Engineered antibodies as molecular degraders via cellular receptors

Abstract

In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of certain circulating proteins.In certain embodiments, the circulating proteins mediate disease and / or disorders in a subject, and the treatment or management of the disease and / or disorders requires the degradation, removal, or reduction in the concentration of the circulating proteins in the subject.Therefore, in certain embodiments, the administration of the compounds of the present disclosure to a subject removes the circulating proteins or reduces their circulating concentration, thereby treating, ameliorating, or preventing the disease and / or disorders. TIFF2025509733000449.tif132128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 17 / 654,984, filed March 15, 2022, which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM067543 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Incorporation by reference of material submitted as a text file through the U.S. Patent Office Electronic Filing System The present invention comprises one or more sequences in a computer readable format in the attached text file entitled "047162-7249WO2_sequence_listing.xml", which is 114.2KB in size and was created on March 14, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

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

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

[0006] There is a need in the art for new compounds and methods that allow for the inhibition, removal, and / or degradation of specific extracellular proteins that mediate diseases and / or disorders in a subject. The present disclosure addresses this need. Summary of the Invention

[0007] A brief summary of disclosures The disclosure provides a compound comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) where Ab, CON, linker, CRBM, k', h, i, h', and j' are defined elsewhere herein.

[0008] The present disclosure further provides pharmaceutical compositions comprising at least one compound contemplated herein and at least one pharma- ceutically acceptable excipient.

[0009] The present disclosure further provides a method of treating a disease or disorder in a subject, comprising administering a therapeutically effective amount of at least one compound contemplated herein. [Brief description of the drawings]

[0010] The drawings illustrate generally, by way of example, but not by way of limitation, various aspects of the present application.

[0011] As used herein, the term "REAG" refers to any reagent containing -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM.

[0012] [Figure 1] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Diagram 2] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Diagram 3] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 4] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Diagram 5] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 6] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 7] 1 illustrates a non-limiting preparation of compounds of the present disclosure that include mannose receptor binders. [Figure 8] 1 illustrates a non-limiting preparation of polymeric compounds containing mannose-6-phosphate receptor binders. [Figure 9] Non-limiting examples of R1 and / or R3 groups in ASGPRBM are shown. [Figure 10] Non-limiting examples of R2 groups in ASGPRBM are shown. [Figure 11A] 11A-11B show a non-limiting synthesis of the ASGPRBM group. [Figure 11B] See legend to Figure 11A. [Figure 12A] Figures 12A-12C show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate. [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. [Figure 13A] Figures 13A-13L show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate. [Figure 13B] See legend to Figure 13A. [Figure 13C] See legend to Figure 13A. [Figure 13D] See legend to Figure 13A. [Figure 13E] See legend to Figure 13A. [Figure 13F] See legend to Figure 13A. [Figure 13G] See legend to Figure 13A. [Figure 13H] See legend to Figure 13A. [Figure 13I] See legend to Figure 13A. [Figure 13J] See legend to Figure 13A. [Figure 13K] See legend to Figure 13A. [Figure 13L] See legend to Figure 13A. [Figure 14A]Figures 14A-14O show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate. [Figure 14B] See legend to Figure 14A. [Figure 14C] See legend to Figure 14A. [Figure 14D] See legend to Figure 14A. [Figure 14E] See legend to Figure 14A. [Figure 14F] See legend to Figure 14A. [Figure 14G] See legend to Figure 14A. [Figure 14H] See legend to Figure 14A. [Figure 14I] See legend to Figure 14A. [Figure 14J] See legend to Figure 14A. [Figure 14K] See legend to Figure 14A. [Figure 14L] See legend to Figure 14A. [Figure 14M] See legend to Figure 14A. [Figure 14N] See legend to Figure 14A. [Figure 14O] See legend to Figure 14A. [Figure 15] FIG. 1 shows a non-limiting synthetic scheme that allows for labeling (derivatization) of an antibody (labeled Ab) with an azide group. [Figure 16] 1 shows a non-limiting synthetic scheme that allows for labeling (derivatization) of CRBM groups with strained alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (such as but not limited to those shown in FIG. 15) can be reacted with a strained alkyne-containing compound (such as but not limited to those shown in FIG. 16) to produce a compound of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description of the Disclosure In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of extracellular proteins (e.g., circulating proteins and / or cell surface proteins that can be bound or embedded in cell membranes). In certain embodiments, the extracellular proteins mediate diseases and / or disorders in a subject, and the treatment or management of the disease and / or disorder requires the degradation, removal, or reduction in the concentration of the extracellular proteins in the subject. Thus, in certain embodiments, administration of the compounds of the present disclosure to a subject removes the extracellular proteins and / or reduces the circulating concentration of the extracellular proteins, thereby treating, ameliorating, or preventing the disease and / or disorder in the subject.

[0014] In certain embodiments, the compounds of the present disclosure include antibodies, such as, but not limited to, monoclonal antibodies, capable of binding to the extracellular protein of interest. In other embodiments, the compounds of the present disclosure further include another group (such as, but not limited to, a small molecule) that binds to a cellular receptor, whereby binding results in endocytosis of the compound (and / or the extracellular protein-compound complex). The receptor binder and the antibody can be linked by a linker, such as polyethylene glycol (PEG), any other linker described herein with adjustable length, or other linkers described herein and including one or more connector molecules, referred to herein as CON. Conjugation of the antibody to the connector molecule can be achieved using any chemical reaction known to those skilled in the art, such as, but not limited to, lysine bioconjugation using an activated ester, such as, but not limited to, NHS ester. When the extracellular protein-compound complex undergoes endocytosis, the extracellular protein is eventually degraded and the compound can be degraded or recycled outside the cell.

[0015] In certain embodiments, the receptor is hepatocyte asialoglycoprotein receptor (ASGPR). In this case, the binding moiety is referred to herein as ASGPR binding moiety or ASGPRBM. The present disclosure is not limited to this receptor, but rather contemplates the use of other receptors described herein or any other endocytosis receptor known in the art.

[0016] Furthermore, the present disclosure is not limited to degradation taking place in hepatocytes, rather, the present disclosure contemplates that non-hepatic cells in the body present specific degradation receptors, which are contemplated to be within the scope of the present disclosure.

[0017] In one aspect, the compounds of the present disclosure bind to extracellular target proteins and remove them from internal circulation (and the body) through the liver.Therefore, the compounds of the present disclosure utilize the body's own mechanism to degrade proteins.Without wishing to be limited by theory, the compounds of the present disclosure bind to specific receptors located in specific cells, such as, but not limited to, hepatocytes, such as, but not limited to, ASGPR.This binding induces the degradation of protein targets by intralysosomal proteolysis.As a result of this mechanism, the circulating levels of extracellular protein targets are reduced.As a result, the corresponding disease symptoms are attenuated in the subject to which the compounds are administered and / or disappear from the patient.

[0018] ASPGR functions to eliminate desialylated glycoproteins that have exposed non-reduced D-galactose (Gal) or N-acetylgalactosamine (GalNac) as terminal groups. ASGPR is expressed at a level of approximately 500,000 per hepatocyte and is minimally present elsewhere in the body. Internalization of targeted glycoproteins by ASGPR exhibits a half-life of approximately 3 minutes. The bifunctional compounds claimed herein selectively bind to extracellular proteins through the antibody portion of the compounds, thereby forming a protein complex. As this protein complex reaches the liver, the asialoglycoprotein receptor binding portion (ASGPRBM) of the molecule engages the intralysosomal pathway of hepatocytes through ASGPR. Endosome-bound ASPGR releases the extracellular protein ligand at pH 5.4, where the ligand is removed from the circulation by hepatocytes. However, ASPGR remains available for recycling and buds into recycling endosomes, escaping lysosomal degradation. Indeed, depending on the cell line, ASPGR can recycle up to about 200 times with a recirculation rate of about 15-20 min. ASPGR exhibits very crude ligand size requirements, possibly reaching a diameter of about 70 nm. In contrast, IgM pentamers are about 20 nm in diameter and therefore fit the ligand size requirements of ASPGR.

[0019] The disclosures of International Patent Application No. PCT / US2019 / 026260, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199634), and International Patent Application No. PCT / US2019 / 026239, filed April 8, 2019 (and published October 17, 2019 as WO 2019 / 199621), are hereby incorporated by reference in their entireties.

[0020] Without wishing to be limited by theory, the use of antibodies, such as, but not limited to, monoclonal antibodies, in the compounds of the present disclosure exhibit distinct advantages over similar bifunctional compounds in the prior art.

[0021] In one aspect, the affinity of an antibody for a target is often in the pM to low nM range, which corresponds to particularly strong binding. In contrast, small molecule protein binders often exhibit affinities for targets in the nM to μM range. Thus, antibodies are expected to exhibit much tighter binding to molecular targets of interest.

[0022] In another aspect, antibodies, such as but not limited to monoclonal antibodies, are highly specific for their intended target, thereby reducing antibody toxicity due to off-target interactions.

[0023] In yet another aspect, the antibody interacts with neonatal Fc receptor (FcRn), also known as Brambell receptor. In humans, FcRn controls the turnover of IgG and serum albumin. FcRn extends the half-life of IgG and serum albumin by reducing lysosomal degradation in endothelial cells and bone marrow-derived cells. IgG, serum albumin, and other serum proteins are continuously internalized through pinocytosis and would likely be degraded in lysosomes. However, IgG and serum albumin are bound by FcRn at a slightly acidic pH (less than 6.5) and recycled to the cell surface where they are released at the neutral pH of blood (greater than 7.0), thereby avoiding lysosomal degradation. Interestingly, both FcRn and ASGPR are expressed on hepatocytes, which is the primary cell type for ASGPR-mediated degradation to occur. Thus, the compounds of the present disclosure can avoid ASGPR-mediated degradation while binding to ASGPRBM through binding to FcRn.

[0024] Rescue of the compounds of the present disclosure by FcRn shows several therapeutic advantages. Generally, compounds that contain circulating protein small molecule binding partners are degraded together with the circulating protein of interest. In contrast, modified antibodies of the present disclosure can participate in multiple rounds of protein binding and targeted degradation by recycling by FcRn. Furthermore, because the compounds of the present disclosure can participate in multiple rounds of degradation, they can be administered at relatively low doses, which is therapeutically advantageous. Furthermore, because the half-life of the compounds of the present disclosure is extended by FcRn rescue, the frequency of administration of the compounds is reduced compared to the frequency of administration required when using compounds that contain circulating protein small molecule binding partners.

[0025] In fact, the antibody-containing compounds of the present disclosure exhibit advantageous properties not only compared to the previously described compounds that contain circulating protein small molecule binding partners, but also compared to underivatized antibodies themselves. The primary function of unmodified antibodies is to bind to and neutralize protein targets. In this situation, each unmodified antibody can participate in one binding event. In contrast, the antibody-containing compounds of the present disclosure function by degrading protein targets, and a percentage of these compounds are recycled by FcRn after a degradation event occurs and become available to participate in another round of binding. Thus, these available antibody-containing compounds of the present disclosure can participate in semi-catalytic proteolysis, a property that is promoted by FcRn-mediated recycling.

[0026] As an additional advantage, the present disclosure allows for the efficient production of novel antibody-containing compounds in which ASGPRBM is conjugated to any chosen antibody (without the need to modify the amino acid sequence of the antibody and / or to extensively test the effect of the amino acid changes on FcRn binding, protein binding, and protein release). This ease of synthesis is useful for investigating the degradation of various protein targets. In certain embodiments, using this method is less expensive than traditional antibody modification methods. In certain embodiments, the less frequent administration regimen of the antibody-containing compounds of the present disclosure (compared to other antibody therapies) reduces the overall treatment cost, lowering the financial burden on insurance companies and patients.

[0027] In accordance with the present disclosure, there may be used conventional methods of chemical synthesis and pharmaceutical formulation, as well as techniques of pharmacology, molecular biology, microbiology, and recombinant DNA within the skill of the art, which are well known and fully explained elsewhere in the literature.

[0028] Reference will now be made in detail to certain aspects of the disclosed subject matter, some examples of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in the context of numbered claims, it will be understood that such illustrated subject matter is not intended to limit the scope of the claims to the disclosed subject matter.

[0029] Throughout this document, values ​​expressed in the form of ranges should be interpreted flexibly to include not only the numerical values ​​expressly set forth as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly set forth. 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 the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the description "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, the description "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0030] In the methods described herein, acts may be performed in any order unless a chronological or operational order is explicitly recited. Moreover, certain acts may be performed simultaneously unless the express language of the claim requires that they must be performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in one operation, and the resulting process is within the literal scope of the claimed process.

[0031] definition The term "about" as used herein allows for a variability of a value or range, for example, within 10%, within 5%, or within 1% of a stated value or a stated range limit, and includes the exact value or range stated.

[0032] In this document, the terms "a", "an", or "the" are used to include one or more, unless the context clearly indicates otherwise. The term "or" is used to mean a non-exclusive "or", unless otherwise indicated. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B". Furthermore, any words or terms used herein and not defined elsewhere should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading of this document and should not be construed as limiting. Information associated with a section heading may occur within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if each was incorporated by reference individually.

[0033] The term "abnormal" when used in the context of an organism, tissue, cell, or component thereof means an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected) respective characteristic. A characteristic that is normal or expected in one cell or tissue type may be abnormal in a different cell or tissue type.

[0034] The term "acyl" as used herein means a group containing a carbonyl moiety bonded through a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroarylalkyl group, and the like. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may contain heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is the trifluoroacetyl group.

[0035] The term "alkyl" as used herein refers to straight-chain and branched alkyl groups, as well as cycloalkyl groups, having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons, or in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups enumerated herein, such as amino groups, hydroxy groups, cyano groups, carboxy groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0036] The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0037] The term "alkoxy" as used herein means an oxygen atom connected to an alkyl group, including cycloalkyl groups, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and can further contain double or triple bonds, and can also contain heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced therewith.

[0038] The term "alkynyl" as used herein refers to straight and branched chain alkyl groups as defined herein except that at least one triple bond is present between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbons, 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), among others.

[0039] The term "amine" as used herein refers to primary, secondary, and tertiary amines, for example having the formula N(group)3, where each group can be independently H, or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N, where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" as used herein also includes ammonium ions.

[0040] The term "amino acid sequence variant" refers to a polypeptide having an amino acid sequence that differs to some extent from a native sequence polypeptide. Typically, an amino acid sequence variant exhibits at least about 70% homology, at least about 80% homology, at least about 90% homology, or at least about 95% homology to the native polypeptide. An amino acid sequence variant exhibits substitutions, deletions, and / or insertions at specific positions within the amino acid sequence of the native amino acid sequence.

[0041] As used herein, the term "amino group" refers to any of the forms -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and -NR3 which cannot be protonated. + "Amino" refers to the protonated form of each form except for the protonated form of the amino group. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0042] The term "aminoalkyl" as used herein means an amine attached to an alkyl group, as defined herein. The amine group can occur at any suitable position within the alkyl chain, for example at the terminus of the alkyl chain or anywhere within the alkyl chain.

