 to 15. In some implementations, j is an integer in the range of 1 to 10. In some implementations, j is an integer in the range of 1 to 5. In some implementations, j is an integer in the range of 1 to 3. In some implementations, j is 1, 2, or 3.

[0309] In some implementations, h is an integer in the range of 0 to 15. In some implementations, h is an integer in the range of 1 to 15. In some implementations, h is an integer in the range of 1 to 10. In some implementations, h is an integer in the range of 1 to 5. In some implementations, h is an integer in the range of 1 to 3. In some implementations, h is 1, 2, or 3.

[0310] In some implementations, h' is an integer in the range of 0 to 15. In some implementations, h' is an integer in the range of 1 to 15. In some implementations, h' is an integer in the range of 1 to 10. In some implementations, h' is an integer in the range of 1 to 5. In some implementations, h' is an integer in the range of 1 to 3. In some implementations, h' is 1, 2, or 3.

[0311] In some implementations, i is an integer in the range of 0 to 15. In some implementations, i is an integer in the range of 1 to 15. In some implementations, i is an integer in the range of 1 to 10. In some implementations, i is an integer in the range of 1 to 5. In some implementations, i is an integer in the range of 1 to 3. In some implementations, i is 1, 2, or 3.

[0312] In some implementations, at least one of h, h', and i is at least 1.

[0313] In some implementations, k', j', h, h' and i are each independently 1, 2 or 3.

[0314] In some implementations, k' is 1, and j' is 1, 2, or 3.

[0315] CRBM

[0316] Folic acid (folate) receptor:

[0317] In some implementations, CRBMs are folic acid or any fragment or derivative thereof capable of binding to the folate (folate) receptor. The folate receptor binds to folate and reduced folate derivatives and mediates the delivery of tetrahydrofolate into the cell, where it is then converted from a monoglutamate form to a polyglutamate form (such as 5-methyltetrahydrofolate), since only the monoglutamate form can be transported across the cell membrane. Human proteins in this family include folate receptor 1 (adults), folate receptor 2 (fetus), and folate receptor γ.

[0318] In some embodiments, folic acid CRBM includes methotrexate or a bioactive fragment thereof:

[0319]

[0320] In some implementations, folic acid CRBM includes premetrexed or a bioactive fragment thereof:

[0321]

[0322] In some embodiments, folic acid CRBM can be incorporated into the compounds of this disclosure via one of its carboxylic acids, such as... Figure 1 The illustration is shown in the figure. In other embodiments, folic acid CRBM can be incorporated into the compounds of this disclosure using N-hydroxysuccinimide (NHS)-activated folate, such as... Figure 1 The diagram illustrates the effects of folic acid (similar chemical reactions also apply to methotrexate and pemetrexed).

[0323]

[0324] Mannose receptors:

[0325] In some embodiments, the CRBM is a group that binds to a mannose receptor. In some embodiments, the CRBM includes the following groups:

[0326]

[0327] In some embodiments, the mannose receptor CRBM can be attached to the compounds of this disclosure (such as, but not limited to, REAG) using one of the following reagents (which may optionally be protected with a suitable protecting group):

[0328]

[0329] Where X is S or O, and R is selected from:

[0330]

[0331] And each occurrence of 'n' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0332] In some embodiments, the mannose receptor CRBM is part of the polymer molecule. Such a molecule may contain one or more independently selected mannose receptor CRBMs as part of the polymer chain. In some embodiments, the CRBM is incorporated into the polymer molecule using a CRBM reagent described elsewhere herein.

[0333] Mannose-6-phosphate (M6P) receptor:

[0334] In some embodiments, the CRBM is a group that binds to a mannose-6-phosphate (M6P) receptor. In some embodiments, the CRBM includes the following groups:

[0335]

[0336] Where X is O or S, and where R 1 Selected from:

[0337]

[0338] In some embodiments, CRBM can be linked to the compounds of this disclosure (such as, but not limited to, REAG) using one of the following reagents (optionally protected with a suitable protecting group):

[0339]

[0340] Where X and R 1 As defined elsewhere in this document, where R 2 Selected from:

[0341]

[0342] And each occurrence of 'n' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0343] In some embodiments, the M6P receptor CRBM is part of a polymer molecule. Such a molecule may include one or more independently selected M6P receptor CRBMs as part of the polymer chain. In some embodiments, the CRBM is incorporated into the polymer molecule using CRBM reagents described elsewhere herein. Figure 2-9 An exemplary mannose receptor binding agent and its preparation are illustrated.

[0344] In some embodiments, the M6P receptor CRBM is one of the following (Yamaguchi et al., 2016, J.Am.Chem.Soc.138(38):12472-12485):

[0345]

[0346]

[0347] In some embodiments, the M6P receptor CRBM is one of the following (Platenburg, US2011 / 0110960):

[0348]

[0349] Low-density lipoprotein receptor-associated protein 1 (LRP1) receptor:

[0350] In some 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 differentiation cluster 91 (CD91)] binding group comprising one of the following amino acid sequences:

[0351] Ac-VKFNKPFVFLNleIEQNTK-NH2 (SEQ ID NO: 1), Toldo et al., 2017, JACC: Basic to Translational Science 2.5:561-574;

[0352] VKFNKPFVFLMIEQNTK (SEQ ID NO:2), Toldo et al., 2017, JACC: Basic to Translational Science 2.5:561-574;

[0353] TWPKHFDKHTFYSILKLGKH-OH (SEQ ID NO:3), Sakamoto et al., 2017, Biochemistryand biophysics reports 12:135-139;

[0354] Angiopep-2: TFFYGGSRGKRNNFKTEEY-OH (SEQ ID NO: 4), Sakamoto et al., 2017, Biochemistry and biophysics reports 12:135-139;

[0355] LRKLRKRLLRDADDLLRKLRKRLLRDADDL (SEQ ID NO: 5), Croy et al., 2004, Biochemistry 43.23:7328-7335;

[0356] TEELRVRLASHLRKLRKRLL (SEQ ID NO:6), Croy et al., 2004, Biochemistry43.23:7328-7335;

[0357] Rap12:EAKIEKHNHYQK (SEQ ID NO:7), Ruan et al., 2018, Journal of ControlledRelease 279:306-315;

[0358] Rap22:EAKIEKHNHYQKQLEIAHEKLR (SEQ ID NO:8), Ruan et al., 2018, Journal of Controlled Release 279:306-315; or

[0359] ANG:TFFYGGSRGKRNNFKTEEY(SEQ ID NO:9) Kim et al., 2016, Scientific Reports 6:34297.

[0360] Low-density lipoprotein receptor (LDLR):

[0361] In some embodiments, CRBM is an LDLR (low-density lipoprotein receptor) binding group comprising one of the following amino acid sequences:

[0362] VH4127: cM-Thz-RLRG-Pen (cyclized c-Pen) (SEQ ID NO:10), Molino et al., 2017, The FASEB Journal 31.5:1807-1827;

[0363] VH434:CMPRLRGC (cyclized CC) (SEQ ID NO:11), Molino et al., 2017, The FASEB Journal 31.5:1807-1827;

[0364] VH101: HLDCMPRGCFRN (cyclized CC) (SEQ ID NO: 12), David et al., 2018, PloS one13.2: 0191052;

[0365] VH202: CQVKSMPRC (cyclized CC) (SEQ ID NO:13), David et al., 2018, PloS one13.2:0191052;

[0366] VH203: CTTMPPRLC (cyclized CC) (SEQ ID NO:14), David et al., 2018, PloS one13.2: 0191052;

[0367] VH204: CKAPQMPRC (cyclized CC) (SEQ ID NO:15), David et al., 2018, PloS one13.2: 0191052;

[0368] VH205: CLNPSMPRC (cyclized CC) (SEQ ID NO:16), David et al., 2018, PloS one13.2: 0191052;

[0369] VH306: CLVSSMPRC (cyclized CC) (SEQ ID NO:17), David et al., 2018, PloS one13.2: 0191052;

[0370] VH307: CLQPMPRLC (cyclized CC) (SEQ ID NO:18), David et al., 2018, PloS one13.2:0191052;

[0371] VH308: CPVSSMPRC (cyclized CC) (SEQ ID NO:19), David et al., 2018, PloS one13.2: 0191052;

[0372] VH309: CQSPMPRLC (cyclized CC) (SEQ ID NO:20), David et al., 2018, PloS one13.2:0191052;

[0373] VH310: CLTPMPRLC (cyclized CC) (SEQ ID NO:21), David et al., 2018, PloS one13.2:0191052;

[0374] VH411:DSGLCMPRLRGCDPR (cyclized CC) (SEQ ID NO:22), David et al., 2018, PloSone 13.2:0191052;

[0375] VH549: TPSAHAMALQSLSVG (SEQ ID NO: 23), David et al., 2018, PLoS one 13.2: 0191052;

[0376] AcVH411: Ac-DSGLCMPRLRGCDPR-NH2 (cyclized CC) (SEQ ID NO:24), David et al., 2018, PloS one 13.2: 0191052;

[0377] PrVH434: Pr-CMPRLRGC-NH2 (cyclized CC) (SEQ ID NO:25), David et al., 2018, PloSone 13.2: 0191052;

[0378] VH445: Pr-cMPRLRGC-NH2 (cyclized CC) (SEQ ID NO:26), David et al., 2018, PloSone 13.2: 0191052;

[0379] VH4127: Pr-cMThzRLRG-Pen-NH2 (cyclized C-Pen) (SEQ ID NO:27), David et al., 2018, PloS one 13.2: 0191052;

[0380] AcVH434: Ac-CMPRLGC-NH2 (cyclized CC) (SEQ ID NO:28), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0381] AcVH445: Ac-cMPRLRGC-NH2 (cyclized CC) (SEQ ID NO:29), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0382] VH4106: Ac-D-Pen-M-Thz-RLRGC-NH2 (cyclized Pen-C) (SEQ ID NO:30), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0383] VH4127: Pr-cM-Thz-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO:31), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0384] VH4128: Pr-cM-Thz-RLR-Sar-Pen-NH2 (cyclized C-Pen) (SEQ ID NO:32), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0385] VH4129: Pr-cM-Pip-RLR-Sar-C-NH2 (cyclized CC) (SEQ ID NO:33), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105;

[0386] VH4130: Pr-cM-Pip-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO:34), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105; or

[0387] VH4131: Pr-cM-Pip-RLR-Sar-Pen-NH2 (cyclized c-Pen) (SEQ ID NO:35), Jacquot et al., 2016, Molecular pharmaceutics 13.12:4094-4105.

[0388] FcγRI receptor:

[0389] In some embodiments, CRBM is an FcγRI binding group comprising one of the following amino acid sequences:

[0390] Cp22: TDT C LMLPLLLG C DEE (cyclized CC) (SEQ ID NO:36), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0391] Cp21: DPI C WYFPRLLG C TTL (cyclized CC) (SEQ ID NO:37), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0392] Cp23: WYP C YIYPRLLG C DGD (cyclized CC) (SEQ ID NO:38), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0393] Cp24: GNI C MLIPGLLG C SYE (cyclized CC) (SEQ ID NO:39), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0394] Cp33: VNS C LLLPNLLG C GDD (cyclized CC) (SEQ ID NO:40), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0395] Cp25: TPV C ILLPSLLG C DTQ (cyclized CC) (SEQ ID NO:41), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0396] Cp26: TVL C SLWPELLG C PPE (cyclized CC) (SEQ ID NO:42), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0397] Cp27: TFS C LMWPWLLG C ESL (cyclized CC) (SEQ ID NO:43), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0398] Cp32: FGT C YTWPWLLG C EGF (cyclized CC) (SEQ ID NO:44), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0399] Cp34: SLF C RLLLTPVG C VSQ (cyclized CC) (SEQ ID NO:45), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0400] P35: HLL V LPRGLLG C TTLA (cyclized CC) (SEQ ID NO:46), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0401] Cp28: TSL C SMFPDLLG C FNL (cyclized CC) (SEQ ID NO:47), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0402] Cp29: SHP C GRLPMLLG C AES (cyclized CC) (SEQ ID NO:48), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0403] P37: TST C SMVPGPLGAV STW (cyclized CC) (SEQ ID NO:49), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0404] Cp30: KDP C TRWAMLLG C DGE (cyclized CC) (SEQ ID NO:50), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0405] Cp31: IMT C SVYPFLLG C VDK (cyclized CC) (SEQ ID NO:51), Bonetto et al., 2009, The FASEB Journal 23.2:575-585;

[0406] Cp36: IHS C AHVMRLLG C WSR (cyclized CC) (SEQ ID NO:52), Bonetto et al., 2009, The FASEB Journal 23.2:575-585.

[0407] Transferrin receptor:

[0408] In some embodiments, CRBM is a transferrin receptor-binding group comprising one of the following amino acid sequences:

[0409] Tf1: CGGGPFWWWP (SEQ ID NO:53), Santi et al., 2016, Bioconjugatechemistry28.2:471-480;

[0410] Tf2: CGGGHKYLRW (SEQ ID NO:54), Santi et al., 2016, Bioconjugatechemistry28.2:471-480;

[0411] Tf3: CGGGKRIFMV (SEQ ID NO:55), Santi et al., 2016, Bioconjugatechemistry28.2:471-480;

[0412] Tf2-scr: CGGGKWHYLR (SEQ ID NO:56), Santi et al., 2016, Bioconjugatechemistry 28.2:471-480;

[0413] TfR-T12 :THRPPMWSPVWP(SEQ ID NO:57), Mu et al., 2017, Scientific reports 7.1:3487;

[0414] HAIYPRH (SEQ ID NO:74), Lee et al., 2001, European journal of biochemistry 268.7:2004-2012);

[0415] THRPPMWSPVWP (SEQ ID NO:58), Lee et al., 2001, European journal of biochemistry268.7:2004-2012);

[0416] THRPPMWSPVWP(SEQ ID NO:59), et al., 2011, Molecular Imaging and Biology 13.2:332-341.

[0417] Macrophage scavenger receptor:

[0418] In some embodiments, CRBM is a macrophage scavenger receptor binding moiety comprising one of the following amino acid sequences:

[0419] PP1: LSLERFLRCWSDAPA (SEQ ID NO:60), Segers et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0420] PP1-13: LERFLRCWSDAPA (SEQ ID NO:61), Segers et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0421] PP1-11: RFLRCWSDAPA (SEQ ID NO:62), Segers et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0422] PP1-9: LRCWSDAPA (SEQ ID NO:63), Segers et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0423] PP1-7: CWSDAPA (SEQ ID NO:64), Segers et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0424] 4F: DWFKAFYDKVAEKFKEAF (SEQ ID NO: 65), Neyen et al., 2009, Biochemistry 48.50: 11858-11871);

[0425] As used in this article, Pen is penicillamine, Thz is thiazolidin-4-carboxylic acid, Sar is sarcosine, Pip is piperidine acid, Nleu is ortholeucine, and NMeLeu is N-methylleucine.

[0426] G-protein-coupled receptors:

[0427] In some embodiments, CRBM is a G protein-coupled receptor (GPCR) binding moiety. In some embodiments, the binding moiety binds to the GPCR and induces receptor internalization. In some embodiments, the receptor is CXCR7 (e.g., see Nalawansha et al., 2019, ACS Cent. Sci. 5(6): 1079-1084). In some embodiments, the binding moiety includes the following:

[0428]

[0429] Each occurrence of R is independently H or a C1-C6 alkyl group. In some embodiments, CRBM may be linked to the compound of this disclosure (e.g., but not limited to, REAG) using one of the following reagents (which may optionally be protected with a suitable protecting group):

[0430]

[0431] Wherein at least one occurrence of R is REAG, and where the remaining occurrences of R are independently H or C1-C6 alkyl.

[0432] Asialic acid glycoprotein receptor (ASGPR):

[0433] This disclosure considers the use of the ASGPR combination portion (ASGPRBM).

[0434] In some embodiments, the ASGPRBM group is any such group described in Huang et al., 2017, Bioconjugate Chem. 28:283-295, which is incorporated herein by reference in its entirety.

[0435] In some embodiments, the ASGPRBM group comprises the following structure:

[0436]

[0437] Where X is a linking group with a length of 1-4 atoms and includes O, S, N(R) N1 ) or C(R N1 (R) N1 ) group, such that:

[0438] When X is a linking group with a length of 1 atom, X is O, S, N(R) N1 ) or C(R N1 (R) N1 ),

[0439] When X is a linking group with a length of 2 atoms, no more than one atom in X is O, S, or N (R). N1 When X is a linking group with a length of 3 or 4 atoms, no more than 2 atoms in X are independently O, S, or N (R). N1 ).

[0440] In some implementations, R N1 Each occurrence of the alkyl group is independently H or optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0441] In some implementations, when the length of X is 2 atoms, X in ASGPRBM is -OC(R) N1 (R) N1 )-、-C(R N1 (R) N1 )-O-、-SC(R N1 (R) N1 )-、-C(R N1 (R) N1 )-S-、-N(R N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-N(R N1 - or -C(R) N1(R) N1 )-C(R N1 (R) N1 )-.

[0442] In some implementations, when the length of X is 3 atoms, X in ASGPRBM is -OC(R) N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-OC(R N1 (R) N1 )-、-OC(R N1 (R) N1 )-O-、-OC(R N1 (R) N1 )-S-、-OC(R N1 (R) N1 )-N(R N1 )-、-SC(R N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-SC(R N1 (R) N1 )-、-C(R N1 (R) N1 )-C(R N1 (R) N1 -S, -SC(R) N1 (R) N1 )-S-、-SC(R N1 (R) N1 )-O-、-SC(R N1 (R) N1 )-N(R N1 )-、-N(R N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-N(R N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-C(R N1 (R) N1 )-N(R N1)-、-N(R N1 )-C(R N1 (R) N1 )-N(R N1 - or -C(R) N1 (R) N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1 ).

[0443] In some implementations, when the length of X is 4 atoms, X in ASGPRBM is -OC(R) N1 (R) N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-OC(R N1 (R) N1 )-C(R N1 (R) N1 )-、-OC(R N1 (R) N1 )-OC(R N1 (R) N1 )-、-SC(R N1 (R) N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-SC(R N1 (R) N1 )-C(R N1 (R) N1 )-、-C(R N1 (R) N1 )-C(R N1 (R) N1 )-SC(R N1 (R) N1 )-、-SC(R N1 (R) N1 )-SC(R N1 (R) N1 )-、-N(R N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1)-C(R N1 (R) N1 - or -C(R) N1 (R) N1 )-N(R N1 )-C(R N1 (R) N1 )-C(R N1 (R) N1 )-.

[0444] In some implementations, X is OCH2 and R N1 It's H.

[0445] In some implementations, X is CH2O and R N1 It's H.

[0446] In some implementations, ASGPRBM includes the following structure:

[0447]

[0448] In some implementations, ASGPRBM includes the following structure:

[0449]

[0450] In some implementations, R 1 for Figure 10 The groups depicted in [the text]. In some embodiments, R [is used]. 3 for Figure 10 The groups depicted in [the text]. In some embodiments, R [is used]. 1 and R 3 Each independently Figure 10 The groups depicted in the text.

[0451] In some implementations, R 1 and R 3 Each is independently H, -(CH2) K OH, optionally substituted with 1-3 independently selected halogens -(CH2) K O (C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1-3 independently selected halogens, -(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (Alynyl group), -(CH2) K COOH, optionally substituted with 1-3 independently selected halogens -(CH2). KC(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens.

[0452] In some implementations, R 1 and R 3 Ph(CH2) is independently substituted with 1-3 independently selected halogens. K -; C1-C4 alkyl groups optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or C1-C4 alkoxy groups optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0453] In some implementations, R 1 and R 3 Each group is independently a group with the following structure:

[0454] -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 ,

[0455] Where R 7 Yes: C1-C4 alkoxy group, optionally 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.

[0456] In some implementations, K is 0. In some implementations, K is 1. In some implementations, K is 2. In some implementations, K is 3. In some implementations, K is 4.

[0457] In some implementations, K' is 1. In some implementations, K' is 2. In some implementations, K' is 3. In some implementations, K' is 4.

[0458] In some implementations, R N3 Each occurrence of R is independently H or C1-C3 alkyl. In some embodiments, R N3 Each occurrence of the alkyl group is independently H or optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups;

[0459] In some implementations, R N4 Each occurrence of this substance is independently of H, C1-C3 alkyl, or Ph-(CH2). K-. In some implementations, R N4 Each occurrence of is independently H, optionally a C1-C3 alkyl group substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2). K -

[0460] In some implementations, R 1 and R 3 Each is selected independently from:

[0461] -(CH2) K OH、 L 1 -≡-、L 1 -(CH2) K -and CYC-(CH2) K -,

[0462] CYC is selected from:

[0463]

[0464] Among them, the use of The marked key indicates a relationship between -(CH2) on CYC. K The site of connection.

[0465] In some implementations, L 1 It is a bond, a linking group, a -CON- linking group, or a -CON- linking group -CON. In some embodiments, L 1 As a key. In some implementations, L 1 It is a linking group. In some embodiments, L 1 It is a -CON- linker. In some embodiments, L 1 It is a -CON-linking group -CON.

[0466] In some implementations, R C The group is a C1-C4 alkyl group that is absent, H, optionally substituted with 1-3 halogens and / or substituted with 1-2 hydroxyl groups, or has the following structure:

[0467]

[0468] Where R 4 R 5 and R 6 Each independently consists of H, F, Cl, Br, I, CN, and NR. N1 R N2 -(CH2) K OH, optionally substituted with 1-3 independently selected halogens -(CH2) KO (C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens, C1-C3-alkoxy optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, optionally substituted with 1-3 independently selected halogens -(CH2). K C(=O)O-(C1-C4 alkyl), OC(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens.

[0469] In some implementations, R N2 Each occurrence of the alkyl group is independently H or optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0470] In some implementations, R C yes:

[0471]

[0472] In some implementations, R 1 and R 3 Each is independently a (C3-C8 saturated carbon ring)-(CH2). K - where the carbon ring is further -L 1 and -R C replace.

[0473] In some implementations, R N Each occurrence of the alkyl group is independently H or optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0474] In some implementations, R 2 for Figure 11 The groups depicted in the text.

[0475] In some implementations, R 2 It is -(CH2) K -N(R N1 )-C(=O)R AM .

[0476] In some implementations, R AM It is a C1-C4 alkyl group, optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, and -(CH2). K COOH, optionally substituted with 1-3 independently selected halogens -(CH2). KC(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -(CH2). K -NR N3 R N4 .

[0477] In some implementations, R 2 yes in:

[0478] R TA It is H, CN, NR N1 R N2 -(CH2) K OH, optionally substituted with 1-3 independently selected halogens -(CH2) K O (C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, optionally substituted with 1-3 independently selected halogens -(CH2). K C(=O)O (C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens.

[0479] or

[0480] R TA It is C3-C 10 The aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbocyclic atoms, each of which is optionally substituted by 1 to 3 independently selected groups from: CN, NR. N1 R N2 -(CH2) K OH, optionally substituted with 1-3 independently selected halogens -(CH2) K O (C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, optionally substituted with 1-3 independently selected halogens -(CH2). K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -(CH2) optionally substituted with 1-3 independently selected halogens. KC(=O)-(C1-C4 alkyl),

[0481] or

[0482] R TA yes It is optionally substituted with 1-3 C1-C3 alkyl groups, which are optionally substituted with 1-3 independently selected halogens.

[0483] or

[0484] R TA yes Each of the -(CH2) K The group is optionally substituted with 1-4 C1-C3 alkyl groups, which are optionally substituted with 1-3 fluorine groups or 1-2 hydroxyl groups.

[0485] In some embodiments, the ASGPRBM group comprises the following structure:

[0486]

[0487] in:

[0488] R A It is a C1-C3 alkyl group optionally substituted with 1-5 independently selected halogens;

[0489] Z A It is -(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 -;

[0490] Z B It does not exist; -(CH2) IM -、-C(=O)-(CH2) IM -or -C(=O)(CH2) IM -NR M -;;

[0491] R M It is an H or a C1-C3 alkyl group optionally substituted with 1-2 hydroxyl groups; and

[0492] Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0493] In some implementations, R A It is methyl or ethyl, each of which is optionally substituted with 1-3 fluorine molecules.

[0494] In some implementations, Z A It contains a PEG group with 1 to 4 ethylene glycol residues.

[0495] In some embodiments, the ASGPRBM group comprises one of the following (Mamidyala et al., 2012, J.Am.Chem.Soc.134:1978-1981):

[0496]

[0497]

[0498]

[0499] In some embodiments, the ASGPRBM group comprises one of the following (Sanhueza et al., 2017, J.Am.Chem.Soc.139:3528-3536):

[0500]

[0501]

[0502] Linking group &CON

[0503] In some embodiments, the linking group is polyethylene glycol, which contains a linking group having 1-12 ethylene glycol residues.

[0504] In some embodiments, the linking group includes the following structure: -CH2CH2(OCH2CH2) m OCH2-、-(CH2) m CH2-, -[N(R) a )-CH(R b (C=O)] m -or polypropylene glycol or polypropylene-co-polyethylene glycol groups containing 1-100 alkylene glycol units;

[0505] Each R a Independently, it is an H, C1-C3 alkyl, or C1-C6 alkanol, or with R b Combined to form pyrrolidine or hydroxypyrrolidine groups;

[0506] Each R bIndependently selected from 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)imidazolium, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazolium or -(CH2)phenol; and

[0507] Where m is an integer in the range of 1 to 15.

[0508] In some embodiments, the linking group includes the structure -[N(R'-(CH2)] 1-15 -C(=O)]-, where R' is H or a C1-C3 alkyl group optionally substituted with 1-2 hydroxyl groups, and m is an integer in the range of 1 to 100.

[0509] In some embodiments, the linking group includes the following structure:

[0510] -ZD-Z'-,

[0511] in:

[0512] Z and Z' are each an independent bond, -(CH2) i -O-、-(CH2) i -S-、-(CH2) i -N(R)-、 -(CH2) i -C(R 2 )=C(R 2 -(cis or trans), -(CH2) i -≡- or -YC(=O)-Y-;

[0513] Each R is independently H, C1-C3 alkyl, or C1-C6 alkanol;

[0514] Each R 2 Independently, it is H or C1-C3 alkyl;

[0515] Each Y is independently a bond, O, S, or N(R);

[0516] Each i is independently 0 to 100; in some embodiments 0 to 75; in some embodiments 1 to 60; in some embodiments 1 to 55; in some embodiments 1 to 50; in some embodiments 1 to 45; in some embodiments 1 to 40; in some embodiments 2 to 35; in some embodiments 3 to 30; in some embodiments 1 to 15; in some embodiments 1 to 10; in some embodiments 1 to 8; in some embodiments 1 to 6; in some embodiments 0, 1, 2, 3, 4 or 5;

[0517] D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m' -or-[(CH2)] n -X1)] j - The condition is that Z, Z', and D are not all keys at the same time;

[0518] X 1 It is O, S, or N(R);

[0519] j is an integer in the range of 1 to 100; in some embodiments it is 1 to 75; in some embodiments it is 1 to 60; in some embodiments it is 1 to 55; in some embodiments it is 1 to 50; in some embodiments it is 1 to 45; in some embodiments it is 1 to 40; in some embodiments it is 2 to 35; in some embodiments it is 3 to 30; in some embodiments it is 1 to 15; in some embodiments it is 1 to 10; in some embodiments it is 1 to 8; in some embodiments it is 1 to 6; in some embodiments it is 1, 2, 3, 4 or 5;

[0520] m' is an integer in the range of 1 to 100; in some embodiments it is 1 to 75; in some embodiments it is 1 to 60; in some embodiments it is 1 to 55; in some embodiments it is 1 to 50; in some embodiments it is 1 to 45; in some embodiments it is 1 to 40; in some embodiments it is 2 to 35; in some embodiments it is 3 to 30; in some embodiments it is 1 to 15; in some embodiments it is 1 to 10; in some embodiments it is 1 to 8; in some embodiments it is 1 to 6; in some embodiments it is 1, 2, 3, 4 or 5.

[0521] n is an integer in the range of 1 to 100; in some embodiments it is 1 to 75; in some embodiments it is 1 to 60; in some embodiments it is 1 to 55; in some embodiments it is 1 to 50; in some embodiments it is 1 to 45; in some embodiments it is 1 to 40; in some embodiments it is 2 to 35; in some embodiments it is 3 to 30; in some embodiments it is 1 to 15; in some embodiments it is 1 to 10; in some embodiments it is 1 to 8; in some embodiments it is 1 to 6; in some embodiments it is 1, 2, 3, 4 or 5.

[0522] In some embodiments, the linking group includes the following structure:

[0523] -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n -,

[0524] Each n and n' is independently an integer in the range of 1 to 25; in some embodiments, it is 1 to 15; in some embodiments, it is 1 to 12; in some embodiments, it is 2 to 11; in some embodiments, it is 2 to 10; in some embodiments, it is 2 to 8; in some embodiments, it is 2 to 6; in some embodiments, it is 2 to 5; in some embodiments, it is 2 to 4; in some embodiments, it is 2 or 3; in some embodiments, it is 1, 2, 3, 4, 5, 6, 7 or 8.

[0525] In some embodiments, the linking group includes the following structure:

[0526] -PEG-CON-PEG-,

[0527] Each PEG is independently a polyethylene glycol group containing 1-12 ethylene glycol residues, and CON is a triazole group.

[0528] In some implementations, CON includes the following structure:

[0529] R' and R" are each independently H, methyl, or bond.