[0043] The term "antibody" as used herein refers to an immunoglobulin molecule that specifically binds to an antigen. An antibody can be an intact immunoglobulin from natural or recombinant sources, or an immunoreactive portion of an intact immunoglobulin. Usually, an antibody is a tetramer of an immunoglobulin molecule. The antibodies in this disclosure can exist in various forms, including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab, and F(ab)2, as well as single chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

[0044] The term "antibody fragment" refers to a portion of an intact antibody, and refers to the antigen-determining variable region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments, linear antibodies, scFv antibodies, single domain antibodies, such as sdAb (VL or VH), e.g. camelid antibodies (Riechmann, 1999, J. Immunol. Meth. 231:25-38), camelid VHH domains composed of VL or VH domains that show sufficient affinity for a target, and multispecific antibodies formed from antibody fragments, such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge in the hinge region, as well as isolated complementarity determining regions (CDRs) or other epitope-binding fragments of antibodies. Antigen-binding fragments may be incorporated into single domain antibodies, maxi-antibodies, mini-antibodies, nano-antibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger & Hudson, 2005, Nature Biotech. 23:1126-1136). Antigen-binding fragments may be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (U.S. Patent No. 6,703,199, which describes fibronectin polypeptide mini-antibodies). Antibody fragments also include human or humanized antibodies, or portions of human or humanized antibodies.

[0045] The term "antigen" or "Ag" as used herein is defined as a molecule that elicits an immune response. This immune response may include antibody production or activation of specific immunocompetent cells, or both. Those skilled in the art will understand that any macromolecule, including virtually any protein or peptide, can act as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. Those skilled in the art will understand that any DNA that includes a nucleotide sequence or partial nucleotide sequence that encodes a protein that elicits an immune response thus encodes an "antigen" as the term is used herein. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded only by the full-length nucleotide sequence of a gene. It is self-evident that the present disclosure includes, but is not limited to, the use of partial nucleotide sequences of two or more genes, and that these nucleotide sequences are configured in various combinations to elicit the desired immune response. Furthermore, those skilled in the art will understand that an antigen is not necessarily encoded by a "gene". It is self-evident that an antigen may be synthetically produced or derived from a biological sample, which may include, but is not limited to, a tissue sample, a tumor sample, a cell, or a biological fluid.

[0046] The term "aralkyl" as used herein refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group refers to an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0047] The term "aryl" as used herein means a cyclic aromatic hydrocarbon group that does not contain a heteroatom in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. The aryl group may be unsubstituted or substituted as defined herein. Representative substituted aryl groups may be mono- or more than twice substituted, such as, but not limited to, a phenyl group substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of the 2-8-positions.

[0048] As used herein, the term "asialoglycoprotein receptor binding moiety" or "ASGPRBM" refers to a group capable of binding to at least one hepatocyte asialoglycoprotein receptor on the surface of a cell, such as, but not limited to, a hepatocyte. When the ASGPRBM, and any additional moieties to which it is attached, bind to a receptor on the surface of the hepatocyte, the molecule comprising the ASGPRBM is taken up by the hepatocyte by the phagocytic machinery, where it is at least partially degraded through lysosomal degradation.

[0049] As used herein, "C 6~10 -C 6~10 The term "biaryl" refers to a C 6~10 C covalently bonded to an aryl moiety 6~10 C means an aryl moiety. 6~10 The aryl moiety can be any suitable aryl group described herein. 6~10 -C 6~10 Non-limiting examples of biaryl include biphenyl and binaphthyl.

[0050] The term "coding sequence" as used herein means a nucleic acid or its complementary sequence, or a part thereof, that can be transcribed and / or translated to produce an mRNA and / or a polypeptide or a fragment thereof. A coding sequence includes exons in genomic DNA or premature primary RNA transcripts that are connected together by the biochemical machinery of a cell to obtain a mature mRNA. The antisense strand is the complement of the nucleic acid, from which the coding sequence can be deduced. In contrast, the term "non-coding sequence" as used herein means a nucleic acid or its complementary sequence, or a part thereof, that is not translated in vivo into amino acids, i.e., tRNA does not interact with or attempt to arrange amino acids. Non-coding sequences include both intron sequences in genomic DNA or premature primary RNA transcripts, and gene-related sequences such as promoters, enhancers, silencers, etc.

[0051] As used herein, the term "complementary" or "complementarity" is used in reference to polynucleotides (i.e., nucleotide sequences) related by base pairing rules. For example, the sequence "AGT" is complementary to the sequence "TCA". Complementarity may be "partial", where only some of the bases of the nucleic acid match according to the base pairing rules. Alternatively, there may be "complete" or "total" complementarity between nucleic acids. The degree of complementarity between nucleic acid strands shows a significant effect on the efficiency and strength of hybridization between nucleic acid strands. This is particularly important in amplification reactions and detection methods that depend on binding between nucleic acids.

[0052] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharma- ceutical acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques of administering compounds in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0053] As used herein, the term "conservative variation" or "conservative substitution" refers to replacing an amino acid residue with another biologically similar residue.Conservative variation or conservative substitution may not change the shape of peptide chain.Examples of conservative variation or conservative substitution include replacing one hydrophobic residue, such as isoleucine, valine, leucine or methionine, with another hydrophobic residue, or replacing one polar residue with another polar residue, such as replacing arginine with lysine, replacing glutamic acid with aspartic acid, or replacing glutamine with asparagine.

[0054] The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Additionally, cycloalkyl groups include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono- or more than twice substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono-, di-, or trisubstituted norbornyl or cycloheptyl groups, which may be substituted, for example, with amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0055] "Disease" refers to a condition in the health of an animal where the animal is unable to maintain homeostasis and where the animal's health will continue to deteriorate if the disease is not remitted.

[0056] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the animal's health.

[0057] A disease or disorder is "in amelioration" when there is a decrease in the severity of a symptom of the disease or disorder, the frequency with which the symptom is experienced by the patient, or both.

[0058] As used herein, the terms "effective amount", "pharmaceutical effective amount", and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to obtain a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be ascertained by one of ordinary skill in the art using routine experimentation.

[0059] As used herein, the term "efficacy" refers to the maximum effect (E) achieved within an assay. max )

[0060] "Encoding" refers to the inherent property of a particular sequence of nucleotides in a polynucleotide, such as a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes and to have a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, and the biological properties resulting therefrom. Thus, a gene codes for a protein when the protein is produced in a cell or other living system by transcription and translation of the mRNA corresponding to the gene. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is usually shown in the sequence listing, and the non-coding strand, which is used as a template for transcription of a gene or cDNA, can be said to code for the protein or other product of the gene or cDNA.

[0061] As used herein, the term "fragment" when applied to a nucleic acid refers to a subsequence of a larger nucleic acid. A "fragment" of a nucleic acid can be at least about 15 nucleotides in length; e.g., at least about 50 nucleotides to about 100 nucleotides; at least about 100 nucleotides to about 500 nucleotides; at least about 500 nucleotides to about 1000 nucleotides; at least about 1000 nucleotides to about 1500 nucleotides; at least about 1500 nucleotides to about 2500 nucleotides; or about 2500 nucleotides (and any integer value therebetween). As used herein, the term "fragment" when applied to a protein or peptide refers to a subsequence of a larger protein or peptide. A "fragment" of a protein or peptide can be at least about 20 amino acids in length; e.g., at least about 50 amino acids in length; at least about 100 amino acids in length; at least about 200 amino acids in length; at least about 300 amino acids in length; or at least about 400 amino acids in length (and any integer value therebetween).

[0062] As used herein, the term "GN3" refers to the following group: TIFF2025509733000002.tif73128

[0063] The terms "halo," "halogen," or "halide" group as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0064] The term "haloalkyl" as used herein includes mono-haloalkyl groups, poly-haloalkyl groups in which all halo atoms may be the same or different, and per-haloalkyl groups in which all hydrogen atoms are replaced with halogen atoms such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0065] As used herein, the term "heavy chain antibody" includes immunoglobulin molecules derived from Camelidae species by immunization with an antigen and subsequent isolation of serum, or by cloning and expression of a nucleic acid sequence encoding the antibody. The term "heavy chain antibody" includes immunoglobulin molecules isolated from animals with heavy chain disease or derived from animals with heavy chain disease. H It further encompasses immunoglobulin molecules prepared by cloning and expression of (variable heavy chain immunoglobulin) genes.

[0066] The term "heteroaryl" as used herein 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 from five to about 8-12 ring members. Heteroaryl groups refer to various heterocyclyl groups that have an aromatic electronic structure. A heteroaryl group referred to as a C2-heteroaryl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted or substituted with groups described herein. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those enumerated herein.

[0067] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzyl, phenyl ... neshydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl). ), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) nyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), benzothiazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5 H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), but are not limited to these.

[0068] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0069] As used herein, "C 6~10 The term "-5-6 membered heterobiaryl" refers to a C-aryl group covalently attached to a 5- or 6-membered heteroaryl moiety through a single bond. 6~10 C means an aryl moiety. 6~10 The aryl and 5- to 6-membered heteroaryl moieties can be any suitable aryl and heteroaryl groups described herein. 6~10 Non-limiting examples of 5-6 membered heterobiaryls include: TIFF2025509733000003.tif18128 is an example. 6~10 When 5-6 membered heterobiaryl is recited as a substituent (e.g., as an "R" group), C 6~10 -5-6 membered heterobiaryl is C 6~10 It is attached to the rest of the molecule through a moiety.

[0070] As used herein, "5- to 6-membered-C 6~10 The term "heterobiaryl" refers to a 5- to 6-membered -C 6~10 When heterobiaryl is recited as a substituent (e.g., as an "R" group), the 5- to 6-membered -C 6~10 C except that the heterobiaryl is attached to the rest of the molecule through a 5- to 6-membered heteroaryl moiety. 6~10 -Same as 5-6 membered heterobiaryl.

[0071] The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or any combination thereof, provided that it is polycyclic. In some embodiments, a heterocyclyl group contains from three to about twenty ring members, while other similar groups have from three to about fifteen ring members. A heterocyclyl group referred to as a C2-heterocyclyl can be a five-membered ring with two carbon atoms and three heteroatoms, a six-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl can be a five-membered ring with one heteroatom, a six-membered ring with two heteroatoms, and so on. The number of carbon atoms and the number of heteroatoms are equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including species containing fused aromatic and non-aromatic groups. For example, dioxolanyl and benzodioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted or substituted as described herein.Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclyl groups can be groups such as, but not limited to, piperidinyl or quinolinyl groups which are mono- or more than twice substituted, and which are 2-, 3-, 4-, 5- or 6-substituted or disubstituted with groups such as those enumerated herein.

[0072] The term "heterocyclylalkyl" as used herein means an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0073] The term "immunoglobulin" or "Ig" as used herein is defined as a class of proteins that function as antibodies. Antibodies expressed by B cells may be referred to as BCR (B cell receptor) or antigen receptor. The five members of this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is the primary antibody present in bodily secretions, such as saliva, tears, breast milk, gastrointestinal secretions, and mucous secretions of the respiratory tract and urogenital tract. IgG is the most common circulating antibody. IgM is the major immunoglobulin produced in the primary immune response in most subjects. IgM is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in defense against bacteria and viruses. IgD is an immunoglobulin with no known antibody function, but may act as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity by triggering the release of mediators from mast cells and basophils upon exposure to allergens.

[0074] As used herein, the term "independently selected from" means that the referenced groups are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, based on this definition, "X 1 , X 2 , and X 3 is independently selected from the noble gases" is intended to include, for example, 1 , X 2 , and X 3 The scenario where all are the same, X 1 , X 2 , and X 3 In the scenario where all are different, X 1 and X 2 is the same but X 3 This would include scenarios where the sigma ...

[0075] An "inducible" promoter is a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, causes the gene product to be produced in a cell substantially only when an inducer corresponding to the promoter is present in the cell.

[0076] "Isolated" means changed or removed from its natural state. For example, a nucleic acid or polypeptide that is naturally present in a living animal is not "isolated," but the same nucleic acid or polypeptide that has been partially or completely separated from the coexisting materials of its natural state is "isolated." An isolated nucleic acid or protein may be present in a substantially purified form, or it may exist in a non-native environment, such as a host cell.

[0077] The term "modulate" as used herein means to mediate a detectable increase or decrease in the activity and / or level of an mRNA, polypeptide, or response in a subject, compared to the activity and / or level of the mRNA, polypeptide, or response in a subject in the absence of treatment or compound, and / or compared to the activity and / or level of the mRNA, polypeptide, or response in an otherwise identical but untreated subject. The term encompasses activating, inhibiting, and / or otherwise affecting a natural signal or response to mediate a beneficial therapeutic response in a subject, preferably a human.

[0078] The term "monovalent" as used herein means that the substituent is connected to the substituted molecule by a single bond. If the substituent is monovalent, e.g., F or Cl, the substituent is attached to the atom it replaces by a single bond.

[0079] The term "organic group" as used herein means any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and esters; sulfur-containing groups such as alkylsulfide groups and arylsulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N( R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) hydrocarbyl, where R can be hydrogen (in instances containing other carbon atoms) or a carbon-based moiety, which may be substituted or unsubstituted.

[0080] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal, or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting aspects, the patient, subject, or individual is a human.

[0081] As used herein, the term "pharmaceutical acceptable" means a material, such as a carrier or diluent, that does not abrogate the biological activity or biological properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesired biological effects or deleterious interactions with any of the components of the composition contained in the composition.

[0082] As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt, solvate, hydrate, or clathrate thereof of the administered compound prepared from a pharmaceutically acceptable non-toxic acid or base, including an inorganic acid or base, an organic acid or base.

[0083] Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0084] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as, for example, calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0085] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting the compound described herein in or to a patient so that it can perform its intended function. Usually, these compounds are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound described herein and not harmful to the patient. Some examples of materials which may serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical preparations. As used herein, "pharmaceutically acceptable carrier" includes any coating, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in the pharmaceutical compositions used in the methods or compounds described herein are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0086] As used herein, the term "polypeptide" refers to a polymer composed of amino acid residues, related natural structural variants, and synthetic non-natural analogs thereof linked through peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Generally, as used herein, the term "protein" refers to a large polypeptide. As used herein, the term "peptide" refers to a short polypeptide. Conventional notation is used herein to represent polypeptide sequences, i.e., the left end of a polypeptide sequence is the amino terminus and the right end of a polypeptide sequence is the carboxyl terminus.

[0087] As used herein, the term "efficacy" refers to the half-maximal response (ED 50 ) is the dose required to produce

[0088] As used herein, the term "REAG" refers to any reagent that includes -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM. As described herein, REAG reacts with a protein binder to incorporate the protein binder into a compound of the disclosure, or a fragment thereof, a derivative thereof, or an intermediate thereof.

[0089] As used herein, the term "room temperature" means a temperature between about 15°C and 28°C.

[0090] The term "specifically binds" as used herein with respect to an antibody refers to an antibody that recognizes a particular antigen but does not substantially recognize or bind to other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. However, this cross-species reactivity does not in itself change the classification of the antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, this cross-reactivity does not in itself change the classification of the antibody as specific. In some cases, the terms "specifically binds" or "specifically binds" may be used with respect to the interaction of an antibody, protein, or peptide with a second chemical species to mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species, e.g., the antibody recognizes and binds to a particular protein structure rather than proteins in general. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free unlabeled A) in a reaction containing labeled "A" and the antibody reduces the amount of labeled A binding to the antibody.