[0530] In some embodiments, CON comprises a diamide structure:

[0531] -C(=O)-N(R 1 )-(CH2) n" -N(R 1 )C(=O)-,

[0532] -N(R 1 )-C(=O)(CH2) n" -C(=O)N(R 1 )-,or

[0533] -N(R 1 )-C(=O)(CH2) n" -N(R 1 )C(=O)-;

[0534] Each R 1 Independently H or C1-C3 alkyl, and n" is an integer from 0 to 8, in some embodiments from 1 to 7, and in some embodiments 1, 2, 3, 4, 5 or 6.

[0535] In some implementations, CON includes the following structure:

[0536]

[0537] in:

[0538] R 1a R 2a and R 3a Each is independently H, -(CH2) M1 -、-(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -、-(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 -or-(CH2) M2 O-(CH2) M1 -C(O)NR 4 -, the condition is R 1a R 2a and R 3a They are not both H;

[0539] Each M1 is independently 1, 2, 3 or 4; in some implementations it is 1 or 2;

[0540] Each M2 is independently 0, 1, 2, 3, or 4; in some implementations, it is 0, 1, or 2.

[0541] Each M3 is independently 0 or 1; and

[0542] Each R 4Independently, it can be H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R is present. 1a R 2a and R 3a M2 and M3 cannot both be 0 at the same time.

[0543] In some implementations, CON includes the following structure:

[0544]

[0545] protein binders

[0546] Any protein binding agent that binds to the protein of interest (in some embodiments, a circulating protein) is useful in formulas (I) and (Ia) of this disclosure. In some non-limiting embodiments, the binding agent is a small molecule. In some non-limiting embodiments, the binding agent is a peptide and / or polypeptide.

[0547] Protein binders can be incorporated into compounds of formula (I) and / or formula (Ia) using any methods known in the art and / or any techniques described or illustrated herein. For example, protein binders can be linked to linking groups and / or CON using amide coupling, ester coupling, nucleophilic substitution, electrophilic substitution, radical coupling, or any other synthetic method known in the art. The linking site of the protein binder should allow the linked protein binder of formula (I) or formula (Ia) to still bind to the protein of interest. Considering the binding mode of the protein binder to the protein of interest, identifying potential linking sites on the protein binder, and / or linking the protein binder to CON and / or linking groups, and determining whether such linking would interfere with the binding of the protein binder to the protein of interest, are all within the scope of standard experiments expected and known to those skilled in the art.

[0548] In some embodiments, the protein binder is an antibody, such as, but not limited to, a monoclonal antibody. The antibody of interest can be incorporated into a compound of formula (I) or (Ia) using any methods known in the art and / or any techniques described or illustrated herein. For example, the antibody can be linked to a linker group and / or CON via a carboxylic acid group on the antibody surface using, for example, amide or ester formation chemistry. For example, the antibody can be linked to a linker group and / or CON via an amino group on the antibody surface using, for example, amide formation chemistry. For example, the antibody can be linked to a linker group and / or CON via a thiol group on the antibody surface using, for example, nucleophilic substitution chemistry. In this case, the surface cysteine ​​residues can be present in the wild-type form of the antibody and / or can be introduced via mutation, for example, site-directed mutagenesis. The linker group and / or CON useful in this disclosure can be any linker group known in the art, provided that the presence of the linker group does not significantly interfere with the antibody's ability to bind to the protein of interest.

[0549] In some embodiments, the protein binder is a polypeptide. The polypeptide of interest can be incorporated into a compound of formula (I) or (Ia) using any methods known in the art and / or any techniques described or illustrated herein. For example, the polypeptide can be linked to a linking group and / or CON via its C-terminus and / or N-terminus using, for example, amide or ester formation chemistry. For example, the polypeptide can be linked to a linking group and / or CON via any intermediate residue using, for example, amide or ester formation chemistry and / or nucleophilic substitution chemistry (e.g., if the polypeptide has thiol residues). The polypeptide can be synthesized using standard Fmoc-SPPS. Introducing a linking group at the N-terminus or C-terminus, followed by the introduction of a functional handle (N3, alkyne, etc.), allows for easy linking to the target domain.

[0550] Protein-based protein binders (such as antibodies, peptides, etc.) can be synthesized using various methods well-known in the art, such as expressing binding proteins that do not require post-translational modification (PTM) in *E. coli* or binding proteins that require PTM in mammalian culture media. These binding proteins can be formulated as bifunctional proteins by introducing non-natural amino acid tags (N3, alkynes, etc.) for binding and then reacting them with the corresponding target domains, or by specifically labeling the proteins using many other well-known bioorthogonal reactions.

[0551] As will be understood by those skilled in the art, any protein binder that can identify and specifically bind to the protein of interest is useful in this disclosure. This disclosure should not be construed as limited to any one known or previously unknown protein binder, provided that the protein binder specifically binds to the protein of interest and inhibits or minimizes the biological activity of the protein of interest.

[0552] In some embodiments, the protein of interest is CD40L. In some embodiments, the protein binding agent that binds to CD40L includes the following (wherein the wavy line indicates a potential non-limiting linker to REAG in the compounds considered in this disclosure):

[0553]

[0554] In some embodiments, the protein of interest is PCSK9. In some embodiments, the protein binding agent that binds to PCSK9 includes the following (wherein the C-terminus of the peptide is optionally amidated, and where the wavy line indicates a potential non-limiting linking site with REAG in the compounds considered in this disclosure):

[0555]

[0556]

[0557] NH-TVFTSWEEYLDWV-X (SEQ ID NO:66), where X = OH or NH2.

[0558] In some embodiments, the protein of interest is PCSK9. In some embodiments, the protein binding agent that binds to PCSK9 includes any binding agent described in WO2018 / 057409. In some embodiments, the protein binding agent includes any of the following (where the wavy line indicates a potential non-limiting connection point with REAG in the compounds considered in this disclosure):

[0559]

[0560]

[0561] In some embodiments, the protein of interest is VEGF. In some embodiments, the protein binding agent that binds to VEGF includes the following (wherein the C-terminus of the peptide is optionally amidated, and where the wavy line indicates a potential non-limiting linking site with REAG in the compounds considered in this disclosure):

[0562] NH-VEPNCDIHVMWEWECFERL-X (SEQ ID NO:67), where X = OH or NH2,

[0563]

[0564] In some embodiments, the protein of interest is TGF-β. In some embodiments, the protein binding agent that binds to TGF-β includes the following (wherein the C-terminus of the peptide is optionally amidated, and where the wavy line indicates a potential non-limiting linking site with REAG in the compounds considered in this disclosure):

[0565] NH-KRFKQDGGC-X (SEQ ID NO:68), where X = OH or NH2,

[0566]

[0567] In some embodiments, the protein of interest is TSP-1. In some embodiments, the protein binding agent that binds to TSP-1 includes the following (wherein the C-terminus of the peptide is optionally amidated, and where the wavy line indicates a potential non-limiting linking site with REAG in the compounds considered in this disclosure):

[0568] NH-RGQILSKLRL-X (SEQ ID NO:69), where X = OH or NH2.

[0569] In some embodiments, the protein of interest is a soluble uPAR. In some embodiments, the protein binding agent that binds to uPAR includes the following (wherein the wavy line indicates a potential non-limiting linker to REAG in the compounds considered in this disclosure):

[0570]

[0571] In some embodiments, the protein of interest is soluble PSMA. In some embodiments, the protein binder that binds to PSMA includes the following (wherein the wavy line indicates a potential non-limiting linker to REAG in the compounds considered in this disclosure):

[0572]

[0573] In some embodiments, the protein of interest is IL-2. In some embodiments, the protein binding agent that binds to IL-2 includes the following (wherein the wavy line indicates a potential non-limiting link site with REAG in the compounds considered in this disclosure):

[0574]

[0575] In some embodiments, the protein of interest is GP120. In some embodiments, the protein binding agent that binds to GP120 includes the following (wherein the wavy line indicates a potential non-limiting linker to REAG in the compounds considered in this disclosure):

[0576]

[0577]

[0578] In some embodiments, the protein of interest is MIF. In some embodiments, the protein binding agent that binds to MIF includes the following (wherein the wavy line indicates a potential non-limiting linker to REAG in the compounds considered in this disclosure):

[0579]

[0580] In some embodiments, the protein of interest is IgA, known in the art or described elsewhere herein. In some embodiments, the protein binding agent that binds to MIF includes any peptide described in Hatanaka et al., 2012, J. Biol. Chem. 287:43126-43136, such as, but not limited to:

[0581] STFCLLGQKDQSYCFTI(SEQ ID NO:70)

[0582] HMRCLHYKGRRVCFLL(SEQ ID NO:71)

[0583] KTMCLRYNHDKVCFRI(SEQ ID NO:72)

[0584] LVLCLVHRTSKHRKCFVI(SEQ ID NO:73)

[0585] A2-3a:SDVCLRYRGRPVCFQV(SEQ ID NO:75)

[0586] Opt-1:HMVCLAYRGRPVCFAL(SEQ ID NO:76)

[0587] Opt-2: HMVCLSYRGRPVCFSL (SEQ ID NO:77)

[0588] Opt-3:HQVCLSYRGRPVCFST(SEQ ID NO:78)

[0589] RDVCLRYRGRPVCFQV(SEQ ID NO:79)

[0590] HDVCLRYRGRPVCFQV(SEQ ID NO:80)

[0591] ADVCLRYRGRPVCFQV(SEQ ID NO:81)

[0592] SAVCLRYRGRPVCFQV(SEQ ID NO:82)

[0593] SMVCLRYRGRPVCFQV SEQ ID NO:83)

[0594] SDRCLRYRGRPVCFQV(SEQ ID NO:84)

[0595] SDACLRYRGRPVCFQV(SEQ ID NO:85)

[0596] SDVCARYRGRPVCFQV(SEQ ID NO:86)

[0597] SDVCLNYRGRPVCFQV(SEQ ID NO:87)

[0598] SDVCLHYRGRPVCFQV(SEQ ID NO:88)

[0599] SDVCLAYRGRPVCFQV(SEQ ID NO:89)

[0600] SDVCLRARGRPVCFQV(SEQ ID NO:90)

[0601] SDVCLRYAGRPVCFQV(SEQ ID NO:91)

[0602] SDVCLRYRARPVCFQV(SEQ ID NO:92)

[0603] SDVCLRYRGSPVCFQV(SEQ ID NO:93)

[0604] SDVCLRYRGAPVCFQV(SEQ ID NO:94)

[0605] SDVCLRYRGRRVCFQV(SEQ ID NO:95)

[0606] SDVCLRYRGRAVCFQV(SEQ ID NO:96)

[0607] SDVCLRYRGRPACFQV(SEQ ID NO:97)

[0608] SDVCLRYRGRPVCRQV(SEQ ID NO:98)

[0609] SDVCLRYRGRPVCAQV(SEQ ID NO:99)

[0610] SDVCLRYRGRPVCFRV(SEQ ID NO:100)

[0611] SDVCLRYRGRPVCFLV(SEQ ID NO:101)

[0612] SDVCLRYRGRPVCFAV(SEQ ID NO:102)

[0613] SDVCLRYRGRPVCFQW(SEQ ID NO:103)

[0614] SDVCLRYRGRPVCFQL(SEQ ID NO:104)

[0615] SDVCLRYRGRPVCFQA(SEQ ID NO:105)

[0616] These peptides can be acyclic (as free thiols) or cyclized into thioxans (disulfide bonds). Furthermore, this disclosure also considers incorporating these peptides into the compounds of this disclosure via N-terminal and / or C-terminal conjugation.

[0617] In some embodiments, the protein binding agent that binds to IgA is any Fc-α receptor mimic peptide described in Heineke et al., 2017, Eur. J. Immunol. 47: 1835-1845, such as, but not limited to:

[0618] Linear peptides:

[0619] GRYQCQYRIGHYRFRYSD(SEQ ID NO:106)

[0620] GRYQAQYRIGHYRFRYSD(SEQ ID NO:107)

[0621] GRYQCQYRIGHYRFRYSD(SEQ ID NO:108)

[0622] Cyclic peptides: CLIPS

[0623] CLIPS-CHYRFRC (SEQ ID NO:109)

[0624] CLIPS-CRIGHYRFRC SEQ ID NO:110)

[0625] CLIPS-YQACHYRFRC(SEQ ID NO:111)

[0626] CLIPS-RYQAQCRIGHYRFC(SEQ ID NO:112)

[0627] CLIPS-GRYQCQYRIGHYRFRYCD(SEQ ID NO:113)

[0628] CLIPS-GRYQACYRIGHYRFRCSD(SEQ ID NO:114)

[0629] CLIPS-GRYQAQCRIGHYRFCYSD(SEQ ID NO:115)

[0630] Cyclic peptide: Oxidized RYQAQCRIGHYRFC (SEQ ID NO:116)

[0631] GRYQCQYRIGHYRFRYCD(SEQ ID NO:117)

[0632] GRYQACYRIGHYRFRCSD(SEQ ID NO:118)

[0633] GRYQAQCRIGHYRFCYSD(SEQ ID NO:119)

[0634] These peptides can be acyclic (as free thiols) or cyclized into thioxans (disulfide bonds). Furthermore, this disclosure also considers incorporating these peptides into the compounds of this disclosure via N-terminal and / or C-terminal conjugation.

[0635] CLIPS indicates that a linear peptide is cyclized via the reaction of the thiol functional group of cysteine ​​with a small rigid entity; this anchor reacts only with thiols and is covalently linked to the peptide. Non-limiting examples of CLIPS crosslinking agents considered in this disclosure include:

[0636]

[0637] TNF binders

[0638] Any TNF-binding agent that binds to TNF is useful in formulas (II) and (IIa) of this disclosure. In some non-limiting embodiments, the binding agent is a small molecule. In some non-limiting embodiments, the binding agent is a peptide and / or polypeptide.

[0639] TNF binders can be incorporated into compounds of formulas (II) and (IIa) using any methods known in the art and / or any techniques described or illustrated herein. For example, TNF binders can be linked to linking groups and / or CON using amide coupling, ester coupling, nucleophilic substitution, electrophilic substitution, radical coupling, or any other synthetic method known in the art. The linking site of the TNF binder should allow the linked TNF binder of formula (II) or (IIa) to still bind to TNF. Considering the binding mode of the TNF binder to TNF and identifying potential linking sites on the TNF binder, and / or linking the TNF binder to CON and / or linking groups, and determining whether such linking would interfere with the binding of the TNF binder to TNF, are all within the scope of standard experiments expected and known to those skilled in the art.

[0640] In some embodiments, the TNF binder is an antibody, such as, but not limited to, a monoclonal antibody. The antibody of interest can be incorporated into a compound of formula (II) or (IIa) using any methods known in the art and / or any techniques described or illustrated herein. For example, the antibody can be linked to a linker group and / or CON via a carboxylic acid group on the antibody surface using, for example, amide or ester formation chemistry. For example, the antibody can be linked to a linker group and / or CON via an amino group on the antibody surface using, for example, amide formation chemistry. For example, the antibody can be linked to a linker group and / or CON via a thiol group on the antibody surface using, for example, nucleophilic substitution chemistry. In this case, the surface cysteine ​​residues can be present in the wild-type form of the antibody, or can be introduced via mutation, for example, site-directed mutagenesis. The linker group and / or CON in this disclosure can be any linker group known in the art, provided that the presence of the linker group does not significantly interfere with the antibody's ability to bind to TNF.