[0091] As used herein, the term "solvent" refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0092] As used herein, the terms "standard temperature" and "standard pressure" mean 20° C. and 101 kPa.

[0093] As used herein, the term "substantially" means "a majority of" or "mostly," similarly meaning at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free" as used herein can mean completely free or insignificant, such that the amount of material present does not affect the material properties of a composition containing the material, and thus the material is from about 0% to about 5%, or from about 0% to about 1%, or not more than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or not more than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or not more than about 0.001% by weight of the composition. The term "substantially free" can mean having an insignificant amount, such that a material is between about 0% and about 5%, or between about 0% and about 1%, or less than about 5%, or less than about 4.5%, equal to, or greater than about 4.5%, or less than 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% or less by weight, or about 0%.

[0094] The term "substituted" as used herein with respect to a molecule or organic group as defined herein means that one or more hydrogen atoms contained therein are replaced with one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein means a group that can or does substitute on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxy, alkoxy, aryloxy, aralkyloxy, oxo(carbonyl), carboxylic acid, carboxylate, and carboxylate ester; sulfur atoms in thiol, alkyl and aryl sulfide, sulfoxide, sulfone, sulfonyl, and sulfonamide groups; nitrogen atoms in groups such as amine, hydroxylamine, nitrile, nitro, N-oxide, hydrazide, azide, and enamine; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be attached to a substituted carbon atom (or other atom) include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety, e.g., R can be hydrogen, (C1-C 100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with one or more of the nitrogen atoms to form a heterocyclyl.

[0095] The term "synthetic antibody" as used herein refers to an antibody produced using recombinant DNA techniques, such as an antibody expressed by a bacteriophage as described herein. The term should also be taken to mean an antibody produced by synthesis of a DNA molecule encoding the antibody and expressing the antibody protein, or by synthesis of an amino acid sequence specifying the antibody, where the DNA or amino acid sequence is obtained using DNA and amino acid sequence synthesis techniques available and well known in the art.

[0096] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathology, with the intent of reducing or eliminating the symptoms.

[0097] The term "thioalkyl" as used herein means a sulfur atom connected to an alkyl group as defined herein. The alkyl group in the thioalkyl can be straight or branched. Examples of straight chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched alkoxy include, but are not limited to, isothiopropyl, sec-thiobutyl, tert-thiobutyl, isothiopentyl, isothiohexyl, and the like. The sulfur atom can occur at any suitable position within the alkyl chain, for example, at the end of the alkyl chain or anywhere within the alkyl chain.

[0098] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0099] As used herein, the term "wild type" refers to a gene or gene product isolated from a natural source. A wild type gene is a gene that is most frequently observed in a population, and thus is arbitrarily intended to be the "normal" or "wild type" form of the gene. In contrast, the term "modified" or "mutant" refers to a gene or gene product that exhibits modified sequence and / or functional properties (i.e., altered characteristics) compared to a wild type gene or gene product. It should be noted that naturally occurring mutants can be isolated. Naturally occurring mutants are identified by the fact that they exhibit altered characteristics (including altered nucleic acid sequence) compared to a wild type gene or gene product.

[0100] The term "autoimmune disease" refers to a disease or illness that occurs when the body's tissues are attacked by its own immune system. Examples of autoimmune diseases include, for example, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among others.

[0101] A more complete list of autoimmune diseases treatable with the compounds and pharmaceutical compositions of the disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutrophil leukemia, and autoimmune pulmonary fibrosis. Autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful adiposity, adult 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), relapsing rheumatism, Parry-Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, related Rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barro concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, Pediatric autoimmune streptococcal neuropsychiatric disorder (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sydenham chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Ligninous conjunctivitis, Mooren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease,Particularly including eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, and pyoderma gangrenosum.

[0102] Throughout the present specification, the term "cancer" or "neoplasia" is used to mean a pathological process that results in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation more rapidly than normal tissues and continue to grow even after the stimuli that initiated the new growth have ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues, and most often invade surrounding tissues, metastasize to several sites, likely recur after removal attempts, and likely cause the death of the patient if not treated appropriately. As used herein, the term neoplasia is used to describe all cancerous conditions and encompasses or includes the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Neoplasia includes, but is not limited to, morphological irregularities in cells in the tissue of a subject or host, and a proliferation of cells in the tissue of a subject that is pathological compared to normal proliferation in the same type of tissue. In addition, neoplasia includes benign and malignant tumors that are invasive or non-invasive (e.g., colon tumors). Malignant neoplasms (cancer) are distinguished from benign neoplasms in that the former exhibit a greater degree of anaplasia, or loss of cellular differentiation and orientation, and are invasive and metastatic.Examples of neoplasms or neoplasias from which target cells of the present disclosure may be derived include cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder, intestinal, breast, cervical, colon, esophageal, head, kidney, liver, lung, neck, ovarian, pancreatic, prostate, and gastric cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; central nervous system tumors (e.g., glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma); Germ line tumors (e.g., intestinal, breast, prostate, cervical, uterine, lung, ovarian, testicular, thyroid, astrocytoma, esophageal, pancreatic, gastric, hepatic, colon, and melanoma); mixed neoplasias, particularly carcinosarcoma and Hodgkin's disease; and mixed origin tumors, such as Wilms' tumor and teratocarcinoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17. th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms are treatable using the compounds of the present disclosure.

[0103] Representative common cancers that may be treated with the compounds of the present 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, renal cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, and lymphoma, among others, which may be treated with one or more compounds of the present disclosure. Because of the activity of the compounds, the disclosure is generally applicable to treating virtually any cancer in any tissue, and thus the compounds, compositions, and methods of the disclosure are generally applicable to the treatment of cancer and to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0104] In certain aspects of the present disclosure, the cancer to be treated is metastatic cancer, recurrent cancer, or drug-resistant cancer, and particularly includes drug-resistant cancer.Apart from this, metastatic cancer can be found in virtually any tissue of cancer patients in late stage of disease, and usually metastatic cancer is found in virtually any tissue, including lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and brain (brain cancer / brain tumor).Therefore, the present disclosure is generally applicable to and can be used to treat any cancer in any tissue, regardless of etiology.

[0105] The term "anti-cancer agent" or "additional anti-cancer agent" refers to a compound other than the chimeric compounds of the present disclosure that can be used in combination with the compounds of the present disclosure to treat cancer. Exemplary anti-cancer agents that can be co-administered in combination with one or more chimeric compounds of the present disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., taxol), among others. Exemplary anti-cancer compounds for use in the present disclosure include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gymatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucantone, LY 317615, neuradiab, vitespan, Rta744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estrogen stradiolol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperazinemethyl)-indolyl j-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18 O i4 -(C2H4O2) X, where x = 1 to 2.4], Goserelin acetate, Leuprolide acetate, Triptorelin pamoate, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Megestrol acetate, Raloxifene, Bicalutamide, Flutamide, Nilutamide, Megestrol acetate, CP-724714; TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, Tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine , chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levodopa, Mysole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine,Marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epothilone B B), BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony Stimulatory factors, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin 11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin 2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,Androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, peg Filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib may be mentioned in particular, immunotherapeutic agents, for example IDO inhibitors (indoleamine 2,3-dioxygenase (IDO) pathway inhibitors) such as Indoximod (NLG-8187), Navoximod (GDC-0919), and NLG802, PDL1 inhibitors (programmed death ligand 1 inhibitors) including, for example, Nivolumab, Durvalumab, and Atezolizumab, PD1 inhibitors such as Pembrolizumab (Merck), and CTLA-4 inhibitors (cytotoxic T-lymphocyte-associated protein 4 / cluster of differentiation 152 inhibitors) including Ipilimumab and Tremelimumab in particular.

[0106] In addition to anticancer drugs, some other agents can be co-administered with the chimeric compounds of the present disclosure in the treatment of cancer.These include active agents, minerals, vitamins, and nutritional supplements that have shown some effectiveness in inhibiting cancer tissue or its growth, or are otherwise useful in the treatment of cancer.For example, one or more of the following phytoestrogens, including dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and beta-sitosterol, can be used in combination with the present compounds to treat cancer.

[0107] The term "inflammatory disease" is used to describe diseases or conditions that involve acute, but often chronic, inflammation as a primary symptom of the disease or condition. Inflammatory diseases include, but are not limited to, neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias), immune response disorders that cause inflammation (e.g., dysregulation of T cell maturation, B cell homeostasis, and T cell homeostasis, combating damaging inflammation), chronic inflammatory diseases including, for example, inflammatory bowel diseases including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren's disease; Hyperglycemic disorders, lipid metabolism, diabetes mellitus (types I and II) affecting the function and / or structure of pancreatic islets, pancreatic beta cell death, as well as severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall syndrome, Werner syndrome, leprechaunism, and lipoatrophic diabetes), and dyslipidemia (e.g., hyperlipidemia, high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), high triglycerides, and metabolic syndrome, which occur in obese subjects. In particular, the following conditions are included: related hyperglycemic disorders, including inflammatory bowel disease, liver disease, kidney disease (apoptosis in plaques, glomerular disease), cardiovascular disease (including infarction, ischemia, stroke, pressure overload, and complications during reperfusion), muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis, and related conditions such as cardiac and neurological manifestations (both central and peripheral), including stroke, age-related dementia, and sporadic Alzheimer's disease, as well as psychiatric conditions, including depression, stroke and spinal cord injury, arteriosclerosis. In these diseases, elevated MIF levels are often observed, and therefore these pathologies and / or conditions respond to treatment using the compounds and / or pharmaceutical compositions of the present disclosure. It is noted that there is some overlap between certain autoimmune and inflammatory diseases described herein.

[0108] Throughout this disclosure, various aspects of the disclosure can be presented in the form of ranges. It should be understood that the description in the form of ranges is merely for convenience and brevity, and should not be interpreted as a rigid limitation on the scope of the disclosure. Thus, a description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within the range. For example, a description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numbers within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0109] compound The disclosure provides compounds comprising formula (I), or a salt, geometric isomer, stereoisomer, or solvate thereof. [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I)

[0110] In certain embodiments, the compound comprises Formula (Ia): or a salt, geometric isomer, stereoisomer, or solvate thereof. [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 -[CRBM] ' (Ia)

[0111] In (I) or (Ia), the Ab is an antibody, such as, but not limited to, a monoclonal antibody, that binds to a biological target, such as, but not limited to, a circulating protein and / or an extracellular protein, such as, but not limited to, a cell surface protein. In certain embodiments, the circulating protein mediates a disease and / or disorder in a subject, and treatment or management of the disease and / or disorder requires degradation, removal, or reduction in concentration of the circulating protein in the subject. In certain embodiments, the Ab in (I) or (Ia) is capable of binding to a circulating protein in the plasma of a subject with the same affinity or substantially similar affinity as the Ab itself.

[0112] In (I) or (Ia), the CRBM is a cellular receptor binding moiety that binds to at least one receptor on the surface of hepatocytes or other degradative cells in a subject, whereby binding results in endocytosis and degradation of (I) and / or (Ia) and / or the biological target. In certain embodiments, the CRBM is an ASGPRBM, which is a cellular receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of hepatocytes or other degradative cells in a subject.

[0113] In (I) or (Ia), each CON is independently a bond or a group that covalently links an Ab to a CRBM, an Ab to a linker, and / or a linker to a CRBM.

[0114] In (I) or (Ia), the linker is a group having a valency ranging from 1 to 15. In certain embodiments, the linker has a valency of 1 to 10. In certain embodiments, the linker has a valency of 1 to 5. In certain embodiments, the linker has a valency of 1, 2, or 3. In certain embodiments, the linker is covalently linked to one or more CRBM and / or Ab groups, optionally through CON, where the linker itself optionally comprises one or more CON groups.

[0115] In certain embodiments, k' is an integer ranging from 1 to 15. In certain embodiments, k' is an integer ranging from 1 to 10. In certain embodiments, k' is an integer ranging from 1 to 5. In certain embodiments, k' is an integer ranging from 1 to 3. In certain embodiments, k' is 1, 2, or 3.

[0116] In certain embodiments, j is an integer ranging from 1 to 15. In certain embodiments, j is an integer ranging from 1 to 10. In certain embodiments, j is an integer ranging from 1 to 5. In certain embodiments, j is an integer ranging from 1 to 3. In certain embodiments, j is 1, 2, or 3.

[0117] In certain embodiments, h is an integer ranging from 0 to 15. In certain embodiments, h is an integer ranging from 1 to 15. In certain embodiments, h is an integer ranging from 1 to 10. In certain embodiments, h is an integer ranging from 1 to 5. In certain embodiments, h is an integer ranging from 1 to 3. In certain embodiments, h is 1, 2, or 3.

[0118] In certain embodiments, h' is an integer ranging from 0 to 15. In certain embodiments, h' is an integer ranging from 1 to 15. In certain embodiments, h' is an integer ranging from 1 to 10. In certain embodiments, h' is an integer ranging from 1 to 5. In certain embodiments, h' is an integer ranging from 1 to 3. In certain embodiments, h' is 1, 2, or 3.

[0119] In certain embodiments, i is an integer ranging from 0 to 15. In certain embodiments, i is an integer ranging from 1 to 15. In certain embodiments, i is an integer ranging from 1 to 10. In certain embodiments, i is an integer ranging from 1 to 5. In certain embodiments, i is an integer ranging from 1 to 3. In certain embodiments, i is 1, 2, or 3.

[0120] In certain embodiments, at least one of h, h', and i is at least one.

[0121] In certain embodiments, k', j', h, h', and i are each independently 1, 2, or 3.

[0122] In certain embodiments, k' is 1 and j' is 1, 2, or 3.

[0123] CRBM Folate Receptor In certain embodiments, the CRBM is folic acid or any fragment or derivative thereof that can bind to the folate receptor. The folate receptor binds to folic acid and reduced folate derivatives and mediates the delivery of tetrahydrofolate to the inside of the cell, which is then converted from monoglutamic acid to polyglutamic acid (e.g., 5-methyltetrahydrofolate) since only the monoglutamic acid form can be transported across the cell membrane. Human proteins from this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor gamma.

[0124] In certain embodiments, the folate CRBM is methotrexate or a biologically active fragment thereof: Contains TIFF2025509733000004.tif27128.

[0125] In certain embodiments, the folate CRBM is pemetrexed or a biologically active fragment thereof: Contains TIFF2025509733000005.tif25128.

[0126] In certain embodiments, the folate CRBM may be incorporated into the compounds of the present disclosure through one of its carboxylic acids. In other embodiments, the folate CRBM may be incorporated into the compounds of the present disclosure using N-hydroxysuccinamidyl (NHS)-activated folic acid (similar chemistry applies to methotrexate and pemetrexed). TIFF2025509733000006.tif69128

[0127] Mannose Receptor In certain embodiments, the CRBM is a group that binds to the mannose receptor. In certain embodiments, the CRBM comprises the following group: TIFF2025509733000007.tif17128

[0128] In certain embodiments, the mannose receptor CRBM is prepared by reacting with the following reagent (optionally protected with an appropriate protecting group): TIFF2025509733000008.tif17128 can be used to bind to a compound of the disclosure, such as, but not limited to, REAG; wherein X is S or O and R is TIFF2025509733000009.tif17137, 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.