[0641] In some embodiments, the TNF binder is a polypeptide. The polypeptide of interest can be incorporated into compounds of formulas (II) and (IIa) using any methods known in the art and / or any techniques described or illustrated herein. For example, the polypeptide can be linked to a linker group and / or CON via its C-terminus and / or N-terminus using, for example, amide or ester formation chemistry. For example, the polypeptide can be linked to a linker group and / or CON via any intermediate residue using amide or ester formation chemistry and / or nucleophilic substitution chemistry (e.g., if the polypeptide has thiol residues). The polypeptide can be synthesized using standard Fmoc-SPPS. In some embodiments, the C-terminus of the polypeptide is amidated. Introducing a linker group at the N-terminus or C-terminus, followed by the introduction of a functional handle (N3, alkyne, etc.), allows for easy linking to the ASGPR targeting domain. In a non-limiting example:

[0642]

[0643] Protein-based TNF binders (such as antibodies and peptides) can be synthesized using various methods well-known in the art, such as expressing binding proteins that do not require post-translational modification in *E. coli* or expressing binding proteins that require PTM in mammalian culture media. These binding proteins can be formulated as bifunctional proteins targeting TNF-ASGPR by introducing non-natural amino acid tags (N3, alkynes, etc.) for linkage and then reacting them with the corresponding ASGPR targeting domain, or by specifically labeling the proteins using many other well-known bioorthogonal reactions.

[0644] As will be understood by those skilled in the art, any TNF binder that can identify and specifically bind to TNF is useful in this disclosure. This disclosure should not be construed as being limited to any known or previously unknown TNF binder, provided that the TNF binder specifically binds to TNF and inhibits or minimizes the biological activity of TNF.

[0645] In some embodiments, the TNF binder includes the peptide STPTRYS (SEQ ID NO:120) (Guangdong Yixue 2008, 29(1):55-57).

[0646] In some embodiments, the TNF binder includes the peptide CALWHWWHC (SEQ ID NO:121) or C(T / S)WLHWWAC (SEQ ID NO:122) (Diyi Daxue Xuebao 2002, 22(7):597-599).

[0647] In some embodiments, the TNF binder includes any Tbab protein described in Zhu et al., 2016, Protein Sci. 25:2066-2075.

[0648] In some embodiments, the TNF binder comprises the peptide (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.

[0649] In some embodiments, the TNF binder includes one of the following peptides:

[0650] DHPT-9:D-DDDEK QLKER WYKRW LEYLD EFKKN(SEQ ID NO:124)

[0651] DHPT-91:D-TEEEK QLKEW WYKHW QEYLE EFKKN(SEQ ID NO:125)

[0652] (Yang et al., 2019, FEBS Lett. 593::1292-1302).

[0653] In some embodiments, the TNF binder includes TNFR1 or TNFR2 (Yang & Yang, 2013, Fenxi Huaxue / Chinese J.Anal.Chem.41:664-669).

[0654] In some embodiments, the TNF binding agent includes anticachexin C1 and / or C2 (Lian et al., 2013, J. Am. Chem. Soc. 135: 11990-11995).

[0655]

[0656] In some implementations, the TNF binder includes adalimumab, infliximab, etanercept, golimumab, and / or sertozumab.

[0657] In some embodiments, the TNF binder includes a 29.2 kDa scFv identified in Safarpour et al., 2018, Iran. J. Pharm. Res. 17: 743-752.

[0658] In some embodiments, the TNF binder includes GACPPCLWQVLCGGSGSGSG (SEQ ID NO:126) (in a non-limiting example, it may be tribromomethyltrimethylbenzene nucleosulfur-linked; Luzi et al., 2015, Protein Eng. Des. Sel. 28:45-52).

[0659] In some implementations, the TNF binder includes Any affinity (~60 amino acids) identified in [Authors' Name], 2009, N. Biotechnol. 26:251-259.

[0660] In some implementations, the TNF binder includes any affinity identified in Kronqvist et al., 2008, Protein Eng. Des. Sel. 21:247-255.

[0661] In some embodiments, the TNF binder includes any affinity identified in Jonsson et al., 2009, Biotechnol. Appl. Biochem. 54:93-103.

[0662] In some embodiments, the TNF binder includes a bispecific albumin / TNF binding peptide identified in Nilvebrant et al., 2011, PLoS One 6.

[0663] In some implementations, the TNF binder includes ubiquitin-based artificial binding proteins identified in Hoffmann et al., 2012, PLoS One 7:2-11.

[0664] In some embodiments, the TNF binder includes the linear peptide (SEQ ID NO:127) or tetrapeptide (SEQ ID NO:128) of HIHDDLLRYYGW identified in Brunetti et al., 2014, Molecules 19:7255-7268.

[0665] In some embodiments, the TNF binder includes any TNF-α binding peptide (P51 and P52) identified in Alizadeh et al., 2017, Eur. J. Pharm. Sci. 96: 490-498.

[0666]

[0667] In some implementations, the TNF binding agent includes an scFv antibody identified in Alizadeh et al., 2015, Adv. Pharm. Bull. 5:661-666.

[0668] In some embodiments, the TNF binder includes any TNF-binding peptide described in WO 2006 / 053568 (such as, but not limited to, KRWSRYF (SEQ ID NO:129), which may be multivalent in some embodiments), which is incorporated herein by reference in its entirety.

[0669] In some embodiments, the TNF binder includes any TNF-binding peptide described in WO 2015 / 055597 (such as, but not limited to, HIHDDLLRYYGW (SEQ ID NO:127), which may be multivalent in some embodiments), which is incorporated herein by reference in its entirety.

[0670] In some embodiments, the TNF binder includes YCWSQYLCY (SEQ ID NO:130), as identified in Arthritis & Rheumatism 2007, 56(4):1164-74.

[0671] In some embodiments, the TNF binder includes DFLPHYKNTSLGHRP (SEQ ID NO:131), as identified in Chirinos-Rojas et al., 1998, J. Immunol..161:5621-5626.

[0672] In some embodiments, the TNF binder comprises YCLYQSWCY (SEQ ID NO: 132). In some embodiments, the TNF binder is its reduced form (i.e., having internal disulfide bonds). In some embodiments, the TNF binder is its oxidized form (i.e., without internal disulfide bonds). See also, as a non-limiting example. Figure 12 .

[0673] In some embodiments, the TNF binder includes one of the following:

[0674]

[0675] (Zaka et al., 2019, J. Biomol. Struct. Dyn. 37:2464-2476).

[0676] In some embodiments, the TNF binder includes one of the following:

[0677]

[0678] (Shen et al., 2014, Eur. J. Med. Chem. 85: 119-126). See also, as a non-limiting example. Figure 13 and Figure 14 .

[0679] In some embodiments, the TNF binder comprises:

[0680]

[0681] As a non-limiting example, see Figure 15 .

[0682] In some embodiments, the TNF binder comprises:

[0683]

[0684] As a non-limiting example, see Figure 16 .

[0685] In some embodiments, the TNF binder comprises:

[0686]

[0687] As a non-limiting example, see Figure 17 .

[0688] In some embodiments, the TNF binder comprises one of the following (Saddala & Huang, 2019, J. Transl. Med. 17: 1-16):

[0689]

[0690] In some embodiments, the TNF binding agent includes SPD-304 and its analogues (He et al., 2005, Science 310:1022-1025; Papaneophytou et al., 2015, Medchemcomm 6:1196-1209):

[0691]

[0692]

[0693] This article provides non-limiting chemical schemes for the preparation and derivation of these compounds:

[0694]

[0695]

[0696] (Mettou et al., 2018, SLASDiscov.23:84-93). See also, as a non-limiting example. Figure 18 .

[0697] In some embodiments, the TNF binder comprises a compound of formula (2a):

[0698]

[0699] in:

[0700] A 1 and A 2Independently, it is a substituted or unsubstituted phenyl group, wherein the substituents include at least one of the following: F, Cl, Br, I, OH, C1-C4 alkyl, C1-C4 alkyl substituted with at least one OH, C1-C4 fluoroalkyl (e.g., but not limited to CF3), C1-C4 alkoxy, C1-C4 haloalkoxy, benzyloxy; and the following heterocycles, which are optionally substituted with at least one of the following: F, Cl, Br, I, OH, C1-C4 alkyl, C1-C4 alkyl substituted with at least one OH, C1-C4 fluoroalkyl (e.g., but not limited to CF3), C1-C4 alkoxy, and C1-C4 haloalkoxy (dashed lines indicate tie points):

[0701]

[0702] Each R 5 Independently hydrogen or optionally substituted C1-C4 alkyl;

[0703] R 1 and R 2 Independently hydrogen or optionally substituted C1-C4 alkyl;

[0704] X 1 and X 2 Independently, it can be a carbonyl group or CH2;

[0705] n is 2, 3, or 4;

[0706] R 3 and R 4 Independently hydrogen or optionally substituted C1-C4 alkyl or R 3 and R 4 They can be combined to form heterocyclic rings. See also, as a non-limiting example. Figure 19 .

[0707] For example, when A 1 and A 2 They are 1-(3-(trifluoromethyl)phenyl)-1H-indole and 6,7-dimethyl-4H-benzopyran-4-one, respectively, and X 1 and X 2 When both are CH2, R 3 and R 4 It can form heterocycles, such as, but not limited to, piperazine rings.

[0708] In some embodiments, the TNF binder includes the small molecule IA-14069.

[0709] In some embodiments, the TNF binder includes (Mouhsine et al., 2017, Sci. Rep. 7:1-10 (2017). In some embodiments, the linking group and / or Con may be linked to the sulfonamide benzene ring. See, as a non-limiting example.) Figure 20 .

[0710] In some embodiments, the TNF binder includes one of the following:

[0711]

[0712] (Melagraki et al., 2017, PLoS Comput.Biol.13:1-27).

[0713] In some embodiments, the TNF binder includes one of the following:

[0714]

[0715] (Melagraki et al., 2018, Front. Pharmacol. 9: 1-12).

[0716] In some embodiments, the TNF binder includes (Ma et al., 2014, J. Biol. Chem. 289:12457-12466). In some embodiments, the linking group and / or CON may be linked to the phenyl group marked with an arrow. See, as a non-limiting example. Figure 21 .

[0717] In some embodiments, the TNF binder includes one of the following:

[0718] Where R denotes a derivational non-restricted site (Kumar et al., 2011, Chem. Commun. 47:5010-5012). See also, as an example of non-restriction, […]. Figure 22 .

[0719] In some embodiments, the TNF binder includes (Jiajiu & Shaw, 2013, Cancer Chemother Pharmacol 72:1-7(2013).

[0720] In some embodiments, the TNF binder includes any dihydro-benzo[cd]indole-6-sulfonamide or analogue described herein (the non-restrictive linking point of the REAG includes an R1 or hydrophobic R group on the right side of the molecule, including a naphthyl group):

[0721]

[0722]

[0723] In some embodiments, the TNF binder includes any of the following:

[0724]

[0725] (Shiu-Hin Chan, 2010, Angew Chem Int Ed Engl. 49:2860-4).

[0726] In some embodiments, the TNF binder includes any of the following:

[0727]

[0728] In some embodiments, the TNF binder includes any of the following:

[0729] (Chen et al., 2017, J. Chem. Inf. Model. 57: 1101-1111).

[0730] In some embodiments, the TNF binder includes any compound disclosed in U.S. Patent No. 10,266,532, which is incorporated herein by reference in its entirety.

[0731] In some embodiments, the TNF binder includes any compound disclosed in U.S. Patent No. 9,879,016, which is incorporated herein by reference in its entirety.

[0732] In some embodiments, the TNF binder includes any compound disclosed in WO 2008 / 142623, which is incorporated herein by reference in its entirety.

[0733] In some embodiments, the TNF binder comprises:

[0734] In some embodiments, the linking group and / or CON can be linked to the compound via a piperazine group (Blevitt et al., 2017, J. Med. Chem. 60:3511-3517). See also, as a non-limiting example. Figure 23 .

[0735] In some embodiments, the TNF binder comprises a compound of formula (2b):

[0736]

[0737] Or its pharmaceutically acceptable salts, tautomers, geometric isomers or stereoisomers, wherein:

[0738] R 1 It is H, OH, F or optionally substituted (C1-C3) alkyl;

[0739] R 2 It is an optionally substituted aryl group, an optionally substituted (C3-C8) cycloalkyl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclic group; or

[0740] R 1 and R 2 They can be combined to form optionally substituted saturated or partially saturated carbon rings or optionally substituted saturated or partially saturated heterocycles;

[0741] A 1 A 2 and A 3 At most two of them are N, and the rest are C(R) independently. A2 );

[0742] X is N and Y is C, where:

[0743] Z 1 It is —C(R) z )2—and Z 2 It is —C(R) z )2—、—N(R z1 ) - Or —O—; or

[0744] Z 1 It is —CH2— and Z 2 Yes—Z 2a —Z 2b —,

[0745] Z 2a With Z 1 Connect, and Z 2b With C(R) 1 (R) 2 ) connect; and Z 2a and Z 2b Independently for —C(R) z )2—、—C(R z )2C(R z )2—、—O— or—N(R z1 —, the condition is Z 2a and Z 2b One of them is —C(R) z )2—or—C(R) z )2C(R z )2—; or —Z 2a —Z2b —Form—N(R) z1 C(O) — or — C(O)N(R) z1 —;

[0746] or

[0747] X is C and Y is N, given R. 1 It is not -OH or -F, where:

[0748] Z 1 It is —C(R) z )2—and Z 2 It is —C(R) z )2—; or

[0749] Z 1 It is —C(R) z )2—and Z 2 Yes—Z 2a —Z 2b —,

[0750] Z 2a With Z 1 Connection and Z 2b With C(R) 1 (R) 2 ) connect, and Z 2a It is —C(R) z )2—、—C(R z )2C(R z )2—、—O— or—N(R z1 ), and Z 2b It is —C(R) z )2—, or —Z 2a —Z 2b —Form—N(R) z1 C(O) — or — C(O)N(R) z1 —;

[0751] R 3 Yes—R 3a —R 3b ,in:

[0752] R 3a It can be an optionally substituted aryl group, an optionally substituted saturated or partially saturated heterocyclic group, or an optionally substituted heteroaryl group;

[0753] R 3b It is H, —CF3, —CN, —C(O)OH, —N(R) a (R) b —C(O)N(R) a (R) b ), -C(O)-optionally substituted heterocyclic groups, -O(Ra —S(O)2(C1-C3)alkyl, —S(O)2N(R c (R) d —S—(C1-C3)alkyl, —S(O)2—R c Optionally substituted (C1-C5) alkyl groups, —(CH2) p -Optionally substituted (C3-C6) cycloalkyl groups, —(CH2) p -Optionally substituted heteroaryl groups or —(CH2) p -Optionally substituted saturated, unsaturated, or partially saturated heterocyclic groups; condition that R 2 When it is an optionally substituted phenyl group, R3 b Not H or methoxy;

[0754] R a and R b Independently selected from H, optionally substituted (C1-C5) alkyl, —C(O)—optionally substituted (C1-C5) alkyl, optionally substituted —(CH2). p —(C3-C6)cycloalkyl and —(CH2) p -Optionally substituted heterocyclic groups;

[0755] R c and R d Independently selected from H, optionally substituted (C1-C5) alkyl groups, optionally substituted —(CH2) groups. p —(C3-C6)cycloalkyl and —(CH2) p -Optionally substituted heterocyclic groups;

[0756] R A2 It can be independently H, CF3, a halogroup, or a (C1-C3) alkyl group;

[0757] R z It can be independently H, F, CF3, -OH or (C1-C3) alkyl;

[0758] R z1 Independently H or (C1-C3) alkyl; and

[0759] p can be 0, 1, or 2 independently.

[0760] In some implementations, R 2 It is not a phenyl group substituted with —OCHF2.

[0761] In some embodiments, the compound is not 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; [5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-7-yl]-2-pyridyl]methanol; 4-[ 5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazine-1-carboxylic acid tert-butyl ester; (1R or S)-7-[6-chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-[(6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; or (1R or S)-1-phenyl-7-[6-(piperazine-1-yl)pyridyl-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0762] In some embodiments, the compound is 1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; 7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; [5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-7-yl]-2-pyridyl]methanol; 4-[ 5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazine-1-carboxylic acid tert-butyl ester; (1R or S)-7-[6-chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; (1R or S)-7-[(6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; or (1R or S)-1-phenyl-7-[6-(piperazine-1-yl)pyridyl-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

[0763] In some embodiments, the compound of formula (2a) includes one of the following:

[0764]

[0765] Where A 2 It is CH or N; A 3 It is CH or N; B 1 It is CH2 or O; B 2 It is CH2 or O; X is C or N; Y is C or N; Z 1 It is CH2 or O; and Z 2 It is CH2 or O.

[0766] In some implementations, R 3a Selected from:

[0767]

[0768] In some implementations, R 3b Selected from:

[0769]

[0770]

[0771] In some implementations, R 3a Or R 3b Compounds that can be used to link TNF linking groups to the compounds disclosed herein can be used, for example, those containing R listed herein. 3a Or R 3b It may be carried out by introducing any hydroxyl, amino, amide, thio, or carboxylic acid group into it. In any case, R 3a Or R 3b The hydroxyl group in R can be used, for example, to form an ester bond; 3a Or R 3b The carboxyl group in R can be used, for example, to form ester or amide bonds; 3a Or R 3b The amino group in R can be used, for example, to form amide and imine groups, etc.; for example, R 3a Or R 3b The amino, amide, or thio groups in the group can be used, for example, to form chemical linkages through alkylation or nucleophilic substitution, etc., as is known to those skilled in the art.

[0772] In some implementations, R 1 Selected from H, methyl and hydroxyl.

[0773] In some implementations, R 1 and R 2 Combined to form one of the following:

[0774]

[0775] In some implementations, R 4 Selected from:

[0776]

[0777] In some embodiments, the compound is selected from:

[0778] 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0779] 4-(3-Fluorophenyl)-7-(2-morpholinylpyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0780] (R)-1-Phenylacet-7-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol;

[0781] (S)-2-(2-morpholinylpyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine;

[0782] 2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0783] 2-(5-(1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0784] (S)-7-(2-((1R,6S)-3,10-diazabicyclo[4.3.1]dec-10-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0785] (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3.5]non-2-amine;

[0786] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0787] 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-cyclopentazo[4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0788] 1-(5-(8-phenyl-7,8-dihydro-6H-cyclopenta[4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0789] 2-(5-(4-(2-methoxyphenyl)-3,4-dihydro-1H-pyran[3',4':4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0790] (S)-7-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0791] (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0792] 2-(5-(8-(pyridin-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0793] 2-(5-(1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0794] (S)-7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0795] (R)-7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0796] 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[0797] 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-1,4-oxazepane;

[0798] 7-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0799] 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)-4-methylpiperidin-4-ol;

[0800] (4-Fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[0801] (4-Fluoro-1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[0802] 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)azacycloheptan-4-ol;

[0803] 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0804] 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0805] 1-(5-(9-(3-fluorophenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0806] 7-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0807] 7-(5-(9-(3-fluorophenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0808] 7-(5-(8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0809] 7-(5-((R)-8-cyclohexyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0810] 7-(5-((S)-4-(2-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0811] 7-(5-(4-(3-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0812] 7-(5-(4-(2-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0813] 4-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)morpholine;

[0814] (R)-7-(5-((R)-9-phenyl-8,9-dihydro-6H-pyrano[3',4':4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0815] (R)-7-(5-((R)-4-phenyl-3,4-dihydro-1H-pyrano[3',4':4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0816] 1-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0817] 7-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0818] 1-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0819] (S)-1-(5-(9-(2-methoxyphenyl)-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0820] 7-(5-((S)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-1(5H)-one;

[0821] (S)-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0822] (S)-4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[0823] (S)-2-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0824] (S)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0825] (R)-3-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)oxetane-3-ol;

[0826] (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)cyclobutanol;

[0827] (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)tetrahydro-2H-pyran-4-ol;

[0828] (R)-7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0829] 2-(5-(4-(2,6-dichlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0830] (S)-2-(5-(4-(2-methoxyphenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0831] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0832] 7-(5-(4-(2-chlorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0833] 7-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-indene]-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[0834] (S)-2-hydroxy-1-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[0835] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-1-ol;

[0836] (R)-1-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0837] (R)-1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0838] (R)-4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0839] (S)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0840] (R)-2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0841] (S)-4-(3-fluorophenyl)-7-(2-morpholinylpyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0842] 7-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one compound with ethane (1:1);

[0843] 7-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0844] (R)-1-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0845] (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)thiomorpholine 1,1-dioxide;

[0846] -(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0847] 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0848] 3,3-Difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0849] (S)-2-(5-(4-(2-(difluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0850] (S)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0851] (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[0852] 1-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0853] 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0854] (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine;

[0855] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0856] 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[0857] 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0858] 3,3-Difluoro-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0859] 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[0860] (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0861] 7-(4-(isopropylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0862] 2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0863] 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0864] (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[0865] 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0866] (S)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0867] 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0868] (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0869] 4-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0870] 2-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0871] N-Methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide;

[0872] 1-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0873] 7-(4-(ethanesulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0874] (S)-7-(2-morpholinylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0875] 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0876] 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0877] (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[0878] 1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[0879] (S)-7-(2-(1,4-oxazapyridine-4-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0880] 4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine;

[0881] 3,3-Difluoro-1-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0882] (1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-3-yl)methanol;

[0883] 1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)azacycloheptan-4-ol;

[0884] (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazine-1-sulfonamide;

[0885] N-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzyl)methanesulfonamide;

[0886] 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0887] 7-(4-(methylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0888] 7-(2-(1,4-oxazacyclohepta-4-yl)pyrimidin-5-yl)-4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0889] 4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide;

[0890] (4-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)morpholin-2-yl)methanol;

[0891] (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)thiomorpholine 1,1-dioxide;

[0892] 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine;

[0893] (R)-4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)morpholine;

[0894] 2-(5-(1-(3-fluorophenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0895] (S)-(4-fluoro-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[0896] 4-(5-(9-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[0897] (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)prop-2-ol;

[0898] (S)-7-(2-(1'-methyl-[4,4'-bipiperidin]-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0899] 2-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0900] 7-(2-morpholinylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0901] (4S)-7-(2-(2-methylmorpholino)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0902] 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[0903] 4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)morpholine;

[0904] 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-2-yl]pyrimidin-2-yl]amino]ethyl acetate;

[0905] (S)-7-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0906] 2-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0907] (S)-7-(2-(4-(methanesulfonyl)piperazin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0908] 2-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[0909] 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenyl)acetonitrile;

[0910] 4-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[0911] 7-(2-Cyclopropylpyrimidin-5-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0912] (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-2-one;

[0913] 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyridin-2-yl)oxy)acetic acid;

[0914] 7-(6-(ethanesulfonyl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0915] 4-(5-(8-(3-fluorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[0916] 10-(3-fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[0917] 4-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[0918] (S)-6-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-6-azaspiro[3,4]oct-2-ol;

[0919] N,N-Dimethyl-4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0920] N-Ethyl-N-methyl-4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0921] 7-(6-morpholinylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0922] 2-(5-(1-Phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)prop-2-ol;

[0923] 2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0924] (S)-4-(2-hydroxyethyl)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[0925] (S)-7-(2-(2-oxa-7-azaspiro[3.5]non-7-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0926] 2-(1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-3-yl)acetic acid;

[0927] 7-(5-methyl-6-morpholinylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0928] 7-(5-(2-methyl-1H-imidazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0929] 2-(5-(1-cyclohexyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[0930] 2-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)prop-2-ol;

[0931] (S)-(4-(methanesulfonyl)-1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[0932] 1-(1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)ethanol;

[0933] (S)-4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-1,4-diazacyclohepta-2-one;

[0934] 2-(4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenoxy)acetonitrile;

[0935] (S)—N-(1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)methanesulfonamide;

[0936] (S)-3-(1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-yl)propionic acid;

[0937] 4-Phenyl-7-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0938] 4-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)piperazin-2-one;

[0939] 7-(5-fluoro-6-methoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0940] N,N-Dimethyl-5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridine-2-amine;

[0941] 7-(2-methylpyridin-4-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0942] (4S)-4-phenyl-7-(2-(2-(trifluoromethyl)morpholinyl)pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0943] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-2,7-diazaspiro[4,4]non-1-one;

[0944] N-Cyclopentyl-5-(4-Phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine;

[0945] 7-(2-(1H-pyrazol-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0946] (4S)-7-(2-(2,6-dimethylmorpholino)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0947] 7-(6-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0948] 7-(5-ethoxypyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0949] 2-(2-morpholinylpyrimidin-5-yl)-9-(m-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0950] 7-(6-(methylthio)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0951] 2-((5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)ethyl acetate;

[0952] (S)-3-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperazin-1-yl)prop-1-ol;

[0953] 9-(3-Fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0954] 2-(2-morpholinylpyrimidin-5-yl)-9-phenyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0955] 4-(2,5-difluorophenyl)-7-(2-morpholinylpyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0956] 1-Phenyl-7-(6-(piperazin-1-yl)pyridin-3-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0957] 9-(2-Methoxyphenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0958] (S)-7-(2-(2-oxa-6-azaspiro[3.4]oct-6-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0959] 7-(5-(1H-imidazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0960] 7-(furano[3,2-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0961] 10-(3-chlorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[0962] N-Ethyl-4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0963] 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenoxy)acetonitrile;

[0964] 2-(2-morpholinylpyrimidin-5-yl)-10-(m-tolyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[0965] 2-((5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)acetic acid;

[0966] N-Cyclopropyl-4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0967] 4-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0968] 1-(4-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)piperazin-1-yl)acetone;

[0969] 7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0970] 7-(benzo[d][1,3]m-dioxacyclopenten-5-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[0971] 9-(3-fluoro-2-methylphenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0972] 8-Phenyl-2-(4-(pyrimidin-2-yl)piperazin-1-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[0973] 9-(4-fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0974] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)tetrahydro-1H-oxazin[3,4-a]pyrazin-3(5H)-one;

[0975] 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)amino)acetic acid;

[0976] 10-(4-fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[0977] 9-(3-Chlorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0978] N-Cyclopropyl-5-(4-Phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine;

[0979] 9-(3-chloro-5-fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0980] N,N-Dimethyl-5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-amine;

[0981] 1-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid;

[0982] 7-(6-isopropoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0983] 7-(6-isopropoxypyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0984] 4-(5-(6-phenyl-7,8-dihydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-c]pyridin-3-yl)pyrimidin-2-yl)morpholine;

[0985] 1-Phenyl-7-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium;

[0986] 5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridinenitrile;

[0987] 7-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0988] 2-(2-morpholinylpyrimidin-5-yl)-9-(p-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-ol;

[0989] 7-(6-(methylsulfonyl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0990] N-(2-methoxyethyl)-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0991] N-Methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[0992] 4-Phenyl-7-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0993] 1-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid;

[0994] 7-(5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0995] 5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)thiophene-2-carboxylic acid;

[0996] 7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0997] (S)-7-(2-(1'-methyl-[4,4'-bipiperidin]-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0998] 7-(2-Methoxypyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[0999] 10-(3-chloro-5-fluorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1000] 3-(2-hydroxyethyl)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidine-3-ol;

[1001] 4-(5-(9-(2-methoxyphenyl)-6,7-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[1002] 10-(4-methoxyphenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1003] 7-(5-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1004] 1-Phenyl-7-(pyridin-3-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1005] 5-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine;

[1006] 2-(2-morpholinylpyrimidin-5-yl)-10-(p-tolyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1007] 5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-nitrile;

[1008] (R)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1009] (S)-7-(2-((R)-3-(methanesulfonyl)pyrrolidone-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1010] 7-([1,2,5]oxadiazolo[3,4-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1011] 2-(5-(6-phenyl-7,8-dihydro-6H-pyrrolo[1,2':1,2]imidazo[4,5-c]pyridin-3-yl)pyrimidin-2-yl)prop-2-ol;

[1012] 7-(2-methylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1013] 1-Phenyl-7-(pyrimidin-5-yl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1014] 7-(6-methoxy-5-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1015] 10-(4-chlorophenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1016] 2-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)phenyl)acetonitrile;

[1017] N-(3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzyl)methanesulfonamide;

[1018] 7-(6-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1019] (S)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)prop-2-ol;

[1020] (S)-7-(2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1021] 4-Phenyl-7-(6-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1022] (4S)-7-(2-(3-(methylsulfonyl)pyrrolidone-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1023] (S)-8-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-1,3,8-triazaspiro[4.5]dec-4-one;

[1024] 7-(6-isopropoxy-5-methylpyridin-3-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1025] 7-(5-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-H-benzo[d]pyrrolo[1,2-a]imidazole;

[1026] N-Methyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[1027] 4-(1-Phenylacetyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[1028] (S)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine;

[1029] N-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)acetamide;

[1030] N-Ethyl-N-methyl-3-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[1031] 5-(1-Phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridine-2-amine;

[1032] 7-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1033] 10-(3,5-dimethoxyphenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1034] N,N-Dimethyl-3-((5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyridin-2-yl)oxy)prop-1-amine;

[1035] (3R,4R)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidine-3,4-diol;

[1036] N-(2-(dimethylamino)ethyl)-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[1037] 10-(3-methoxyphenyl)-2-(2-morpholinylpyrimidin-5-yl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridine-10-ol;

[1038] 7-(1,5-dimethyl-1H-pyrazol-4-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1039] N,N-Dimethyl-3-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzamide;

[1040] 7-(3-(methylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1041] 4-Phenyl-7-(pyrido[2,3-b]pyrazin-7-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1042] 1-Methyl-5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyridin-2(1H)-one;

[1043] (3S,4S)-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)pyrrolidine-3,4-diol;

[1044] 4-Phenylacet-7-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1045] (S)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[1046] (S)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[1047] 2-(2-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-9-yl)phenol;

[1048] 4-(5-(6-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:4,5-b']dipyridin-3-yl)pyrimidin-2-yl)piperazin-2-one;

[1049] (S)-7-(2-(3-morpholinylazacyclobutane-1-yl)pyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1050] 7-(5-(methylsulfonyl)pyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1051] (R)-7-(2-morpholinylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1052] 7-(2-methylpyridin-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1053] 1-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)azacyclobutane-3-carboxylic acid;

[1054] 7-(1-Methyl-1H-pyrrolo-3-yl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole; or

[1055] 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.