[0129] In certain embodiments, the mannose receptor CRBM is part of a polymer molecule. The molecule may contain one or more independently selected mannose receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein.

[0130] Mannose-6-phosphate (M6P) receptor In certain embodiments, the CRBM is a group that binds to the mannose-6-phosphate (M6P) receptor. In certain embodiments, the CRBM comprises the following group: TIFF2025509733000010.tif16128 where X is O or S and R 1 is selected from the group consisting of: TIFF2025509733000011.tif48128

[0131] In certain embodiments, the CRBM is prepared by reacting with the following reagent (optionally protected with an appropriate protecting group): TIFF2025509733000012.tif16128 can be used to bind to a compound of the disclosure, such as, but not limited to, REAG; In the formula, X and R 1 is as defined elsewhere herein, and R 2 teeth, TIFF2025509733000013.tif38137, and each occurrence of "n" is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0132] In certain embodiments, the M6P receptor CRBM is part of a polymer molecule. The molecule may include one or more independently selected M6P receptor CRBMs as part of the polymer chain. In certain embodiments, the CRBM may be incorporated into the polymer molecule using the CRBM reagents described elsewhere herein. Figures 1-8 show exemplary mannose receptor binders and their preparation.

[0133] In certain embodiments, the M6P receptor CRBM is one of the following (Yamaguchi, et al., 2016, J. Am. Chem. Soc. 138(38):12472-12485): TIFF2025509733000014.tif109128

[0134] In certain embodiments, the M6P receptor CRBM is one of the following (US2011 / 0110960 to Platenburg): TIFF2025509733000015.tif90143

[0135] Low-density lipoprotein receptor-related protein 1 (LRP1) receptor In certain embodiments, the CRBM has the amino acid sequence: TIFF2025509733000016.tif118144 is an LRP1 [low density lipoprotein receptor-related protein 1; also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or cluster of differentiation 91 (CD91)] binding group.

[0136] Low density lipoprotein receptor (LDLR) In certain embodiments, the CRBM has the amino acid sequence: TIFF2025509733000017.tif104140TIFF2025509733000018.tif239141 is a LDLR (low density lipoprotein receptor) binding group that contains one of the following:

[0137] FcγRI receptor In certain embodiments, the CRBM has the amino acid sequence: TIFF2025509733000019.tif225141 is an FcγRI binding group.

[0138] Transferrin Receptor In certain embodiments, the CRBM has the amino acid sequence: TIFF2025509733000020.tif104141 is a transferrin receptor binding group containing one of the following:

[0139] Macrophage scavenger receptor In certain embodiments, the CRBM has the amino acid sequence: It is a macrophage scavenger receptor binding portion containing one of TIFF2025509733000021.tif79145.

[0140] As used herein, Pen is penicillamine, Thz is thiazolidine-4-carboxylic acid, Sar is sarcosine, Pip is pipecolic acid, Nleu is norleucine and NMeLeu is N-methylleucine.

[0141] G protein-coupled receptors In certain embodiments, the CRBM is a G protein-coupled receptor (GPCR) binding moiety. In certain embodiments, the binding moiety binds to a GPCR and induces internalization of the receptor. In certain embodiments, the receptor is CXCR7 (see, e.g., Nalawansha, et al., 2019, ACS Cent. Sci. 5(6):1079-1084). In certain embodiments, the binding moiety is TIFF2025509733000022.tif34128, wherein each occurrence of R is independently H or C1-C6 alkyl. In certain embodiments, the CRBM can be prepared by reacting the following reagent (optionally protected with a suitable protecting group): TIFF2025509733000023.tif34128 can be used to bind to a compound of the disclosure, such as, but not limited to, REAG; wherein at least one occurrence of R is REAG, and the remaining occurrences of R are independently H or C1-C6 alkyl.

[0142] Asialoglycoprotein receptor (ASGPR) The present disclosure contemplates the use of an ASGPR binding moiety (ASGPRBM).

[0143] In certain embodiments, the ASGPRBM group is any group described in Huang, et al., 2017, Bioconjugate Chem. 28:283-295, which is incorporated by reference in its entirety.

[0144] In certain embodiments, the ASGPRBM group has the structure: TIFF2025509733000024.tif22128, where X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X can be O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker three or four atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) Like, O, S, N(R N1 ), or C(R N1 )(R N1 ) groups.

[0145] In certain embodiments, R N1 Each occurrence of is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0146] In certain embodiments, when X is two atoms in length, X in the ASGPRBM is -OC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[0147] In certain embodiments, when X is 3 atoms long, X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-SC(R N1 )(RN1 )-, -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 ).

[0148] In certain embodiments, when X is four atoms in length, X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-OC(RN1 )(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 )-.

[0149] In certain embodiments, X is OCH2 and R N1 is H.

[0150] In certain embodiments, X is CH2O and R N1 is H.

[0151] In certain embodiments, the ASGPRBM has the structure: Contains TIFF2025509733000025.tif18128.

[0152] In certain embodiments, the ASGPRBM has the structure: Includes TIFF2025509733000026.tif19128.

[0153] In certain embodiments, R 1 is a group shown in Figure 9. In certain embodiments, R 3 is a group shown in Figure 9. In certain embodiments, R 1 and R 3 are each independently a group shown in FIG.

[0154] In certain embodiments, R 1 and R 3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, -(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (Alkynyl), -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K -C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens.

[0155] In certain embodiments, R 1 and R 3 are each independently Ph(CH2) K -, which is optionally substituted with 1 to 3 independently selected halogens; C1 to C4 alkyl optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups; or C1 to C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxyl groups.

[0156] In certain embodiments, R 1 and R 3 each independently has the following structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 where R 7 is a C1-C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxy groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2.

[0157] In certain embodiments, K is 0. In certain embodiments, K is 1. In certain embodiments, K is 2. In certain embodiments, K is 3. In certain embodiments, K is 4.

[0158] In certain embodiments, K' is 1. In certain embodiments, K' is 2. In certain embodiments, K' is 3. In certain embodiments, K' is 4.

[0159] In certain embodiments, R N3 Each occurrence of is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0160] In certain embodiments, R N4 each occurrence is independently H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2) K -It is.

[0161] In certain embodiments, R 1 and R 3 are each independently selected from the group consisting of: TIFF2025509733000027.tif25128, wherein CYC is a group consisting of: TIFF2025509733000028.tif102144, wherein: The bond shown in TIFF2025509733000029.tif2128 is -(CH2) K indicates the site on CYC to which it is connected.

[0162] In certain embodiments, L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON.

[0163] In certain embodiments, R C is absent, H, C1-C4 alkyl optionally substituted with 1-3 optionally substituted halogens and / or 1-2 hydroxyl groups, or the following structure: TIFF2025509733000030.tif21128, wherein R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens, C1-C3 alkoxy optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K It is -C(=O)O-(C1-C4 alkyl), -OC(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens.

[0164] In certain embodiments, R N2Each occurrence of is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0165] In certain embodiments, R C teeth The file is TIFF2025509733000031.tif23142.

[0166] In certain embodiments, R 1 and R 3 are each independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocycle is -L 1 and -R C is further substituted with

[0167] In certain embodiments, R N Each occurrence of is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0168] In certain embodiments, R 2 is the group shown in FIG.

[0169] In certain embodiments, R 2 Ha-(CH2) K -N(R N1 )-C(=O)R AM It is.

[0170] In certain embodiments, R AM is H, C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens KC(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) K -NR N3 R N4 It is.

[0171] In certain embodiments, R 2 teeth TIFF2025509733000032.tif15128, wherein R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, each of which is selected from the group consisting of CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2)K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) optionally substituted with 1 to 3 independently selected halogens. K C(=O)-(C1-C4 alkyl), or R TA teeth TIFF2025509733000033.tif44128, which is optionally substituted with 1 to 3 C1-C3 alkyl groups, each of which is optionally substituted with 1 to 3 independently selected halogens; or R TA teeth TIFF2025509733000034.tif26128, wherein each -(CH2) K The group is optionally substituted with 1 to 4 C1 to C3 alkyl groups, which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups.

[0172] In certain embodiments, the ASGPRBM group has the structure: Contains TIFF2025509733000035.tif46148, During the ceremony, R A is a C1-C3 alkyl optionally substituted with 1 to 5 independently selected halogens; Z A Ha-(CH2) IM -, -O-(CH2) IM -, -S-(CH2) IM -, -NR M -(CH2) IM -, -C(=O)-(CH2) IM -, a PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH2) IM NR M - and; Z B is absent, -(CH2)IM -, -C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M - and; R M is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups; Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6.

[0173] In certain embodiments, R A is methyl or ethyl, either of which may be substituted with 1 to 3 fluorines.

[0174] In certain embodiments, Z A is a PEG group containing 1 to 4 ethylene glycol residues.

[0175] In certain embodiments, the ASGPRBM group comprises one of the following (Mamidyala, et al., 2012, J. Am. Chem. Soc. 134:1978-1981): TIFF2025509733000036.tif166149TIFF2025509733000037.tif210141TIFF2025509733000038.tif117146

[0176] In certain embodiments, the ASGPRBM group comprises one of the following (Sanhueza, et al., 2017, J. Am. Chem. Soc. 139:3528-3536): TIFF2025509733000039.tif117144

[0177] Linker and CON In certain embodiments, the linker is a polyethylene glycol-containing linker having 1 to 12 ethylene glycol residues.

[0178] In certain embodiments, the linker has the structure: -CH2CH2(OCH2CH2) mOCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together with to form a pyrrolidine or hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15.

[0179] In certain embodiments, the linker has the structure -[N(R ' -(CH2) 1~15 —C(═O)]—, where R′ is H or a C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1 to 100.

[0180] In certain embodiments, the linker has the structure: -ZD-Z'- Including, During the ceremony, Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2) i -S-, TIFF2025509733000040.tif18149; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 are independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); each i is independently 0 to 100; in certain embodiments, 0 to 75; in certain embodiments, 1 to 60; in certain embodiments, 1 to 55; in certain embodiments, 1 to 50; in certain embodiments, 1 to 45; in certain embodiments, 1 to 40; in certain embodiments, 2 to 35; in certain embodiments, 3 to 30; in certain embodiments, 1 to 15; in certain embodiments, 1 to 10; in certain embodiments, 1 to 8; in certain embodiments, 1 to 6; in certain embodiments, 0, 1, 2, 3, 4, or 5; D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -, -(CH2) m' - or - [(CH2) n -X1)] j - with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; m' is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; in certain embodiments, from 1, 2, 3, 4, or 5; n is an integer ranging from 1 to 100; in certain embodiments, from 1 to 75; in certain embodiments, from 1 to 60; in certain embodiments, from 1 to 55; in certain embodiments, from 1 to 50; in certain embodiments, from 1 to 45; in certain embodiments, from 1 to 40; in certain embodiments, from 2 to 35; in certain embodiments, from 3 to 30; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 10; in certain embodiments, from 1 to 8; in certain embodiments, from 1 to 6; and in certain embodiments, from 1, 2, 3, 4, or 5.

[0181] In certain embodiments, the linker has the structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n - Including, In the formula, each n and n' is independently an integer ranging from 1 to 25; in certain embodiments, from 1 to 15; in certain embodiments, from 1 to 12; in certain embodiments, from 2 to 11; in certain embodiments, from 2 to 10; in certain embodiments, from 2 to 8; in certain embodiments, from 2 to 6; in certain embodiments, from 2 to 5; in certain embodiments, from 2 to 4; in certain embodiments, from 2 or 3; and in certain embodiments, from 1, 2, 3, 4, 5, 6, 7, or 8.

[0182] In certain embodiments, the linker has the structure: -PEG-CON-PEG- Including, wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. The file is TIFF2025509733000041.tif13128.

[0183] In certain embodiments, CON has the structure: Contains TIFF2025509733000042.tif78128, wherein R′ and R″ are each independently H, methyl, or a bond.

[0184] In certain embodiments, CON has the diamide structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1 )-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- Including, In the formula, each R 1 is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, and in certain embodiments 1 to 7, and in certain embodiments 1, 2, 3, 4, 5, or 6.

[0185] In certain embodiments, CON has the structure: TIFF2025509733000043.tif13128, During the ceremony, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2) M1 -C(O)NR 4 -, where R 1a , R 2a , and R 3a but not simultaneously H; each M1 is independently 1, 2, 3, or 4, and in certain embodiments, 1 or 2; each M2 is independently 0, 1, 2, 3, or 4, and in certain embodiments 0, 1, or 2; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a M2 and M3 in cannot all be 0 at the same time.

[0186] In certain embodiments, CON has the structure: Contains TIFF2025509733000044.tif42128.

[0187] Ab Any antibody (Ab) that binds to an extracellular protein is useful within the scope of this disclosure. In certain non-limiting embodiments, the antibody is a monoclonal antibody.

[0188] Non-limiting examples of extracellular proteins contemplated within the scope of the present disclosure include 1-40-β-amyloid, 5′-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, Canis lupus familiaris)IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clumping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli (E.coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, episialin, FGF 23, fibrin II, beta chain, fibronectin extra domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon gamma, interferon Ron gamma-inducing protein, interleukin 1α, interleukin 13, interleukin 17α, interleukin 17α, TNF, interleukin 17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, tectal plate specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, and VWF.

[0189] Non-limiting examples of antibodies useful within the scope of the present disclosure include Abagovomab, Abrezekimab, Adalimumab, Aducanumab, Afasevikumab, Afelimomab, Alirocumab, Altumomab, Altumomab, Pentetate Altumomab, pentetate, Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Biciromab, Bimetazumab, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine, Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumab pegol, Cibisatamab, Clazakizumab, Clivatuzumab, Clivatuzumab tetraxetanTetraxetan, Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab-alitox Aritox, Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomab-sitaxetan cituxetan, Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Firivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Furunevetomab Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, IndatuximabRavtansine, Infliximab, Istiratumab, Ixekizumab, Labetuzumab, Lacnotuzumab, Lampalizumab, Lanadelumab, Landogrozumab, Lebrikizumab, Remalesomab, Lendalizumab, Lenzilumab, Lerdelimumab Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab butafenatox Tafenatox, Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab Merpentanemerpentan, obiltoxaximab, oleclumab, olendalizumab, olokizumab, omalizumab, onartuzumab, olegovomab, orticumab, otilimab, ozanezumab, ozoralizumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, pentumomab, perakizumab, pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab b), Raxibacumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab govitecan govitecan, Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab vedotinvedotin, solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvratoxumab, tabalumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritoxumab aritox, tesidolumab, tezepelumab, tiburizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, vapaliximab, varisacumab, vepalimomab, besencumab, vobarilizumab, bunakizumab, and xentuzumab.