[1056] In some embodiments, the compound is selected from:

[1057] 7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1058] 3,3-Difluoro-1-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[1059] (S)-2-(5-(4-(2-(difluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)prop-2-ol;

[1060] (S)-2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1061] (R)-7-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[1062] 1-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1063] 4-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[1064] (R)-4-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)morpholine;

[1065] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1066] 7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1067] 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-2-one;

[1068] 2-(5-(1-(2,5-dimethylphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[1069] 3,3-Difluoro-1-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[1070] 7-(5-(4-(3-fluorophenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1071] (R)-2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[1072] 7-(4-(isopropylsulfonyl)phenyl)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole;

[1073] 2-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1074] 4-(5-(8-(2,5-dimethylphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[1075] (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[1076] 4-(5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)morpholine;

[1077] 1-(5-(9-phenyl-6,7,8,9-tetrahydroimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1078] (R)-2-(5-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)prop-2-ol;

[1079] 2-(5-(10-(2-methoxyphenyl)-7,8,9,10-tetrahydro-6H-cycloheptane[4,5]imidazo[1,2-a]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1080] N-Methyl-4-(1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)benzenesulfonamide;

[1081] (S)-7-(2-morpholinylpyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine;

[1082] (S)-7-(5-(4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)-7-azaspiro[3,5]non-2-ol;

[1083] 2-(5-(1-(2-methoxyphenyl)-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-7-yl)pyrimidin-2-yl)prop-2-ol;

[1084] (R)-2-(5-(1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-yl)prop-2-ol;

[1085] 2-[[5-[9-(2-methoxyphenyl)-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-2-yl]pyrimidin-2-yl]amino]ethyl acetate;

[1086] 2-((5-(9-(2-methoxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-2-yl)pyridin-2-yl)oxy)acetic acid.

[1087] In some embodiments, the compound is selected from:

[1088] (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)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1089] 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol;

[1090] 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)pyrimidin-2-amine;

[1091] 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-3-ol;

[1092] 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1093] 2'-(2-morpholinylpyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1094] 1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-indene]-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[1095] (1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-3-yl)methanol;

[1096] (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)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1097] 2'-(2-(1,4-oxazacyclohepta-4-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1098] 3,3-Difluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-ol;

[1099] 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)pyrimidin-2-yl)piperazin-1-yl)prop-1-one;

[1100] 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)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1101] (4-Fluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[1102] 2'-(2-morpholinylpyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1103] 1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)azacyclohepta-4-ol;

[1104] (S)-2-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)prop-2-ol;

[1105] (R)-2-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)prop-2-ol;

[1106] (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)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1107] 3-((5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol;

[1108] 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)pyrimidin-2-amine;

[1109] 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-3-ol;

[1110] 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1111] 2'-(2-morpholinylpyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1112] 1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-indene]-7-yl)pyrimidin-2-yl)piperidin-4-ol;

[1113] (1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-3-yl)methanol;

[1114] (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)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1115] 2'-(2-(1,4-oxazacyclohepta-4-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1116] 3,3-Difluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-ol;

[1117] 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)pyrimidin-2-yl)piperazin-1-yl)prop-1-one;

[1118] 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)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1119] (4-Fluoro-1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[1120] 2'-(2-morpholinylpyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1121] 1-(5-(2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)azacyclohepta-4-ol;

[1122] (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1123] (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)pyridin-2-yl)oxy)cyclohexanol;

[1124] (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)pyridin-2-yl)oxy)cyclohexanol;

[1125] 3-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyridin-2-yl)oxy)cyclopentanol;

[1126] 2'-(2-morpholinylpyrimidin-5-yl)-6',7'-dihydrospiro[cyclohexane-1,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine];

[1127] 2'-(2-morpholinylpyrimidin-5-yl)-6',7'-dihydrospiro[benzodihydropyran-4,9'-pyrano[4',3':4,5]imidazo[1,2-b]pyridazine];

[1128] 2'-(2-(piperazin-1-yl)pyrimidin-5-yl)-6'H,8'H-spiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1129] 2'-(2-methoxypyrimidin-5-yl)-6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine];

[1130] 2'-(2-ethoxypyrimidin-5-yl)-6',8-dihydrospiro[benzodihydropyran-4,9'-pyrido[3,2':4,5]imidazo[2,1-c][1,4]oxazine];

[1131] 2'-(2-(methylsulfonyl)pyrimidin-5-yl)-6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1132] 2'-(2-(1,4-diazacyclohept-1-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1133] 5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)-N-isopropylpyrimidine-2-amine;

[1134] 2'-(2-morpholinylpyrimidin-5-yl)-6',8-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1135] 2-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)prop-2-ol;

[1136] 2'-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1137] 5-(6'H,8'H-spiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine;

[1138] (8aR)-7-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1139] 1-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-ol;

[1140] 1-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-3-ol;

[1141] 1-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)azacyclobutane-3-ol;

[1142] 1-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)pyrrolidine-3-ol;

[1143] 3-((5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)amino)cyclobutanol;

[1144] 1-(5-(6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)-3-methylazacyclobutane-3-ol;

[1145] 2'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[benzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1146] 2'-(5,5-dimethyl-2,5-dihydro-1H-pyrrolo-3-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1147] 2'-(2,5-dihydro-1H-pyrrolo-3-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1148] 2'-(2-(piperazin-1-yl)pyrimidin-5-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1149] 2'-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1150] 2'-(2-methoxypyrimidin-5-yl)-6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1151] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1152] 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)pyrimidin-2-yl)-3-methylpiperazin-1-yl)acetone;

[1153] 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)pyrimidin-2-yl)-3-methylpiperazin-1-yl)acetone;

[1154] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1155] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl-1-one;

[1156] 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)pyrimidin-2-yl)-3-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1157] 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)pyrimidin-2-yl)-3-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1158] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1159] 2-(5-(2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)prop-2-ol;

[1160] 2'-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-6',8'-dihydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-3(2H)-one;

[1161] 2'-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-6'-ol;

[1162] 2'-(1-(pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2H,6'H,8'H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1163] 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-dihydropyridin-1(2H)-yl)-3-methoxy-3-methylbut-1-one;

[1164] (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)pyrimidin-2-yl)piperidin-4-ol;

[1165] (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)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1166] (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)pyridin-2-yl)oxy)cyclohexanol;

[1167] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1168] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1169] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1170] 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)pyrimidin-2-yl)-2-methylpiperazin-1-yl)-2-hydroxyethyl ketone;

[1171] 1-(5-(6',8'-dihydrospiro[isobenzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-ol;

[1172] (8aR)-7-(5-(6',8'-dihydrospiro[isobenzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazine-3(2H)-one;

[1173] 2'-(2-morpholinylpyrimidin-5-yl)-6',8'-dihydrospiro[isobenzodihydropyran-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine];

[1174] 2-(5-(2,3-dihydro-6'H,8'H-spiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)propyl-2-amine;

[1175] (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)pyrimidin-2-yl)propyl-2-amine; or

[1176] 2'-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-3-ol.

[1177] In some embodiments, the compound is selected from:

[1178] ((R)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)pyrrolidine-2-yl)methanol;

[1179] ((S)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)pyrrolidine-2-yl)methanol;

[1180] (R)-1-(2-(methanesulfonyl)ethyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1181] (R)-1-(2-hydroxy-2-methylpropyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1182] 1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)ethanol;

[1183] 2-Cyclopropyl-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)ethanol;

[1184] (5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol;

[1185] 1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)ethanol;

[1186] 1-Cyclopropyl-2-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1187] 1-((R)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1188] 1-((S)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1189] (1R,3R)-3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-2-yl)pyridin-2-yl)oxy)cyclopentanecarboxylon;

[1190] (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1191] 2-(5-(8-(pyridin-2-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1192] 1-((S)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1193] 2-Hydroxy-1-((R)-2-methyl-4-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1194] (R)-7-(5-((R)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1195] 1-((R)-4-(5-((R)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1196] (R)-7-(5-((S)-8-(3-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1197] (R)-7-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1198] (S)-7-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1199] (R)-1-(5-(8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1200] 2-Hydroxy-1-((R)-4-(5-((R)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1201] (R)-7-(5-((S)-8-(2-methoxyphenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1202] 1-((R)-4-(5-((R)-8-(3-(hydroxymethyl)phenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1203] 1-((R)-4-(5-((R)-8-(3-(hydroxymethyl)phenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)-2-methylpiperazin-1-yl)acetone;

[1204] (S)-1-(5-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl2-amino-3-methylbutyrate;

[1205] (R)-1-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl dihydrophosphate hydrochloride;

[1206] (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1207] 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclopentanol;

[1208] (R)-4-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol;

[1209] (R)-2-(2-(oxacyclobut-3-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1210] 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol;

[1211] (R)-2-(2-(oxacyclobut-3-ylmethoxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1212] (R)-2-(2-(((R)-1-methylpyrrolidin-3-yl)oxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1213] (R)-2-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)ethanol;

[1214] (R)-2-(2-(((S)-1-methylpyrrolidin-3-yl)oxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1215] (1S,4s)-4-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol;

[1216] (8R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1217] (8R)-8-phenyl-2-(2-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1218] (R)-2-(2-(cyclopentyloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1219] (R)-2-(2-(cyclohexyloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1220] 4-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanecarboxylic acid(R)-methyl ester;

[1221] 3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclopentane carboxylic acid methyl ester;

[1222] (R)-2-(2-butoxypyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine;

[1223] (1R,3R)-3-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-2-yl)pyridin-2-yl)oxy)cyclopentanecarboxylon;

[1224] (R)-8-phenyl-2-(2-((S)-pyrrolidine-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1225] (8R)-8-phenyl-2-(2-(piperidin-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1226] (R)-8-phenyl-2-(2-((R)-pyrrolidine-3-yloxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1227] (8R)-2-(2-(6-azaspiro[3.4]oct-1-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1228] (R)-2-(2-(6-azaspiro[3.4]oct-2-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1229] (8R)-2-(2-(6-azaspiro[3.5]non-1-yloxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1230] 1-(5-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyrimidin-2-yl)piperidin-4-ol;

[1231] (R)-1-((4,4-difluorocyclohexyl)methyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1232] (R)-1-(2-methoxyethyl)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one;

[1233] (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2(1H)-one;

[1234] 4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-(tetrahydrofuran-3-yl)pyridin-2(1H)-one;

[1235] (R)-4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one;

[1236] (R)-8-phenyl-2-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1237] 4-((4-(6',8'-dihydro-2H-spiro[benzofuran-3,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine]-2'-yl)pyridin-2-yl)oxy)cyclohexanol;

[1238] (R)-1-(5-(3-fluoro-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1239] 2-(2-morpholinylpyrimidin-5-yl)-9-phenyl-7,9-dihydro-6H-pyran[4',3':4,5]imidazo[1,2-b]pyridazine;

[1240] trans-4-((4-(4-(2-methoxyphenyl)-3,4-dihydro-2H-pyran[2',3':4,5]imidazo[1,2-a]pyridin-7-yl)pyridin-2-yl)oxy)cyclohexanol;

[1241] (8aS)-7-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one;

[1242] 3,3-Difluoro-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1243] 1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1244] 2-(2-(1,4-oxazacyclohepta-4-yl)pyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine;

[1245] (1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-3-yl)methanol;

[1246] (4-Fluoro-1-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanol;

[1247] 2-Hydroxy-1-(4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-1-yl)prop-1-one;

[1248] 2-Hydroxy-1-(4-(5-(9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetone;

[1249] (R)-8-phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1250] (R)-2-(2-(2-methoxyethoxy)pyridin-4-yl)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1251] (R)-2-methyl-1-((4-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)prop-2-ol;

[1252] (R)-8-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1253] (1S,4s)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexanol;

[1254] (1R,4r)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[1':22',1:2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexanol;

[1255] ((1R,4r)-4-(((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)methyl)cyclohexyl)methanol;

[1256] (R)-8-phenyl-2-(1-(pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine;

[1257] 2-(4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)cyclohex-3-en-1-yl)methyl acetate;

[1258] 1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1259] (S)-1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1260] (R)-1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1261] (S)-2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1262] (R)-2-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1263] (R)-2-(5-(8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)propyl-2-amine;

[1264] 2-(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido-[3',2':4,5]imidazo[2,1-c][1,4]oxazine; or

[1265] (1R,4R)-4-((4-((R)-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)oxy)cyclohexanol.

[1266] In some embodiments, the compound is selected from:

[1267] 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-carboxyimidazole[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1268] 9-Phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6,7,8,9-tetrahydro-6,8-formylimidozono[1,2-a:5,4-b']dipyridine;

[1269] 4-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-formylimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine;

[1270] 1-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-formylimidozolo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1271] 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1272] 1-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1273] 2-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-carboxyimidozolo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)prop-2-ol;

[1274] 9-Phenyl-2-(2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)-6,7,8,9-tetrahydro-6,8-formylimidozono[1,2-a:5,4-b']dipyridine;

[1275] 1-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-formylimidozolo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol;

[1276] 4-(5-(9-phenyl-6,7,8,9-tetrahydro-6,8-formylimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)morpholine;

[1277] 2-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)prop-2-ol; or

[1278] 1-(5-((6R,8S,9S)-9-phenyl-6,7,8,9-tetrahydro-6,8-epoxyimidazo[1,2-a:5,4-b']dipyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol.

[1279] The disclosures of U.S. Patents 10,266,532B2 and 9,856,253B2, and U.S. Patent Applications US20160304517A1 and US2018 / 0179198A1 are incorporated herein by reference in their entirety.

[1280] In some embodiments, the TNF binder comprises a compound of formula (2c):

[1281]

[1282] Or its pharmaceutically acceptable salts, tautomers, geometric isomers or stereoisomers, wherein:

[1283] X, Y, and Z are independently CR 4 Or N;

[1284] The condition is that neither Y nor Z is N;

[1285] A is —C(R) z )2—;

[1286] E is CH2 or O and G is CH; or E is CH2 and G is CH or N;

[1287] R 1 It is an optionally substituted aryl group or an optionally substituted heteroaryl group;

[1288] R 2 Yes—R 2a -R 2b ,in:

[1289] R 2a It can be a substituted saturated, unsaturated or partially saturated heterocyclic group or a substituted heteroaryl group;

[1290] R 2b It is —N(R) a (R) b ), —O(R a ), optionally substituted (C1-C5) alkyl, optionally substituted (C3-C6) cycloalkyl,

[1291] (CH2) p -Optionally substituted heteroaryl groups or —(CH2) p -Optionally substituted heterocyclic group; wherein

[1292] R a and R b Independently selected from H, optionally substituted (C1-C5) alkyl groups, and —(CH2). n -Optionally substituted heterocyclic groups;

[1293] R 4 It can be independently H, a halogroup, CF3, or a (C1-C3) alkyl group;

[1294] R z It can be independently H, a halogroup, CF3, or a (C1-C3) alkyl group;

[1295] n is 0 or 1; and

[1296] p is 0 or 1.

[1297] In some embodiments, the compound of formula (2c) includes Where G is N or CH; and Z is CH or CF.

[1298] In some embodiments of the compound of formula (2c), R 1 Selected from:

[1299]

[1300] In some embodiments of the compound of formula (2c), R 2 Selected from:

[1301]

[1302] In some implementations, R 2 This can be used to attach TNF linking groups to compounds disclosed herein. For example, this can be achieved using R listed herein. 2 This can be achieved by any hydroxyl, amino, amide, thiophene, or carboxylic acid group present in or that can be introduced into it. In any case, R 2 The hydroxyl group in R can be used, for example, to form an ester bond; 2 The carboxyl group in R can be used, for example, to form ester or amide bonds; 2 The amino group in R can be used to form, for example, amide and imine groups; 2 The amino, amide, or thiophene groups in the group can be used to form chemical bonds, for example, through alkylation or nucleophilic substitution, as is known to those skilled in the art.

[1303] In some embodiments, the compound is selected from:

[1304] 3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1305] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1306] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1307] 1-(5-(3-(2-(difluoromethoxy)phenyl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-6-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid;

[1308] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1309] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1310] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1311] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1312] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholinyl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1313] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholinyl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1314] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholinyl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1315] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholinyl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1316] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1317] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1318] 3-(2-(difluoromethoxy)phenyl)-6-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1319] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolid-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1320] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolid-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1321] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolid-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1322] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolid-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1323] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]non-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1324] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]non-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1325] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazozo[1,2-a]indazole-9(1H)-one;

[1326] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazo[1,2-a]indazole-9(1H)-one;

[1327] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazo[1,2-a]indazole-9(1H)-one;

[1328] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazo[1,2-a]indazole-9(1H)-one;

[1329] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1330] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((3-methoxypropyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1331] (S)-6-(2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1332] (R)-6-(2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1333] 6-(2-(difluoromethoxy)phenyl)-3-(2-morpholinylpyrimidin-5-yl)-8,9-dihydro-6H-pyridazin[1,2-a]indazole-11(7H)-one;

[1334] 6-(2-(difluoromethoxy)phenyl)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8,9-dihydro-6H-pyridazin[1,2-a]indazole-11(7H)-one;

[1335] 6-(2-(difluoromethoxy)phenyl)-3-(2-(1,1-dioxothiomorpholinyl)pyrimidin-5-yl)-8,9-dihydro-6H-pyridazin[1,2-a]indazole-11(7H)-one;

[1336] 3-(2-methoxyphenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1337] (R)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1338] (S)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1339] 2-Methyl-6-(6-(2-morpholinylpyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile;

[1340] 6-(2-morpholinylpyrimidin-5-yl)-3-phenyl-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1341] 4-Methoxy-3-(6-(2-morpholinylpyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile;

[1342] 2-Methoxy-3-(6-(2-morpholinylpyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzonitrile;

[1343] 3-(1-Isopropyl-1H-pyrazol-5-yl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1344] 2-Methyl-6-(6-(2-morpholinylpyrimidin-5-yl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazole-3-yl)benzamide;

[1345] Racemic-(1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1346] Racemic-(1R,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1347] Racemic-(1R,10bR)-1-(2-(difluoromethoxy)phenyl)-9-(2-morpholinylpyrimidin-5-yl)-3,4-dihydro-1H-[1,4]oxazine[3,4-a]isoindole-6(10bH)-one;

[1348] (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1349] (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1350] (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1351] (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1352] (1S,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1353] (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1354] (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((R)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1355] (1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1356] (1R)-1-(2-(difluoromethoxy)phenyl)-8-(2-(2-hydroxypropyl-2-yl)-4-methylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one;

[1357] (R)-6-(2-((R)-4-acetyl-2-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1358] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazozo[1,2-a]indazole-9(1H)-one;

[1359] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1360] (R)-6-(2-((R)-4-acetyl-3-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1361] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazo[1,2-a]indazole-9(1H)-one;

[1362] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1363] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1364] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazozo[1,2-a]indazole-9(1H)-one;

[1365] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1366] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1367] (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1368] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1369] (R)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1370] (S)-3-(2-(difluoromethoxy)phenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1371] 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1372] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1373] (S)-3-(2-(difluoromethoxy)-5-methylphenyl)-7-fluoro-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1374] (S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1375] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1376] (R)-3-(2-(difluoromethoxy)-5-methylphenyl)-6-(2-(2-hydroxypropyl-2-yl)pyrimidin-5-yl)-2,3-dihydro-1H,9H-pyrazolo[1,2-a]indazole-9-one;

[1377] (R)-6-(2-((R)-4-acetyl-3-methylpiperazin-1-yl)pyrimidin-5-yl)-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1378] (R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-3-hydroxy-4-(2-hydroxyacetyl)piperazin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one;

[1379] 9b-(2-methoxyphenyl)-8-(2-morpholinylpyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindole-5(9bH)-one; or

[1380] 3-(5-(hydroxymethyl)-2-methoxyphenyl)-6-(2-morpholinylpyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazole-9(1H)-one.

[1381] AATM

[1382] Any autoantibody-targeting moiety (AATM) that binds to an autoantibody is useful in this disclosure. In some non-limiting embodiments, the autoantibody is pathological. Any autoantibody known in the art is considered in this disclosure.

[1383] In some embodiments, AATM is any peptide and / or small molecule that binds to FcRn, as known in the art or described elsewhere herein.

[1384] In some implementations, AATM contains an FcRn antagonist, such as, but not limited to, rozanolixizumab (see, for example, Kiessling et al., 2017, Sci. Transl. Med. 9: eaan1208).

[1385] In some implementations, AATM contains an FcRn antagonist, such as, but not limited to, efgartigimod (see, for example, Ulrichts et al., 2018, J. Clin. Invest. 128(10):4372).

[1386] In some embodiments, AATM comprises 2,4-dinitrobenzene or any derivative or analog thereof (wherein the benzene ring is optionally substituted):

[1387]

[1388] In some embodiments, AATM comprises the following cyclic peptide FcIII or any reduced form thereof (e.g., any corresponding free thiol derivative thereof; see, for example, Science 2000287:1279-1283). Chemical groups marked with * are non-limiting linking sites of linking groups or CON in the compounds of this disclosure.

[1389]

[1390] Also expressed as (SEQ ID NO:139, C-terminal amidated internal cystine form).

[1391] In some embodiments, AATM comprises the following cyclic peptide FcIII-4C (amide) or any reduced form thereof (e.g., any corresponding free thiol derivative thereof; see Bioconjugate Chem. 201627:1569). Chemical groups marked with * are linking groups or non-limiting linking positions of CON in the compounds of this disclosure.

[1392]

[1393] Also expressed as (SEQ ID NO:140, C-terminal amidated internal cystine form).

[1394] In some embodiments, AATM comprises compounds of formula (3a) or (3b):

[1395]

[1396] in:

[1397] R 1Each 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, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl;

[1398] m is 0, 1, 2, 3 or 4;

[1399] X 2 The alkyl group is a bond, optionally substituted C1-C6 alkyl group, or optionally substituted C1-C6 heteroalkyl group;

[1400] R 2 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, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl;

[1401] n is 0, 1, 2, 3 or 4;

[1402] X 3 The alkyl group is a bond, optionally substituted C1-C6 alkyl group, or optionally substituted C1-C6 heteroalkyl group;

[1403] R 3 It is H, R, -OH, -NH2, -NHR, -C(=O)OH or -SH, where each occurrence of R is a C1-C6 alkyl or C3-C8 cycloalkyl;

[1404] R 4It is a cycloalkyl group, including polycycloalkyl groups, which is optionally substituted by 1 to 4 groups independently selected from the following: 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, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl;

[1405] AATM is through R 3 Or R 1 Or R 2 At least one of them is connected to a linking group or CON.

[1406] In some embodiments, AATM comprises one of the following compounds (see WO 2006 / 024175 A1). Each chemical group marked with * indicates a non-limiting linking position of the linking group or CON in the compounds of this disclosure.

[1407]

[1408] In some embodiments, AATM comprises the following compounds, wherein... The labeled chemical bonds indicate the non-restricted linking positions of the linking groups or CON in the compounds disclosed herein (see Chemistry & Biology 18:1179-1188).

[1409]

[1410] in:

[1411] 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, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl;

[1412] m is 0, 1, 2, 3 or 4;

[1413] 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, wherein each occurrence of R is independently H, C1-C6 alkyl or C3-C8 cycloalkyl.

[1414] The disclosures of U.S. Patent No. 9,879,016B2 and U.S. Patent Application No. US2016 / 0304526 A1 are incorporated herein by reference in their entirety.

[1415] Other ASGPR binding components based on galactose and taro sugar

[1416] In some embodiments, this disclosure relates to compounds with a general chemical structure according to Formula II that can be used to clear circulating proteins associated with a disease state or condition in a patient or subject:

[1417]

[1418] The term “extracellular protein-targeting ligand” as used herein is interchangeable with the term CPBM (cell protein-binding part). The term “ASGPR ligand” as used herein is interchangeable with the asiaglycoprotein receptor (ASGPR) binding part as defined herein.

[1419] In the compounds of Formula II, each [CON] is an optional linker chemical moiety that, when present, is directly linked to [CPBM] or [CRBM], or links [LINKER-2] to [CPBM] or [CRBM].

[1420] In the compounds of formula II:

[1421] [LINKER-2] is a chemical moiety with a valence of 1 to 15, which is optionally covalently linked to one or more [CRBM] and / or [CPBM] groups via [CON] including a [MULTICON] group, wherein the [LINKER-2] itself optionally contains one or more [CON] or [MULTICON] groups;

[1422] k' is an integer from 1 to 15;

[1423] j' is an integer from 1 to 15;

[1424] h and h' are each an independent integer from 0 to 15;

[1425] i L It is an integer between 0 and 15;

[1426] The conditions are h, h', and i L At least one of them is 1.

[1427] The [MULTICON] group can link one or more [CRBM] or [CPBM] to one or more [LINKER-2] groups. In various embodiments, the valence of [LINKER-2] is from 1 to 10. In various embodiments, the valence of [LINKER-2] is from 1 to 5. In various embodiments, the valence of [LINKER-2] is 1, 2, or 3. In various embodiments, in compounds of formula II, [LINKER-2] includes a linking group as defined herein. A Linking groups B Linking groups C Linking groups D One or more of the following: and / or combinations thereof.

[1428] In compounds of formula II, xx are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25.

[1429] In compounds of formula II, yy is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25.

[1430] In compounds of formula II, zz is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25.

[1431] In the compounds of formula II, X 1 It consists of 1 to 5 independent selections from O, S, N(R) b ) and C(R 4 (R) 4 A series of atoms, where if X 1 If it is one atom, then X 1 It is O, S, N(R) 6 ) or C(R 4 (R) 4 If X 1 If it has 2 atoms, then X 1 No more than one atom is O, S or N (R 6 If X 1 If it has 3, 4, or 5 atoms, then X 1 No more than two atoms are O, S or N (R 6 );

[1432] R 3 Each time it appears, it is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaryl, alkenyl, ynyl and heteroaryl, heterocyclic, -OR 8 and -NR 8 R 9 ;

[1433] R 4 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaryl, alkenyl, ynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 -NR 6 R 7 ,

[1434] R 6 and R 7 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, and haloalkyl, heteroaryl, heterocyclic, -alkyl-OR. 8 ,-alkyl-NR 8 R 9 C(O)R 3 S(O)R 3 C(S)R 3 and S(O)2R 3 ;

[1435] R 8 and R 9 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, aryl, heteroaryl, and heterocyclic.

[1436] A. The galactose-based ASGPR-binding cell receptor-binding moiety of Formula II

[1437] In some embodiments, the compound of formula II is selected from:

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449]

[1450]

[1451]

[1452]

[1453]

[1454]

[1455] In some embodiments, the compound of formula II has one of the following structures:

[1456]

[1457]

[1458] In various implementations, the ASGPR ligand is in C 1 Or C 5 (R 1 or R 5The ASGPR ligand is linked at a position to form a degradation compound. In various embodiments, the ASGPR ligand is located at C... 6 Positional linkages are used to form degradation compounds. For example, when the ASGPR ligand has the following structure:

[1459]

[1460] Then, non-limiting examples of ASGPR-binding compounds of formula II include:

[1461]

[1462] Or its disubstituted or trisubstituted form or pharmaceutically acceptable salt, wherein disubstituted or trisubstituted refers to the number of additional galactose derivatives moietyly linked to the linking group.

[1463] This document illustrates any implementation of ASGPR ligands in degradative agents, where the ASGPR ligands are typically in C... 5 Location associated with extracellular protein targeting ligands (e.g., this could refer to adjacent C...) 6 (Carbon hydroxyl group or other functional moiety that can be used for linking purposes). When the linking group and the extracellular protein targeting ligand pass through C... 1 When positionally linked, the carbon can be appropriately functionalized for, for example, linkage with hydroxyl, amino, allyl, alkynyl, or hydroxy-allyl groups.

[1464] In various implementations, the ASGPR ligand is not in C 3 Or C 4 These sites are linked because they are associated with calcium chelation by ASGPR binding in the liver. In some embodiments, the ASGPR ligands that can be used for compounds incorporated into formula II are selected from:

[1465]

[1466]

[1467]

[1468]

[1469]

[1470]

[1471]

[1472]

[1473]

[1474]

[1475]

[1476] In some embodiments, the compound of formula II is selected from:

[1477]

[1478]

[1479]

[1480]

[1481]

[1482] B. Formula II: ASGPR-binding cell receptor-binding moiety based on taroside B.

[1483] In some embodiments, the compound of formula II is selected from:

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497]

[1498]

[1499]

[1500]

[1501]

[1502]

[1503]

[1504]

[1505]

[1506]

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516]

[1517]

[1518]

[1519]

[1520]

[1521]

[1522] In some embodiments, the compound of formula II is an extracellular protein degradation compound, wherein the ASGPR ligand is the ligand described herein.