[0190] The antibody of interest can be incorporated into the compound of the present disclosure using any method known in the art and / or any technique described or exemplified herein. For example, the antibody can be attached to the linker through a carboxylic acid group on the surface of the antibody, for example, using amide or ester forming chemistry. For example, the antibody can be attached to the linker through an amine group on the surface of the antibody, for example, using amide forming chemistry. For example, the antibody can be attached to the linker through a thiol group on the surface of the antibody, for example, using nucleophilic substitution chemistry. In this case, the surface cysteine ​​residue can be present in the wild type of Ab and / or can be introduced by mutation, for example, using site-directed mutagenesis. Linkers useful within the scope of the present disclosure can be any linkers known in the art, as long as the presence of the linker does not significantly interfere with the ability of Ab to bind to circulating proteins.

[0191] In a non-limiting example, the antibody useful within the scope of the present disclosure can bind to circulating protein.As will be understood by those skilled in the art, any antibody that can recognize and specifically bind to circulating protein is useful in the present disclosure.The present disclosure should not be interpreted as being limited to any one antibody, known or unknown, provided that the antibody can specifically bind to circulating protein and prevent or minimize the biological activity of circulating protein.

[0192] Methods for making and using these antibodies are well known in the art. For example, polyclonal antibody production can be achieved by inoculating a desired animal with an antigen and isolating antibodies from the animal that specifically bind to the antigen. Monoclonal antibodies directed to full-length or peptide fragments of proteins or peptides can be prepared using any well-known monoclonal antibody preparation procedure, such as those described in Harlow et al. (1989, Antibodies, A Laboratory Manual, Cold Spring Harbor, New York) and Tuszynski et al. (1988, Blood 72:109-115). Chemical synthesis techniques may be used to synthesize large quantities of the desired peptide. Alternatively, DNA encoding the desired peptide can be cloned and expressed from an appropriate promoter sequence in cells suitable for producing large quantities of the peptide. Monoclonal antibodies directed to the peptide are generated from mice immunized with the peptide using standard procedures referred to herein. However, the present disclosure should not be construed as being limited solely to methods and compositions that include these antibodies, but rather should be construed to include other antibodies as that term is defined elsewhere herein.

[0193] In some cases, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as rodents (e.g., mice), primates (e.g., humans), etc. The techniques for preparing these monoclonal antibodies are well known and are described, for example, in Harlow et al., ANTIBODIES: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1988); Harlow et al., Using Antibodies: A Laboratory Manual, (Cold Spring Harbor Press, New York, 1998); Breitling et al., Recombinant Antibodies (Wiley-Spektrum, 1999); and Kohler et al., 1997 Nature 256: 495-497; and U.S. Patent Nos. 5,693,762; 5,693,761; 5,585,089; and 6,180,370.

[0194] Nucleic acids encoding the antibodies obtained using the procedures described herein can be cloned and sequenced using techniques available in the art and described, for example, in Wright et al. (Critical Rev. Immunol. 1992, 12:125-168) and the references cited therein. Additionally, antibodies useful within the present disclosure can be "humanized" using the techniques described in Wright et al., supra, and the references cited therein, and Gu et al. (Thrombosis and Hematocyst 1997, 77:755-759).

[0195] Alternatively, antibodies can be generated using phage display technology. To create a phage display library, a cDNA library is first obtained from mRNA isolated from cells, e.g., hybridomas, that express the desired protein, e.g., the desired antibody, to be expressed on the phage surface. Reverse transcriptase is used to generate cDNA copies of the mRNA. cDNAs specifying immunoglobulin fragments are obtained by PCR, and the resulting DNA is cloned into a suitable bacteriophage vector to generate a bacteriophage DNA library containing DNA specifying immunoglobulin genes. Procedures for generating bacteriophage libraries containing heterologous DNA are well known in the art and are described, for example, in Sambrook et al. (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York).

[0196] Bacteriophage encoding a desired antibody can be engineered so that the protein is displayed on the surface of the bacteriophage so that it is available for binding to its corresponding binding protein, for example, the antigen to which the antibody is directed. Thus, when a bacteriophage expressing a particular antibody is incubated in the presence of a cell expressing the corresponding antigen, the bacteriophage will bind to the cell. Bacteriophage that do not express the antibody will not bind to the cell. This panning technique is well known in the art and is described, for example, in Wright et al. (Critical Rev. Immunol. 1992, 12:125-168).

[0197] Processes such as the one described herein have been developed for the production of human antibodies using M13 bacteriophage display (Burton et al., 1994, Adv. Immunol. 57:191-280). Essentially, a cDNA library is created from mRNA obtained from a population of antibody-producing cells. The mRNA encodes, and thus the cDNA encodes, a rearranged immunoglobulin gene. The amplified cDNA is cloned into an M13 expression vector, creating a library of phages that express human Fab fragments on their surface. Phages displaying the antibody of interest are selected by antigen binding and propagated into bacteria to produce soluble human Fab immunoglobulins. Thus, in contrast to conventional monoclonal antibody synthesis, this procedure immortalizes the DNA encoding the human immunoglobulins rather than the cells expressing the human immunoglobulins.

[0198] The procedure just given describes the generation of phages encoding the Fab portion of an antibody molecule. However, the present disclosure should not be construed as being limited to the generation of phages encoding Fab antibodies only. Rather, phages encoding single chain antibodies (scFv / phage antibody libraries) are also included in the present disclosure. Fab molecules contain the entire Ig light chain, i.e., Fab molecules contain both the variable and constant regions of the light chain, but only the variable region and the first constant region domain (CH1) of the heavy chain. Single chain antibody molecules contain a single chain of protein that contains an Ig Fv fragment. An Ig Fv fragment contains only the variable regions of the heavy and light chains of an antibody, without the constant regions contained therein. A phage library containing scFv DNA can be generated according to the procedure described in Marks et al. (1991, J Mol Biol 222:581-597). Panning of the phages thus generated for isolation of the desired antibodies is performed in a manner similar to that described for the phage library containing Fab DNA.

[0199] The present disclosure should also be construed to include synthetic phage display libraries capable of synthesizing heavy and light chain variable regions containing nearly any possible specificity (Barbas, 1995, Nature Medicine 1:837-839; de Kruif et al., 1995, J Mol Biol 248:97-105).

[0200] Further galactose- and talose-based ASGPR binding moieties In one aspect, the invention relates to compounds of the general chemical structure of Formula II that are useful for clearing circulating proteins associated with a disease state or condition in a patient or subject. TIFF2025509733000045.tif10128 Formula II

[0201] As used herein, the term "extracellular protein targeting ligand" is used interchangeably with the term CPBM (cellular protein binding moiety). As used herein, the term "ASGPR ligand" is used interchangeably with the asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0202] In compounds of formula II, each [CON] is an optional connector chemical moiety, which, if present, is either directly connected to a [CPBM] or a [CRBM] or connects a [Linker-2] to a [CPBM] or a [CRBM].

[0203] In a compound of formula II, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, [Linker-2] is a chemical moiety having a valence of 1-15 that is covalently attached to one or more [CRBM] and / or [CPBM] groups through [CON], which optionally contains a [MULTICON] group, where said [Linker-2] itself optionally contains one or more [CON] or [MULTICON] groups; k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer of 0 to 15; i L is an integer between 0 and 15; where h, h', and i L At least one of is at least 1.

[0204] [MULTICON] groups may connect one or more [CRBM]s or [CPBM]s to one or more [Linker-2]s. In various embodiments, [Linker-2] has a valence of 1-10. In various embodiments, [Linker-2] has a valence of 1-5. In various embodiments, [Linker-2] has a valence of 1, 2, or 3. In various embodiments, in compounds of formula II, [Linker-2] may be one or more linkers as defined herein. A , Linker B , Linker C , Linker D , and / or combinations thereof.

[0205] In compounds of formula II, xx is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25.

[0206] 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.

[0207] 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.

[0208] In the compound of formula II, X 1 is O, S, N(R b ), and C(R 4 )(R 4) 1 to 5 adjacent atoms independently selected from 1 If is one atom, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 If there are two atoms, X 1 Not more than one atom of 6 ) and X 1 If X has 3, 4, or 5 atoms, 1 Up to two atoms of are O, S, or N(R 6 ) and; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 More selected; R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 More selected; R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; R 8 and R 9is independently at each occurrence selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0209] A. Galactose-Based ASGPR-Binding Cell Receptor Binding Moieties of Formula II In certain embodiments, the compound of formula II is TIFF2025509733000046.tif155128TIFF2025509733000047.tif204111TIFF2025 509733000048.tif201104TIFF2025509733000049.tif149128TIFF202550973300 0050.tif199108TIFF2025509733000051.tif117128TIFF2025509733000052.tif 213111TIFF2025509733000053.tif93128TIFF2025509733000054.tif132128TIFF TIFF2025509733000055.tif137128TIFF2025509733000056.tif150128TIFF2025509733000057.tif161129TIFF2025509733000058.tif148128TIFF2025509733000059.tif160132TIFF2025509733000060.tif196104TIFF2025509733000061.tif170128TIFF2025509733000062.tif167128TIFF2025509733000063.tif126128 is selected.

[0210] In one embodiment, the compound of formula II has one of the following structures: TIFF2025509733000064.tif117128

[0211] In various embodiments, the ASGPR ligand is reacted with C to form a decomposition compound. 1 or C 5 (R 1 or R 5In various embodiments, the ASGPR ligand is linked at the C 6 For example, the ASGPR ligand is linked at TIFF2025509733000065.tif17128, non-limiting examples of ASGPR binding compounds of formula II include: TIFF2025509733000066.tif50128, or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives bound to the linker moiety.

[0212] In any of the embodiments herein in which an ASGPR ligand is selected for use in a degradation agent, the ASGPR ligand is typically linked to a C 5 to an extracellular protein targeting ligand at position (e.g., the linker is adjacent C 6 (This may refer to a carbon hydroxyl or other functional moiety that can be used for linking purposes). 1 When attached through a position, the carbon in question is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group.

[0213] In various embodiments, the ASGPR ligand is C 3 C rank 4 In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are: TIFF2025509733000067.tif68128TIFF2025509733000068.tif133128TIFF2025509733000069.tif196121TI FF2025509733000070.tif217123TIFF2025509733000071.tif212125TIFF2025509733000072.tif154128TIFF Selected from 2025509733000073.tif180128TIFF2025509733000074.tif174128TIFF2025509733000075.tif146130TIFF2025509733000076.tif155128TIFF2025509733000077.tif157132TIFF2025509733000078.tif131128.

[0214] In certain embodiments, the compound of formula II is Selected from TIFF2025509733000079.tif43128TIFF2025509733000080.tif140129TIFF2025509733000081.tif89128TIFF2025509733000082.tif189128TIFF2025509733000083.tif121128.

[0215] B. Talc-based ASGPR-binding cell receptor binding moieties of formula II In certain embodiments, the compound of formula II is TIFF2025509733000084.tif68128TIFF2025509733000085.tif188128TIFF2025509733000086.tif170128TIFF2025509733000087.tif182128TIFF2025509733000088.tif183128TIFF2025509733000089.tif146128TIFF2025509733000090.tif186128TIFF2025509733000091.tif189128TIFF2025509733000092.tif214111TIFF2025509733000093.tif156128TIFF2025509733000094.tif202108TIFF2025509733000095.tif158128TIFF2025509733000096.tif99128TIFF2025509733000097.tif133128TIFF2025509733000098.tif136128TIFF2025509733000099.tif201135TIFF2025509733000100.tif99128TIFF2025509733000101.tif216132TIFF2025509733000102.tif214128TIFF2025509733000103.tif22495TIFF2025509733000104.tif205112TIFF2025509733000105.tif209139TIFF2025509733000106.tif181128TIFF2025509733000107.tif191128TIFF2025509733000108.tif177128TIFF2025509733000109.tif222117TIFF2025509733000110.tif125128TIFF2025509733000111.tif166128TIFF2025509733000112.tif166128TIFF2025509733000113.tif197104TIFF2025509733000114.tif209100TIFF2025509733000115.tif128128TIFF2025509733000116.Selected from tif157128TIFF2025509733000117.tif157128TIFF2025509733000118.tif168128TIFF2025509733000119.tif148128TIFF2025509733000120.tif144128TIFF2025509733000121.tif68128.

[0216] In one embodiment, the compound of formula II is an extracellular proteolytic compound, where the ASGPR ligand is a ligand described herein. TIFF2025509733000122.tif50128

[0217] In one embodiment, in the compound of formula II, the ASGPR ligand is a C1 or C5 (R 1 or R 5 In one embodiment, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is TIFF2025509733000123.tif17128, non-limiting examples of ASGPR binding compounds of formula II include: TIFF2025509733000124.tif110128 or a di- or tri-substituted version thereof, or a pharma- ceutically acceptable salt thereof, where di- or tri-substituted refers to the number of additional galactose derivatives attached to the linker moiety. In certain embodiments, the compound of formula II is TIFF2025509733000125.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0218] In certain embodiments, the compound of formula II is TIFF2025509733000126.tif140128TIFF2025509733000127.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0219] In certain embodiments, the compound of formula II is TIFF2025509733000128.tif140128TIFF2025509733000129.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0220] In certain embodiments, the compound of formula II is TIFF2025509733000130.tif139128TIFF2025509733000131.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0221] In certain embodiments, the compound of formula II is TIFF2025509733000132.tif139128TIFF2025509733000133.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0222] In certain embodiments, the compound of formula II is TIFF2025509733000134.tif139128TIFF2025509733000135.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0223] In certain embodiments, the compound of formula II is TIFF2025509733000136.tif139128TIFF2025509733000137.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0224] In certain embodiments, the compound of formula II is TIFF2025509733000138.tif139128TIFF2025509733000139.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0225] In certain embodiments, the compound of formula II is TIFF2025509733000140.tif152128TIFF2025509733000141.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0226] In certain embodiments, the compound of formula II is TIFF2025509733000142.tif152128TIFF2025509733000143.tif145128TIFF2025509733000144.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0227] In certain embodiments, the compound of formula II is TIFF2025509733000145.tif152128TIFF2025509733000146.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0228] In certain embodiments, the compound of formula II is TIFF2025509733000147.tif152128TIFF2025509733000148.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0229] In certain embodiments, the compound of formula II is TIFF2025509733000149.tif152128TIFF2025509733000150.tif145128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0230] In certain embodiments, the compound of formula II is TIFF2025509733000151.tif152128TIFF2025509733000152.tif146128, wherein in certain embodiments, R 2 Ha-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -(6-membered heteroaryl), R 2 Each of the groups may be optionally substituted with 1, 2, 3, or 4 independent substituents as described herein, e.g., 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0231] In certain embodiments, the compound of formula II is TIFF2025509733000153.tif152128TIFF2025509733000154.tif164128TIFF2025509733000155.tif 200112TIFF2025509733000156.tif200112TIFF2025509733000157.tif198114TIFF20255097330001 Selected from 58.tif164128TIFF2025509733000159.tif200112TIFF2025509733000160.tif200112TIFF2025509733000161.tif202112TIFF2025509733000162.tif195130TIFF2025509733000163.tif72128.

[0232] In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are TIFF2025509733000164.tif60128TIFF2025509733000165.tif151128TIFF2025509733000166.tif112128TIFF202550 9733000167.tif158128TIFF2025509733000168.tif133128TIFF2025509733000169.tif162128TIFF202550973300017 Selected from 0.tif139128TIFF2025509733000171.tif192107TIFF2025509733000172.tif189128TIFF2025509733000173.tif216123TIFF2025509733000174.tif61128TIFF2025509733000175.tif154128TIFF2025509733000176.tif197125.

[0233] C. ASGPR Ligand / Binding Moieties in Compounds of Formula II In certain embodiments, in the compound of formula II, R 1 is hydrogen.

[0234] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000177.tif5128.

[0235] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000178.tif5128.

[0236] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000179.tif5128.

[0237] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000180.tif5128.

[0238] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000181.tif5128.

[0239] In certain embodiments, in the compound of formula II, R 1 teeth The file is TIFF2025509733000182.tif5128.

[0240] In certain embodiments, in the compound of formula II, R 1 is a C0-C6 alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.

[0241] In certain embodiments, in the compound of formula II, R 1 is alkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0242] In certain embodiments, in the compound of formula II, R 1 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is haloalkyl, optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is F.

[0243] In certain embodiments, in the compound of formula II, R 1 is Cl.

[0244] In certain embodiments, in the compound of formula II, R 1 is Br.

[0245] In certain embodiments, in the compound of formula II, R1 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0246] In certain embodiments, in the compound of formula II, R 1 is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0247] In certain embodiments, in the compound of formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0248] In certain embodiments, in the compound of formula II, R 1 is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0249] In certain embodiments, in the compound of formula II, R 1 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0250] In certain embodiments, in the compound of formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.

[0251] In certain embodiments, in the compound of formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.

[0252] In certain embodiments, in the compound of formula II, R 1 -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 , C0-C6 alkyl-SR 6 , C0-C6 alkyl-NR 6 R 7 , C0-C6 alkyl-C(O)R 3 , C0-C6 alkyl-S(O)R 3 , C0-C6 alkyl-C(S)R3 , C0-C6 alkyl-S(O)2R 3 , C0-C6 alkyl-N(R 8 )-C(O)R 3 , C0-C6 alkyl-N(R 8 )-S(O)R 3 , C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-OC(O)R 3 , C0-C6 alkyl-OS(O)R 3 , C0-C6 alkyl-OC(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkylN3, or C0-C6 alkyl-OS(O)2R 3 each of which is optionally substituted with 1, 2, 3, or 4 substituents.

[0253] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0254] In certain embodiments, in the compound of formula II, R 2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0255] In certain embodiments, in the compound of formula II, R 2 is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, 3, or 4 substituents.

[0256] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000183.tif34128.

[0257] In certain embodiments, in the compound of formula II, R2 is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents.

[0258] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)-R 3 It is.

[0259] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(S)-R 3 It is.

[0260] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)(NR 6 )-R 3 It is.

[0261] In certain embodiments, in the compound of formula II, R 2 is optionally substituted with one, two, three or four substituents -N=S(O)(R 3 )2.

[0262] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 C(O)NR 9 S(O)2R 3 It is.

[0263] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -S(O)2-R 10 It is.

[0264] In certain embodiments, in the compound of formula II, R2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 8 -C(NR 6 )-R 3 It is.

[0265] In certain embodiments, in the compound of formula II, R 2 is hydrogen.

[0266] In certain embodiments, in the compound of formula II, R 2 is R 10 It is.

[0267] In certain embodiments, in the compound of formula II, R 2 is alkyl-C(O)-R 3 It is.

[0268] In certain embodiments, in the compound of formula II, R 2 -C(O)-R 3 It is.

[0269] In certain embodiments, in the compound of formula II, R 2 is alkyl.

[0270] In certain embodiments, in the compound of formula II, R 2 is haloalkyl.

[0271] In certain embodiments, in the compound of formula II, R 2 HA-OC(O)R 3 It is.

[0272] In certain embodiments, in the compound of formula II, R 2 Ha-NR 8 -C(O)R 10 It is.

[0273] In certain embodiments, in the compound of formula II, R 2 is alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0274] In certain embodiments, in the compound of formula II, R 2 is aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0275] In certain embodiments, in the compound of formula II, R 2 is alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0276] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkenyl.

[0277] In certain embodiments, in the compound of formula II, R 2 is --O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0278] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -alkynyl.

[0279] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -heteroaryl.

[0280] In certain embodiments, in the compound of formula II, R 2 is -NR, which may be substituted with 1, 2, 3, or 4 substituents; 6 -aryl.

[0281] In certain embodiments, in the compound of formula II, R 2 is --O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

[0282] In certain embodiments, in the compound of formula II, R2 is --O-aryl optionally substituted with 1, 2, 3, or 4 substituents.

[0283] In certain embodiments, in the compound of formula II, R 2 is --O-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.

[0284] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000184.tif10128.

[0285] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000185.tif17128.

[0286] In certain embodiments, in the compound of formula II, R 2 teeth TIFF2025509733000186.tif95128, where R is an optional substituent as defined herein.

[0287] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000187.tif41128.

[0288] In certain embodiments, in the compound of formula II, R 2A teeth TIFF2025509733000188.tif97128, where R is an optional substituent as defined herein.

[0289] In certain embodiments, in the compound of formula II, R 2A teeth Selected from TIFF2025509733000189.tif41128.

[0290] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000190.tif138128.

[0291] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000191.tif132136.

[0292] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000192.tif8128.

[0293] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000193.tif8128.

[0294] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000194.tif37128.

[0295] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000195.tif37128.

[0296] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000196.tif18128.

[0297] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000197.tif14128.

[0298] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000198.tif41128.

[0299] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000199.tif41128.

[0300] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000200.tif11128.

[0301] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000201.tif11128.

[0302] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000202.tif37128.

[0303] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000203.tif35128.

[0304] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000204.tif57128.

[0305] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000205.tif57128.

[0306] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000206.tif31128.

[0307] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000207.tif31128.

[0308] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000208.tif69128.

[0309] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000209.tif69128.

[0310] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000210.tif22128.

[0311] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000211.tif22128.

[0312] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000212.tif22128.

[0313] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000213.tif22128.

[0314] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000214.tif18128.

[0315] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000215.tif17128.

[0316] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000216.tif19128.

[0317] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000217.tif19128.

[0318] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000218.tif90128.

[0319] In certain embodiments, in the compound of formula II, R 2 or R 2A teeth Selected from TIFF2025509733000219.tif99128.

[0320] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000220.tif26128.

[0321] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000221.tif26128.

[0322] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000222.tif9128.

[0323] In certain embodiments, in the compound of formula II, R 2 teeth Selected from TIFF2025509733000223.tif9128.

[0324] In certain embodiments, in the compound of formula II, R 2 is selected from .

[0325] In certain embodiments, in the compound of formula II, R 2 is a spirocyclic heterocycle, e.g. TIFF2025509733000224.tif11128 but not limited to it.

[0326] In certain embodiments, in the compound of formula II, R 2 is a silicon-containing heterocycle, e.g. TIFF2025509733000225.tif13128, but not limited to it.

[0327] In certain embodiments, in the compound of formula II, R 2 is replaced by SF5, e.g. TIFF2025509733000226.tif20128 but not limited to it.

[0328] In certain embodiments, in the compound of formula II, R 2 is substituted with sulfoxime, e.g. TIFF2025509733000227.tif20128 but not limited to it.

[0329] In certain embodiments, in the compound of formula II, R 10 is selected from bicyclic heterocycles.

[0330] In certain embodiments, in the compound of formula II, R 10 is selected from spirocyclic heterocycles.

[0331] In certain embodiments, in the compound of formula II, R 10 Ha-NR 6 -heterocycles.

[0332] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509733000228.tif12128.

[0333] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509733000229.tif38128.

[0334] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509733000230.tif18128.

[0335] In certain embodiments, in the compound of formula II, R 10 teeth Selected from TIFF2025509733000231.tif30128.

[0336] In certain embodiments, in the compound of formula II, the ring is Selected from TIFF2025509733000232.tif127128.

[0337] In certain embodiments, in the compound of formula II, R 30 teeth Selected from TIFF2025509733000233.tif31128.

[0338] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000234.tif13128.

[0339] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000235.tif11128.

[0340] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000236.tif13128.

[0341] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000237.tif11128.

[0342] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000238.tif13128.

[0343] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000239.tif13128.

[0344] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000240.tif13128.

[0345] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000241.tif13128.

[0346] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000242.tif11128.

[0347] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000243.tif11128.

[0348] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000244.tif11128.

[0349] In certain embodiments, in the compound of formula II, R 200 teeth The file is TIFF2025509733000245.tif11128.

[0350] Linker In a non-limiting embodiment, in the compound of formula II, the linker A and linker B is independent, TIFF2025509733000246.tif9128, wherein: R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 represents independently at each occurrence a bond, an alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-, -P(O)(R 3 )O-, -P(O)(R 3 )-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, and heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2] n-O-, CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -, -[-(CH2)2-O-] n -, -[O-(CH2)2] n -, -[O-CH(CH3)C(O)] n -, -[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -, -[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or dicarboxylic acid; 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 is independently for each occurrence hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azido, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl, and heterocycle; The remaining variables are as defined herein.

[0351] In one embodiment, in the compound of formula II, the linker A is a bond and a linker B teeth The file is TIFF2025509733000247.tif9128.

[0352] In one embodiment, in the compound of formula II, the linker B is a bond and a linker A teeth The file is TIFF2025509733000248.tif9128.

[0353] In one embodiment, in the compound of formula II, the divalent residue of the amino acid is TIFF2025509733000249.tif180129, where the amino acids can be oriented in either direction, and the amino acids can be L- or D-forms, or a mixture thereof.

[0354] In one embodiment, in the compound of formula II, the divalent residue of a dicarboxylic acid is generated by a nucleophilic addition reaction. TIFF2025509733000250.tif19128

[0355] Non-limiting examples of the divalent residue of a dicarboxylic acid produced by the nucleophilic addition reaction include: An example is TIFF2025509733000251.tif48128.

[0356] In one embodiment, in the compound of formula II, the divalent residue of a dicarboxylic acid is produced by a condensation reaction. TIFF2025509733000252.tif19128

[0357] Non-limiting examples of the divalent residue of a dicarboxylic acid produced by the condensation reaction include: TIFF2025509733000253.tif58128 is an example.

[0358] Non-limiting examples of the divalent residue of a saturated dicarboxylic acid include: An example is TIFF2025509733000254.tif44128.

[0359] Non-limiting examples of the divalent residue of a saturated dicarboxylic acid include: TIFF2025509733000255.tif21128 is an example.

[0360] Non-limiting examples of divalent residues of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 CH2-).

[0361] Non-limiting embodiments of divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paulic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid. TIFF2025509733000256.tif78128

[0362] Non-limiting examples of divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y- Linoleic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3(CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), paulinic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)3CH2-), mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0363] In certain embodiments, in the compound of formula II, the linker C teeth TIFF2025509733000257.tif26128, wherein: R 22 is independently at each occurrence alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R7 ) selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; The remaining variables are as defined herein.

[0364] In certain embodiments, in the compound of formula II, the linker D teeth TIFF2025509733000258.tif38128, wherein: R 32 represents independently in each occurrence an alkyl group, N + selected from the group consisting of X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is selected from the group consisting of R 21 optionally substituted with 1, 2, 3, or 4 more independently selected substituents; X- is an anionic group, e.g., Br- or Cl - and; All other variables are as defined herein.

[0365] In certain embodiments, in the compound of formula II, the linker A teeth TIFF2025509733000259.tif20128, wherein the heteroaryl, heterocycle, cycloalkyl, and aryl are each optionally substituted with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl, as valences allow.

[0366] In certain embodiments, in the compound of formula II, the linker A teeth TIFF2025509733000260.tif80128, wherein heteroaryl, heterocycle, cycloalkyl, and and are each optionally substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences allow.

[0367] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000261.tif74128.

[0368] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000262.tif177128.

[0369] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D teeth, TIFF2025509733000263.tif81128, where tt is independently selected from 1, 2, or 3, and ss is 3 minus tt (3-tt).

[0370] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D teeth, TIFF2025509733000264.tif44128, where tt and ss are as defined herein.

[0371] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D teeth, TIFF2025509733000265.tif136128TIFF2025509733000266.tif170128TIFF2025509733000267.tif170128TIFF2025509733000268.tif21691, wherein heteroaryl, heterocycle, cycloalkyl, and aryl may each be optionally substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences permit; and tt and ss are as defined herein.

[0372] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D teeth, TIFF2025509733000269.tif121128TIFF2025509733000270.tif157128, wherein the heteroaryl, heterocycle, cycloalkyl, and aryl are each optionally substituted with 1, 2, 3, or 4 of halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle, or cycloalkyl, as valences permit; and tt and ss are as defined herein.

[0373] In certain embodiments, in the compound of formula II, the linker B , Linker C , or the linker D teeth, TIFF2025509733000271.tif52128, wherein heteroaryl and aryl may each be optionally substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as valences allow; and tt and ss are as defined herein.

[0374] In certain embodiments, in the compound of formula II, the linkerA teeth Selected from TIFF2025509733000272.tif48128.

[0375] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000273.tif60128.

[0376] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000274.tif49128.

[0377] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000275.tif50128.

[0378] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000276.tif78128.

[0379] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000277.tif66128.

[0380] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000278.tif169128.

[0381] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000279.tif229126.

[0382] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000280.tif29128.

[0383] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000281.tif86128.

[0384] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000282.tif122128.

[0385] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000283.tif58128.

[0386] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000284.tif123128.

[0387] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000285.tif63132.

[0388] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000286.tif122128.

[0389] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000287.tif140128.

[0390] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000288.tif117128.

[0391] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000289.tif164128.

[0392] In certain embodiments, in the compound of formula II, the linker D is Selected from TIFF2025509733000290.tif87128.

[0393] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000291.tif180128.

[0394] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000292.tif57128.

[0395] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000293.tif113128.

[0396] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000294.tif191128.

[0397] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000295.tif22128.

[0398] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000296.tif13128.

[0399] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000297.tif96128.

[0400] In certain embodiments, the linker A teeth TIFF2025509733000298.tif138128, each of which is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0401] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000299.tif16128.

[0402] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000300.tif33128.

[0403] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000301.tif33128.

[0404] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000302.tif34128.

[0405] In certain embodiments, in the compound of formula II, the linkerA teeth Selected from TIFF2025509733000303.tif46128.

[0406] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000304.tif14128.

[0407] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000305.tif136128TIFF2025509733000306.tif136128.

[0408] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000307.tif94128.

[0409] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000308.tif134136.

[0410] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000309.tif38128.

[0411] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000310.tif34128.

[0412] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000311.tif70128.

[0413] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000312.tif56128.

[0414] In certain embodiments, in the compound of formula II, the linker A teeth Selected from TIFF2025509733000313.tif67128.

[0415] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000314.tif29128.

[0416] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000315.tif11128.

[0417] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000316.tif40128.

[0418] In certain embodiments, in the compound of formula II, the linker B are selected from, and each is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0419] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000317.tif56128.

[0420] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000318.tif21128.

[0421] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000319.tif26128.

[0422] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000320.tif34128.

[0423] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000321.tif55128.

[0424] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000322.tif43128.

[0425] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000323.tif102128.

[0426] In certain embodiments, in the compound of formula II, the linker B teeth Selected from TIFF2025509733000324.tif60129.