[1523]

[1524] In some embodiments, in compounds of formula II, the ASGPR ligand is at C1 or C5 (R 1 or R 5 The ASGPR ligand is linked at position C6 to form a degradation compound. In some embodiments, in compounds of formula II, the ASGPR ligand is linked at C6. In various embodiments, when the ASGPR ligand has the following structure,

[1525]

[1526] Then, non-limiting examples of ASGPR-binding compounds of formula II include:

[1527]

[1528] Or its disubstituted or trisubstituted form or a pharmaceutically acceptable salt, wherein disubstituted or trisubstituted refers to the number of additional galactose derivatives moietyly linked to the linking group. In some embodiments, compounds of formula II are selected from:

[1529]

[1530] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1531] In some embodiments, the compound of formula II is selected from:

[1532]

[1533]

[1534] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1535] In some embodiments, the compound of formula II is selected from:

[1536]

[1537]

[1538] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1539] In some embodiments, the compound of formula II is selected from:

[1540]

[1541]

[1542] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1543] In some embodiments, the compound of formula II is selected from:

[1544]

[1545]

[1546] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1547] In some embodiments, the compound of formula II is selected from:

[1548]

[1549]

[1550] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1551] In some embodiments, the compound of formula II is selected from:

[1552]

[1553]

[1554] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1555] In some embodiments, the compound of formula II is selected from:

[1556]

[1557]

[1558] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6-(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1559] In some embodiments, the compound of formula II is selected from:

[1560]

[1561]

[1562] In some implementations, R 2 Selected from -NR b COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1563] In some embodiments, the compound of formula II is selected from:

[1564]

[1565]

[1566]

[1567] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1568] In some embodiments, the compound of formula II is selected from:

[1569]

[1570]

[1571] In some implementations, R 2 Selected from -NR6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1572] In some embodiments, the compound of formula II is selected from:

[1573]

[1574]

[1575] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1576] In some embodiments, the compound of formula II is selected from:

[1577]

[1578]

[1579] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1580] In some embodiments, the compound of formula II is selected from:

[1581]

[1582]

[1583] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), where each R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four independent substituents selected from F, Cl, Br, haloalkyl or alkyl.

[1584] In some embodiments, the compound of formula II is selected from:

[1585]

[1586]

[1587]

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596] In some embodiments, the ASGPR ligands that can be used in compounds incorporated into Formula II are selected from:

[1597]

[1598]

[1599]

[1600]

[1601]

[1602]

[1603]

[1604]

[1605]

[1606]

[1607]

[1608]

[1609] C. ASGPR ligands / binding sites in compounds of formula II

[1610] In some embodiments, in the compound of formula II, R 1 It is hydrogen.

[1611] In some embodiments, in the compound of formula II, R 1 yes

[1612] In some embodiments, in the compound of formula II, R1 is

[1613] In some embodiments, in the compound of formula II, R1 is

[1614] In some embodiments, in the compound of formula II, R1 is

[1615] In some embodiments, in the compound of formula II, R1 is

[1616] In some embodiments, in the compound of formula II, R1 is

[1617] In some embodiments, in the compound of formula II, R 1 It is a C0-C6 alkyl-cyano group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1618] In some embodiments, in the compound of formula II, R 1 It is an alkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1619] In some embodiments, in the compound of formula II, R 1 It is an alkenyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1It is an alkynyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1 It is a haloalkyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1 It is F.

[1620] In some embodiments, in the compound of formula II, R 1 It is Cl.

[1621] In some embodiments, in the compound of formula II, R 1 It is Br.

[1622] In some embodiments, in the compound of formula II, R 1 It is an aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1623] In some embodiments, in the compound of formula II, R 1 It is an aralkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1624] In some embodiments, in the compound of formula II, R 1 It is a heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1625] In some embodiments, in the compound of formula II, R 1 It is a heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1626] In some embodiments, in the compound of formula II, R 1 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[1627] In some embodiments, in the compound of formula II, R 1 It is a heterocyclic alkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1628] In some embodiments, in the compound of formula II, R 1 It is a haloalkoxy group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1629] In some embodiments, in the compound of formula II, R 1 It is -O-alkenyl, -O-ynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0-C6 alkyl-S(O)2R 3 C0-C6 alkyl-N(R) 8 )-C(O)R 3 C0-C6 alkyl-N(R) 8 )-S(O)R 3 C0-C6 alkyl-N(R) 8 )-C(S)R 3 C0-C6 alkyl-N(R) 8 )-S(O)2R 3 C0-C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 2. C0-C6 alkyl N3 or C0-C6 alkyl-OS(O)2R 3 Each of these can be optionally substituted with 1, 2, 3 or 4 substituents.

[1630] In some embodiments, in the compound of formula II, R 2 It is an aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1631] In some embodiments, in the compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[1632] In some embodiments, in the compound of formula II, R 2 It is a heteroaryl group containing one or two heteroatoms independently selected from N, O and S, which are optionally substituted with 1, 2, 3 or 4 substituents.

[1633] In some embodiments, in the compound of formula II, R 2 Selected from

[1634] In some embodiments, in the compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[1635] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 -S(O)-R 3 .

[1636] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 -C(S)-R 3 .

[1637] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 -S(O)(NR 6 )-R 3 .

[1638] In some embodiments, in the compound of formula II, R 2 -N=S(O)(R is optionally substituted with 1, 2, 3 or 4 substituents. 3 )2.

[1639] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 C(O)NR 9 S(O)2R 3 .

[1640] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 -S(O)2-R 10 .

[1641] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 8 -C(NR 6 )-R 3 .

[1642] In some embodiments, in the compound of formula II, R 2 It is hydrogen.

[1643] In some embodiments, in the compound of formula II, R 2 It is R 10 .

[1644] In some embodiments, in the compound of formula II, R 2 It is an alkyl-C(O)-R 3 .

[1645] In some embodiments, in the compound of formula II, R 2 It is -C(O)-R3 .

[1646] In some embodiments, in the compound of formula II, R 2 It is an alkyl group.

[1647] In some embodiments, in the compound of formula II, R 2 It is a haloalkyl group.

[1648] In some embodiments, in the compound of formula II, R 2 It is -OC(O)R 3 .

[1649] In some embodiments, in the compound of formula II, R 2 Yes -NR 8 -C(O)R 10 .

[1650] In some embodiments, in the compound of formula II, R 2 It is an alkenyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1651] In some embodiments, in the compound of formula II, R 2 It is an allyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1652] In some embodiments, in the compound of formula II, R 2 It is an alkynyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1653] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 6 -Alkenyl.

[1654] In some embodiments, in the compound of formula II, R 2 It is an -O-alkenyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1655] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 6 -Alkyne group.

[1656] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 6 - Mixed aromatic compounds.

[1657] In some embodiments, in the compound of formula II, R 2-NR is optionally substituted with 1, 2, 3 or 4 substituents. 6 -Aryl.

[1658] In some embodiments, in the compound of formula II, R 2 It is an -O-heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1659] In some embodiments, in the compound of formula II, R 2 It is an -O-aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1660] In some embodiments, in the compound of formula II, R 2 It is an -O-ynyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[1661] In some embodiments, in the compound of formula II, R 2 Selected from and

[1662] In some embodiments, in the compound of formula II, R 2 Selected from:

[1663]

[1664] In some embodiments, in the compound of formula II, R 2 Selected from:

[1665]

[1666] Where R is an optional substituent as defined in this paper.

[1667] In some embodiments, in the compound of formula II, R 2 Selected from:

[1668]

[1669] In some embodiments, in the compound of formula II, R 2A Selected from:

[1670]

[1671] Where R is an optional substituent as defined in this paper.

[1672] In some embodiments, in the compound of formula II, R 2A Selected from:

[1673]

[1674] In some embodiments, in the compound of formula II, R 2 Selected from:

[1675]

[1676]

[1677] In some embodiments, in the compound of formula II, R 2 Selected from:

[1678]

[1679] In some embodiments, in the compound of formula II, R 2 Selected from

[1680] In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from:

[1681]

[1682] In some embodiments, in the compound of formula II, R 2 Selected from:

[1683]

[1684] In some embodiments, in the compound of formula II, R 2 Selected from:

[1685]

[1686] In some embodiments, in the compound of formula II, R 2 Selected from:

[1687]

[1688] In some embodiments, in the compound of formula II, R 2 Selected from:

[1689]

[1690] In some embodiments, in the compound of formula II, R 2 Selected from:

[1691]

[1692] In some embodiments, in the compound of formula II, R 2 Selected from:

[1693]

[1694] In some embodiments, in the compound of formula II, R 2 Selected from:

[1695]

[1696] In some embodiments, in the compound of formula II, R 2 Selected from:

[1697]

[1698] In some embodiments, in the compound of formula II, R 2 Selected from:

[1699]

[1700] In some embodiments, in th...

Claims

1. A compound, or a salt, geometric isomer, stereoisomer or solvate thereof, selected from: [Protein binders] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (I) in: The protein binding agent is a molecule that binds to an extracellular protein or an autoantibody, optionally wherein the extracellular protein is TNF; The CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a degradation cell in a subject, whereby binding of (I) results in endocytosis and degradation of the extracellular protein; Each CON is independently a bond or group that covalently links the protein-binding agent to the CRBM, the protein-binding agent to the linking group, and / or the linking group to the CRBM; The linking group is a group having a valence in the range of 1 to 15; k' is an integer in the range of 1 to 15; h is an integer in the range of 0 to 15; i is an integer in the range of 0 to 15; h' is an integer in the range of 0 to 15; j is an integer in the range of 1 to 15; Wherein the compound is selected from: in: Extracellular protein targeting ligands are molecules that bind to extracellular proteins or autoantibodies; X 1 is 1 to 5 independently selected from O, S, N(R 6 ) and C(R 4 )(R 4 ) group, where if X 1 is 1 group, then X 1 O, S, N (R 6 ) or C(R 4 )(R 4 ), if X 1 is 2 groups, then X 1 No more than one of the groups is O, S or N (R 6 ), if X 1 is 3, 4 or 5 groups, then X 1 No more than 2 groups are O, S or N (R 6 ); R 2 Selected from: (i) aryl, heterocycle and heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted by 1, 2, 3 or 4 substituents, (ii) (iii)-NR 8 -S(O)-R 3 、-NR 8 -C(S)-R 3 、-NR 8 -S(O)NR 6 )-R 3 、-N=S(O)R 3 )2.-NR 8 C(O)NR 9 S(O)R 3 、-NR 8 -S(O)2-R 10 and-NR 8 -C(NR 6 )-R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 、-C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 and-NR 8 -C(O)R 10 ; R 10 Selected from aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2 or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 、Alkyl-NR 6 R 8 NR 8 -NR 6 -C(O)R 3 NR 8 -S(O)2-R 3 , alkenyl, allyl, alkynyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -Alkynyl, -NR 6 -heteroaryl, -NR 6 -aryl, -O-heteroaryl, -O-aryl and -O-alkynyl, said R 10 Each of is optionally substituted with 1, 2, 3 or 4 substituents; R 1 and R 5 independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, CI, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl, OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl C(S) R 3 、C0-C6 alkyl-S(O)2R 3 、C0-C6 alkyl-N(R 8 )-C(O)R 3 、C0-C6 alkyl-N(R 8 -S(O)R 3 、 C0-C6 alkyl N(R 8 )-C(S)R 3 、C0-C6 alkyl-N(R 8 )-S(O)2R 3 、C0-C6 alkyl-OC(O)R 3 、C0-C6 alkyl-OS(O)R 3 、C0-C6 alkyl-OC(S)R 3 、-N=S(O)(R 3 )2, C0-C6 alkyl N3 and C0-C6 alkyl-OS(O)2R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 and-NR 8 R 9 ; R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 , R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 、-alkyl-NR 8 R 9 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 , R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; Ring is a 3-8 membered fused cyclic group optionally substituted by 1, 2, 3 or 4 substituents, Each linking group A The ASGPR ligand is linked to the linker B A covalently linked bond or moiety, Linking group B The linking group A a bond or moiety that covalently links to an extracellular protein targeting ligand; Linking group C is to connect each linking group A a chemical group that is a targeting ligand to the extracellular protein; and Linking group D is to connect each linking group A a chemical group that is a targeting ligand to the extracellular protein; and Among them, when R 2 YesNR 6 -Alkenyl, -NR 6 -Alkynyl, -NR 8 -C(O)R 10 、-NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl or -NR 6 -aryl, the extracellular protein targeting ligand does not include an oligonucleotide; and The optional substituents are selected from alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 、F、CI、Br、I、-NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , This results in a stable compound, as valency permits.

2. The compound according to claim 1, which is selected from:

3. The compound according to claim 1, which is selected from:

4. A compound according to any one of claims 1 to 3, wherein R 1 It's H.

5. The compound according to any one of claims 1 to 4, wherein R 2 YesR 10 .

6. A compound according to any one of claims 1 to 5, wherein R 10 Yes - NR 6 -heteroaryl.

7. A compound according to any one of claims 1 to 6, wherein R 6 It's H.

8. A compound according to any one of claims 1 to 7, wherein -NR 6 - Heteroaryl is selected from:

9. The bifunctional compound of any one of claims 1-8, wherein the extracellular protein targeting ligand is a TNF binding moiety.

10. The compound according to any one of claims 1 to 8, wherein the extracellular protein targeting ligand is an autoantibody.

11. The compound according to any one of claims 1 to 10, wherein the linking group A Selected from:

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

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

14. A method of treating, ameliorating and / or preventing a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 11.

15. The method of claim 14, wherein the disease or disorder comprises an autoimmune disease, cancer and / or inflammation.

16. The method of claim 15, wherein the autoimmune disease is Addison's disease, autoimmune polyglandular syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, 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, basic mixed cold agglutininemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful lipomatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, and enthesinosis. Inflammatory arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry-Romberg syndrome, Parsner-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, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton muscular dystrophy syndrome, multiple sclerosis, patternII, Oshtolan Mountain syndrome, Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sindenham's chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Blepharoconjunctivitis, Moren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, Eosinophilia EGPA, giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum.

17. The method of claim 15, wherein the cancer is prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, laryngeal cancer, Hodgkin's disease, non-Hodgkin's disease, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral cavity / pharynx, esophagus, larynx, kidney cancer, or lymphoma.

18. The method of claim 15, wherein the inflammation is a neurodegenerative inflammatory disease, a disease of impaired immune response causing inflammation, a chronic inflammatory disease, a hyperglycemic disease, diabetes (I and II)), pancreatic beta cell death and related hyperglycemic diseases, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related diseases, stroke and spinal cord injury or arteriosclerosis.

19. The method of any one of claims 14-18, wherein the subject is further administered at least one additional therapeutic agent that treats, ameliorates and / or prevents the disease or disorder.

20. The method of any one of claims 14-19, wherein the subject is a mammal.

21. The method of any one of claims 14-20, wherein the subject is a human.

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