[0427] In certain embodiments, in the compound of formula II, the linker B -Linker A teeth Selected from TIFF2025509733000325.tif18128.

[0428] In certain embodiments, in the compound of formula II, the linker B -Linker A teeth Selected from TIFF2025509733000326.tif37128.

[0429] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000327.tif38128.

[0430] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000328.tif59128.

[0431] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000329.tif38128.

[0432] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000330.tif86128.

[0433] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000331.tif48128.

[0434] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000332.tif74128.

[0435] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000333.tif86128TIFF2025509733000334.tif163128TIFF2025509733000335.tif49128.

[0436] In certain embodiments, in the compound of formula II, the linker C are selected from, and each is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0437] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000336.tif66128.

[0438] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000337.tif20128.

[0439] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000338.tif20128.

[0440] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000339.tif41128.

[0441] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000340.tif41128.

[0442] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000341.tif30128.

[0443] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000342.tif45128.

[0444] In certain embodiments, in the compound of formula II, the linker C teeth Selected from TIFF2025509733000343.tif74128.

[0445] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is Selected from TIFF2025509733000344.tif63128.

[0446] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is Selected from TIFF2025509733000345.tif115128.

[0447] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is Selected from TIFF2025509733000346.tif24128.

[0448] In certain embodiments, in the compound of formula II, the linker C -(Linker A )2 is Selected from TIFF2025509733000347.tif185128.

[0449] In certain embodiments, in the compound of formula II, the linker D teeth Selected from TIFF2025509733000348.tif45128.

[0450] In certain embodiments, in the compound of formula II, the linker D teeth TIFF2025509733000349.tif81128, each of which is 21 It may be substituted with 1, 2, 3, or 4 substituents selected from:

[0451] In certain embodiments, in the compound of formula II, the linker B -(Linker A )teeth Selected from TIFF2025509733000350.tif60128.

[0452] In certain embodiments, in the compound of formula II, the linker C -(Linker A )teeth Selected from TIFF2025509733000351.tif170128.

[0453] In certain embodiments, in the compound of formula II, the linker D -(Linker A )teeth Selected from TIFF2025509733000352.tif88128.

[0454] In various embodiments, R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, 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 is selected from.

[0455] In various embodiments, in the compound of formula II, R 5 are independently hydrogen, heteroalkyl, TIFF2025509733000353.tif19128, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, 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 alkylN3, and C0-C6 alkyl-OS(O)2R 3 each of which is optionally substituted with 1, 2, 3, or 4 substituents.

[0456] In various embodiments, in the compound of formula II, R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 is selected from.

[0457] In various embodiments, in the compound of formula II, R 8 and R 9 is independently at each occurrence selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0458] In various embodiments, the compound of formula II has the structure of formula II-A: In various embodiments, in the compound of formula II, [Ab] is as defined herein.

[0459] A compound of formula II-A, or a salt, stereoisomer, or solvate thereof, having the structure: TIFF2025509733000354.tif10128 formula II-A During the ceremony, [Ab] is an antibody that binds to an extracellular protein; [ASGPBM] is an asialoglycoprotein receptor binding portion having a structure selected from TIFF2025509733000355.tif220111; Each [CON] is an optional connector chemical moiety that, if present, connects [LIN] to [CPBM] or [ASGPBM]; [LIN] is [Linker] or [Linker-2], each of which is a chemical moiety having a valence of 1-15 that is covalently attached to one or more [ASGPBM] or [CPBM] groups, optionally through [CON], where said [LIN] itself optionally contains one or more [CON] groups; Z B is non-existent, (CH2) IM , C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M and; R M is H or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups; R2 is TIFF2025509733000356.tif15128; In the formula, R AM is H, C1-C4 alkyl optionally substituted with up to three halo groups and one or two hydroxyl groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, -C(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -(CH2) K -NR N3 R N4 or R2 is TIFF2025509733000357.tif13128, During the ceremony, R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 halo groups K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 halo groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K -C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -C(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing up to five heteroaryl atoms, each of which may contain up to three of the following: CN, NR N1 R N2 , -(CH2)K OH, -(CH2) optionally substituted with 1 to 3 halo groups K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 halo groups or 1-2 hydroxy groups, -O-(C1-C3-alkyl) optionally substituted with 1-3 halo groups, -(CH2) K COOH, optionally substituted with 1 to 3 halo groups -(CH2) K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) optionally substituted with 1 to 3 halo groups, or -(CH2) optionally substituted with 1 to 3 halo groups. K or may be substituted with C(O)-(C1-C4 alkyl); R TA is optionally substituted with up to three C1-C3 alkyl groups, which may be substituted with up to three halo groups; TIFF2025509733000358.tif48128; or R TA teeth TIFF2025509733000359.tif57128; R N , R N1 , R N2 , R N3 , R N4 are each independently H or a C1-C3 alkyl group optionally substituted with 1 to 3 halo groups or 1 or 2 hydroxy groups, and each -(CH2) K The group is optionally substituted with 1-4 C1-C3 alkyl groups, which may be substituted with 1-3 fluoro groups or 1-2 hydroxyl groups; IM, independently for each occurrence, is an integer from 0 to 6; K, independently in each occurrence, is an integer from 0 to 4; k' is an integer ranging from 1 to 15; j' is an integer ranging from 1 to 15; h and h' are each independently an integer ranging from 0 to 15; i L is between 0 and 15; where h, h', and i L At least one of is at least 1.

[0460] In various embodiments, in the compound of formula II-A, R2 is -NC(=O)CH3.

[0461] D. ASGPR binding moieties of other series Furthermore, the ASGPR activity is Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem, doi: 199-201. 10.1021 / acs.bioconjchem.0c00202; Majouga, AG, et al., “Identification of Novel Small-Molecule ASGP-R Ligands,” Current Drug Delivery, 2016, 13, 1303–1312; Olshanova, AS, et al., "Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the targeted delivery to hepatocellular carcinoma cells," Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., "New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids," Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019; Congdon , MD , et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00555; and Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509 (2021) 108417, doi: 10.1016 / j.carres.2021.108417. The following ASGPR binding moieties are exemplary and are not intended to be limiting.

[0462] 1. GalNAc-tyrosine moiety In some embodiments, the ASGPR binding moiety can be a moiety having the structure of M1, M2, M3, or M4, or a combination thereof. In the structures of M1, M2, M3, and M4, X is independently at each occurrence O, NH, or S. In various embodiments, a compound of formula I or formula II can have one, two, or three ASGPR binding moieties having the structure of M1, M2, M3, or M4. TIFF2025509733000360.tif93128

[0463] In various embodiments, the ASGPR binding moieties M1-M4 may be conjugated to any suitable [CON], [Linker], or [Linker-2], as described herein and in Congdon, MD, et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00555.

[0464] 2. Trivalent triazole moiety In some embodiments, the ASGPR binding moiety can be a moiety having the structure M5. TIFF2025509733000361.tif39128

[0465] In structure M5, each R is independently R1 or R2 at each occurrence. TIFF2025509733000362.tif48128

[0466] In various embodiments, the compound of formula I or formula II comprises an ASGPR binding moiety having the structure M5. In various embodiments, each R in M5 is R1. In various embodiments, each R in M5 is R2.

[0467] In various embodiments, the ASGPR binding moiety M5 may be conjugated / attached to any suitable [CON], [Linker], or [Linker-2], as described herein and in Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem, doi: 10.1021 / acs.bioconjchem.0c00202.

[0468] 3. Galactose-derived and agarose-derived behenate moieties In various embodiments, the ASGPR binding moiety can be the galactose behenate derived moiety M7. TIFF2025509733000363.tif25128

[0469] In structure M7, Y is OH or NHAc.

[0470] In various embodiments, the ASGPR binding moiety is an agarose behenate derived moiety M8: It could be TIFF2025509733000364.tif61128.

[0471] In various embodiments, the ASGPR binding moieties M7 and M8 may be conjugated to any suitable [CON], [Linker], or [Linker-2], as described herein and in Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509 (2021) 108417, doi: 10.1016 / j.carres.2021.108417.

[0472] 4. Other small molecule ASGPR binding moieties In various embodiments, the ASGPR binding moiety can be any of compounds 2-18 below. TIFF2025509733000365.tif203143

[0473] In various embodiments, in compounds 15 and 16, R is CHOAc, COOH, or CHOH. Compounds 2-18 are described herein and Majouga, AG, et al., "Identification of Novel Small-Molecule ASGP-R Ligands," Current Drug Delivery, 2016, 13, 1303-1312, doi: 10.2174 / 1567201813666160719144651; Olshanova, AS, et al. al., "Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the delivery to hepatocellular carcinoma cells," Russian Chemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., "New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids," Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019, may be conjugated / attached to any suitable [CON], [Linker], or [Linker-2]. Compounds 2-18 may be attached through any suitable reactive group contained therein. Without being limited thereto, compounds 2-13 may be attached to [CON], [Linker], or [Linker-2] through or by reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone, or aromatic halogen contained in compounds 2-18.Suitable reaction modes for attaching compounds 2-18 to [CON], [Linker], or [Linker-2] as described herein include, but are not limited to, substitution (e.g., alkylation of an OH or NH group), esterification (forming an ester), amidation (forming an amide), transesterification (exchanging one ester for another), transamidation (exchanging one amide for another), azide-alkyne cycloaddition, and other reactions capable of forming CC, NC, or OC bonds with vinyl and alkynyl groups, such as cycloaddition, amination, oxidation, alkylation, and rearrangement reactions (e.g., Claisen, Cope, etc.).

[0474] The present disclosure encompasses polyclonal antibodies, monoclonal antibodies, synthetic antibodies, etc. One of skill in the art will understand, based on the disclosure set forth herein, that an important characteristic of an antibody that is useful within the scope of the present disclosure is that the antibody specifically binds to a circulating protein.

[0475] The compounds described herein may have one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic forms. It should be understood that the compounds described herein encompass racemates, optically active forms, positional isomers, and stereoisomers, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, but not limited to, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, a mixture of one or more isomers is utilized as the therapeutic compounds described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0476] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharma- ceutically acceptable salts of compounds having the structures of any of the compounds described herein, as well as metabolites and active metabolites of these compounds that exhibit the same activity. Solvates include solvates with water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol), acetate esters, and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents, such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated forms.

[0477] In certain aspects, the compounds described herein can exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0478] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmacologic, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to the biologically, pharmacologic, or therapeutically active form of the compound by one or more steps or processes.

[0479] In certain embodiments, sites on the aromatic ring moiety of the compounds described herein are susceptible to various metabolic reactions. By incorporating suitable substituents on the aromatic ring structure, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl groups.

[0480] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In certain embodiments, isotope-labeled compounds are useful in drug distribution studies and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium provides increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, 11C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriately isotopically labeled reagent in place of an otherwise non-labeled reagent.

[0481] In certain aspects, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0482] The compounds described herein, and other related compounds having different substituents, can be prepared using the techniques and materials described herein and in other publications such as Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), the disclosures of which are all incorporated by reference. The general methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various moieties found in the formulas shown herein.

[0483] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein.

[0484] In certain embodiments, reactive functional groups such as hydroxyl, amino, imino, thio, or carboxy groups are protected to avoid their undesired participation in reactions. Protecting groups are used to block some or all reactive moieties to prevent them from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group is removable by a different means. The need for differential removal is met by protecting groups that are cleaved under completely different reaction conditions.

[0485] In certain embodiments, the protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid labile and are used to protect carboxy- and hydroxy-reactive moieties in the presence of Cbz-protected amino groups, which are hydrogenolysis-removable, and Fmoc-protected amino groups, which are base labile. Carboxylic acid- and hydroxy-reactive moieties are blocked with base-labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups, such as t-butyl carbamate, or blocked with carbamates, which are acid- and base-stable, but hydrolytically removable.

[0486] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while concurrent amino groups are blocked with fluoride labile silyl carbamates.

[0487] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and subsequently removed by metal or pi-acid catalysis. For example, allyl blocking carboxylic acids are deprotected by palladium catalysis in the presence of acid labile t-butyl carbamate or base labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and will not react. When released from the resin the functional group becomes available for reaction.

[0488] Typically, the blocking / protecting group may be selected from: TIFF2025509733000366.tif72128

[0489] Other protecting groups, along with detailed descriptions of techniques applicable to the creation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

[0490] composition Compositions comprising the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharma- ceutically acceptable carrier. In certain embodiments, the compositions are formulated for oral or parenteral administration, such as transdermal, transmucosal (e.g., sublingual, intralingual, buccal (transbuccal), urethral (transurethral), intravaginal (e.g., vaginal and perivaginal), nasal (intranasal), and rectal (rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0491] Treatment The compounds of the present disclosure can be used to treat certain diseases and / or disorders, such as, but not limited to, autoimmune diseases, cancer, inflammation, or any other disease and / or disorder described herein.

[0492] Non-limiting examples of diseases and / or disorders include acute sciatica, progressive solid tumors, allergic asthma, allergic reactions, ALS and multiple sclerosis, Alzheimer's disease, amyloidosis, anaplastic large cell lymphoma, angioedema, angiogenesis, angiogenesis, ocular vascular disease, ankylosing spondylitis, psoriasis, anthrax (prevention and treatment), arthritis, asthma, asthma and white blood cell disorders, asthma, atopic dermatitis, atypical hemolytic uremic syndrome, autoimmune diseases, autoimmune disorders, B cell cancers, B cell malignancies, anthrax, bleeding, bleeding due to hemophilia, cancer, cancer (diagnosis), and the like. , viral infections, chronic and juvenile myelomonocytic leukemia, renal clear cell carcinoma, clinical signs of atopic dermatitis in dogs, cold agglutinin disease, colorectal cancer, Crohn's disease, psoriasis, psoriatic arthritis, and asthma, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, ulcerative colitis, cryopyrin-associated periodic fever syndrome, diabetes mellitus, diagnostic agents, Escherichia coli-induced diarrhea, Duchenne muscular dystrophy, dyslipidemia, eczema, fibrosis, gastric or gastroesophageal junction adenocarcinoma, gastrointestinal cancer, geographic atrophy secondary to age-related macular degeneration, hemophilia A, hemophagocytic lymphohistiocytosis, High-risk neuroblastoma and refractory bone marrow disease, Hodgkin's lymphoma, hypercholesterolemia, idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, cancer, immune-mediated inflammatory disorders, infectious diseases / influenza A, inflammation, inflammation of the airways, skin and gastrointestinal tract, inflammatory autoimmune diseases, inflammatory lesions and metastases (detection), influenza A, invasive Candida infections, macular degeneration (wet type), metastatic cancer, retinopathy of prematurity, metastatic pancreatic cancer, migraine, migraine and cluster headaches, multiple sclerosis, multiple sclerosis, psoriasis, psoriatic arthritis, orthopedic disuse and sarcopenic muscle wasting muscle wasting disorders, muscular dystrophies, hospital acquired pneumonia, oncological / immunological indications, osteoarthritis in dogs, osteoarthritis, rheumatoid arthritis, osteomyelitis, osteoporosis, bone metastases, etc., ovarian cancer, ovarian cancer, pain, pain and inflammatory diseases, pancreatic and colorectal cancer, pancreatic cancer, Parkinson's disease, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uraemic syndrome, paroxysmal nocturnal hemoglobinuria, atypical HUS, psoriasis vulgaris, primary systemic amyloidosis, progressive supranuclear palsy, psoriasis, inflammatory bowel disease, multiple sclerosis, reduction of scarring after glaucoma surgery, reduction of side effects of cardiac surgery,Recurrent or refractory cervical cancer, reversal of the anticoagulant effect of dabigatran, rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, hemolytic disease of the newborn, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, sepsis, sepsis caused by gram-negative bacteria, severe asthma and chronic spontaneous urticaria, SLE, dermatomyositis inflammation, polymyositis, solid malignancies, solid tumors, spinal cord injury and multiple sclerosis, Staphylococcus aureus infection, systemic lupus erythematosus, systemic lupus erythematosus without renal or CNS involvement, systemic lupus erythematosus, lupus nephritis, acute graft-versus-host disease, systemic sclerosis, thromboembolism, thrombotic thrombocytopenic purpura, thrombosis, triple-negative breast cancer, uveitis, rheumatoid arthritis, psoriasis, viral infections, wet age-related macular degeneration, X-linked hypophosphatemia.

[0493] The method described herein comprises administering to a subject a therapeutically effective amount of at least one compound described herein, which may be formulated in a pharmaceutical composition.In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition.In certain embodiments, the method further comprises administering to a subject an additional therapeutic agent for treating disease or disorder.

[0494] In certain embodiments, administration of a compound described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve a similar result in treating a disease or disorder in the subject. For example, in certain embodiments, the compound described herein enhances the activity of the additional therapeutic compound, thereby reducing the dose of the additional therapeutic compound to achieve the same effect.

[0495] In certain embodiments, the compounds described herein and the therapeutic agent are administered simultaneously to a subject. In other embodiments, the compounds described herein and the therapeutic agent are co-formulated and administered simultaneously to a subject.

[0496] In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[0497] Combination therapy The compounds useful within the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating a disease or disorder, and / or additional therapeutic agents that reduce or ameliorate the symptoms of a disease or disorder and / or the side effects of therapeutic agents used in treating a disease or disorder. These additional therapeutic agents can include compounds that are commercially available or available to those skilled in the art by synthesis. When additional therapeutic agents useful for treating a disease or disorder are used, these additional therapeutic agents are known to treat the disease or disorder or reduce its symptoms.

[0498] In various embodiments, synergistic effects are observed when the compounds described herein are administered with one or more additional therapeutic agents or compounds. Synergistic effects can include, for example, sigmoid-E max The combination of drugs can be calculated using any suitable method, for example, the concentration-effect curve, the isobologram curve, and the combination index curve, by applying the above-mentioned equations to the experimental data.

[0499] Administration / Dosage / Formulation The dosing regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered before or after the onset of a disease or disorder in the subject. Furthermore, several divided and staggered doses may be administered daily or sequentially, or the dose may be continuously infused or bolus injected. Furthermore, the dosage of the therapeutic formulation may be proportionally increased or decreased as required by the therapeutic or prophylactic situation.

[0500] The administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, can be carried out using known procedures at dosages and for periods of time effective to treat the disease or disorder in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary according to factors such as the current state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. The administration regimen can be adjusted to achieve an optimal therapeutic response. For example, several divided doses can be administered daily, or the dose can be proportionally reduced as required by the therapeutic situation. A non-limiting example of an effective amount range for the therapeutic compounds described herein is about 1 to 5,000 mg / kg body weight / day. One skilled in the art would be able to consider the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0501] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response, desired composition, and desired mode of administration for a particular patient, without being toxic to the patient.

[0502] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, physical condition, general health, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0503] A medical practitioner, such as a physician or veterinarian, having ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start the dosage of the compound described herein used in the pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained.

[0504] In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage form for ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically separate unit suitable as a unit dosage form for the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect, in combination with a required pharmaceutical medium.The unit dosage form of the compound described herein is determined by and directly depends on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding / formulating said therapeutic compound.

[0505] In certain embodiments, the compositions described herein are formulated using one or more pharma- ceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compounds described herein and a pharma- ceutically acceptable carrier.

[0506] The carrier can be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0507] In certain embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from 1 to 5 or more times per day. In other embodiments, the compositions described herein are administered to a patient at a dosing frequency ranging from, but not limited to, once a day, once every 2 days, once every 3 days to once a week, and once every 2 weeks. Those skilled in the art will appreciate that the dosing frequency of the various combination compositions described herein will vary from individual to individual depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, general health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed as being limited to any particular dosing regime, and the exact dosing frequency and composition administered to any patient will be determined by the attending physician taking into account all other factors related to the patient.

[0508] The compounds described herein for administration may be administered in the form of a single dose in the range of about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, or about 2 mg to about 4,000 mg. The amount may be within the range of about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all integer or decimal increments therebetween.

[0509] In some embodiments, the dosage of the compounds described herein is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds described herein used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all integer or fractional increments thereof.

[0510] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second agent, and instructions for using the compound to treat a disease or disorder or reduce one or more symptoms thereof in a patient.

[0511] The preparations can be used in admixture with conventional excipients, i.e., pharma- ceutically acceptable organic or inorganic carrier substances, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable administration mode known in the art.The pharmaceutical preparations may be sterilized, and if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, flavoring substances, and / or aromatic substances.If desired, they may be combined with other effective agents, such as other analgesics.

[0512] The route of administration of any composition described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical.The compound used in the composition described herein can be formulated for administration by any suitable route, for example, oral or parenteral administration, for example, transdermal, transmucosal (e.g. sublingual, intralingual, buccal (buccal), urethral (urethral), intravaginal (e.g. vaginal and perivaginal), intranasal (intranasal), and rectal (rectal)), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0513] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, electuaries, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0514] Oral route For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and these compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to improve appearance or to delay the release of the active ingredient. Oral preparations may be presented as hard gelatin capsules in which the active ingredient and inert diluents are mixed.

[0515] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets can be coated using suitable methods and coating materials, such as the OPADRY™ film coating system available from Colorcon, West Point, Pennsylvania (e.g., OPADRY™ OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY™ White, 32K18400). Liquid formulations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid preparations can be prepared in a conventional manner with pharma- ceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).

[0516] Parenteral Administration For parenteral administration, the compounds described herein can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, which may contain other formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents, can be used.

[0517] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are usually used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0518] Further dosage forms Additional dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Application Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional suitable formulations for use with the compounds and compositions described herein include those described in PCT Application Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0519] Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term release formulations, rapid release formulations, and controlled release formulations, including sustained release formulations, delayed release formulations, and pulsatile release formulations.

[0520] The term sustained release is used in its ordinary sense to refer to a drug formulation that gradually releases drug over an extended period of time and that can, but does not necessarily, result in substantially constant blood levels of drug over an extended period of time, which can be as long as a month or more and should be a longer release than the same amount of agent administered in bolus form.

[0521] For sustained release, the compound can be formulated with suitable polymer or hydrophobic material that provides sustained release to the compound.Therefore, the compound used in the methods described herein can be administered in the form of microparticles, for example, by injection, or in the form of wafer or disk, by implantation.

[0522] In some cases, the dosage form used can be realized as slow release or controlled release of one or more active ingredients in the dosage form, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, or microspheres, or their combinations in various ratios to achieve desired release profile.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use in the pharmaceutical compositions described herein.Therefore, the single unit dosage form suitable for oral administration, such as tablets, capsules, gel capsules, and caplets, which are adapted for controlled release, are included in the compositions and dosage forms described herein.

[0523] Most controlled release formulations have a common goal of improving drug therapy compared to that achieved by the corresponding non-controlled formulation.Ideally, the use of an optimally designed controlled release formulation in medical treatment is characterized by a minimum amount of drug substance used to cure or control a condition in a minimum amount of time.The advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance.In addition, controlled release formulations can be used to affect the onset of action or other characteristics such as blood levels of the drug, and therefore can affect the occurrence of side effects.

[0524] Most controlled release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and then slowly and continuously release other amounts of drug that maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0525] The controlled release of active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled release component" is defined herein as a compound including, but not limited to, a polymer, a polymer matrix, a gel, a permeable membrane, a liposome or a microsphere, or a combination thereof that facilitates the controlled release of active ingredient. In one embodiment, the compound described herein is administered to a patient alone or in combination with another agent using a sustained release formulation. In one embodiment, the compound described herein is administered to a patient alone or in combination with another agent using a sustained release formulation.

[0526] The term delayed release is used herein in its ordinary sense to refer to a drug formulation that provides for initial release of drug after some delay following drug administration, which may include, but is not necessarily, a delay of from about 10 minutes to about 12 hours.

[0527] The term pulsatile release is used herein in its ordinary sense to refer to a drug formulation that provides release of drug in a manner that produces a pulsatile plasma profile of the drug following drug administration.

[0528] The term immediate release is used in its ordinary sense to refer to a drug formulation that provides for release of drug immediately following drug administration.

[0529] Short term, as used herein, means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all integer or fractional increments therein.

[0530] As used herein, rapidly means any period of time up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any and all integer or fractional increments therein.

[0531] Administration The therapeutically effective amount or dose of the compounds described herein depends on the age, sex, and weight of the patient, the patient's current medical condition, and the progression of the disease or disorder in the patient being treated. Those skilled in the art can determine the appropriate dosage depending on these and other factors.

[0532] Suitable doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, e.g., from about 0.1 mg to about 1,000 mg per day, e.g., from about 1 mg to about 500 mg, e.g., from about 5 mg to about 250 mg. Doses can be administered in single or multiple doses, e.g., from 1 to 4 or more times per day. When multiple doses are used, the amount in each dose can be the same or different. For example, a dose of 1 mg per day can be administered as two 0.5 mg doses with an interval of about 12 hours between the doses.

[0533] It will be understood that the amount of compound administered per day can be administered, in non-limiting examples, every day, every other day, every second day, every third day, every fourth day, or every fifth day. For example, for every other day administration, a dose of 5 mg per day can be administered starting on Monday, a first subsequent dose of 5 mg per day can be administered on Wednesday, and a second subsequent dose of 5 mg per day can be administered on Friday.

[0534] If the patient's condition improves, at the physician's discretion, administration of the compounds described herein may continue, or the dose of the drug administered may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary anywhere from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0535] When improvement of the patient's condition occurs, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is then reduced to a level at which improvement in the disease is maintained. In certain embodiments, the patient may require long-term intermittent treatment for any recurrence of symptoms and / or infection.

[0536] The compounds described herein can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage form for a patient to be treated, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily administration, or for one of multiple daily administrations (e.g., about 1-4 or more times per day). When multiple daily administrations are used, the unit dosage form can be the same or different for each administration.

[0537] The toxicity and therapeutic efficacy of the treatment regimen in question are optionally determined in cell culture or experimental animals, and the LD 50 (a dose lethal to 50% of the population) and ED 50These include, but are not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 and ED 50 The data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in humans. The dosages of these compounds are administered at ED 100 mg / kg with minimal toxicity. 50 It is preferred that the dosage form be within a circulating concentration range that includes the active ingredient(s) and ... are within a range of circulating concentrations that include the active ingredient(s). The dosage amount optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0538] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, aspects, claims, and examples described herein. These equivalents are considered to be within the scope of this disclosure and are considered to be covered by the claims appended hereto. For example, it should be understood that within the scope of this application, it is possible to modify reaction conditions, including but not limited to reaction time, reaction size / volume, experimental reagents such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, by art-recognized substitutes and using no more than routine experimentation.

[0539] Wherever values ​​and ranges are recited herein, it should be understood that all values ​​and ranges subsumed within those values ​​and ranges are intended to be encompassed within the scope of the disclosure. Moreover, all values ​​that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0540] The following examples further illustrate aspects of the present disclosure, but do not in any way limit the teachings or disclosure of the present disclosure described herein. EXAMPLES

[0541] Experimental Example The present disclosure will now be described with reference to the following examples, which are presented for illustrative purposes only, and the present disclosure should in no way be construed as being limited to these examples, but rather as encompassing any variations that become evident as a result of the teachings set forth herein.

[0542] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following examples, make and utilize the disclosed compounds, and practice the claimed methods. Thus, the following examples illustrate specific embodiments of the disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

[0543] The materials and methods used in the experiments shown in this Example are described herein in this application.

[0544] 11A-11B show a non-limiting synthesis of the ASGPRBM group.

[0545] Figures 12A-12C show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0546] Figures 13A-13L show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0547] Figures 14A-14O show non-limiting syntheses of specific ASGPRBM groups. Although this example discloses the non-limiting Cbz protecting group, the synthesis may be carried out using any other suitable protecting group known to those skilled in the art. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0548] FIG. 15 shows a non-limiting synthetic scheme that allows for the labeling (derivatization) of an antibody (labeled Ab) with an azide group, where pBpa stands for p-benzoyl-phenylalanine.

[0549] Figure 16 shows a non-limiting synthetic scheme that allows for labeling (derivatization) of CRBM groups with strained alkyne-containing groups. In certain non-limiting embodiments, any azide-containing compound (such as but not limited to those shown in Figure 15) may be reacted with a strained alkyne-containing compound (such as but not limited to those shown in Figure 16) to produce a compound of the present disclosure.

[0550] Numbered Aspects The following numbered aspects are presented, however, the numbering should not be construed as indicating any level of importance. Aspect 1 provides: A compound comprising formula (I) or a salt, geometric isomer, stereoisomer, or solvate thereof: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to an extracellular protein; The CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a degradative cell in a subject, whereby binding of (I) results in endocytosis and degradation of extracellular proteins; each CON is independently a bond or a group that covalently links an Ab to a CRBM, an Ab to a linker, and / or a linker to a CRBM; The linker is a group having a valence in the range of 1 to 15; k' is an integer ranging from 1 to 15; h is an integer ranging from 0 to 15; i is an integer ranging from 0 to 15; h' is an integer ranging from 0 to 15; j is an integer ranging from 1 to 15. Aspect 2 provides: The compound of embodiment 1, wherein the linker has a valency of 1, 2, or 3. Aspect 3 provides: The compound of any one of embodiments 1-2, wherein k′ is 1, 2, or 3. Aspect 4 provides the following: The compound of any one of embodiments 1-3, wherein j is 1, 2, or 3. Aspect 5 provides the following: The compound of any one of embodiments 1-4, wherein h is 1, 2, or 3. Aspect 6 provides the following: The compound of any one of embodiments 1-5, wherein h′ is 1, 2, or 3. Aspect 7 provides the following: The compound of any one of embodiments 1-6, wherein i is 1, 2, or 3. Aspect 8 provides the following: The compound of any one of embodiments 1-7, wherein at least one of h, h', and i is at least 1. Aspect 9 provides the following: The compound of any one of embodiments 1-8, wherein k', j', h, h', and i are each independently 1, 2, or 3. Aspect 10 provides the following: The compound of any one of embodiments 1-9, wherein k' is 1 and j' is 1, 2, or 3. Aspect 11 provides the following: [Ab]-[CON] 0~1 -[Linker]-[CON] 0~1 - The compound of any one of embodiments 1-10, wherein [CRBM] (Ia). Aspect 12 provides the following: The compound of any one of embodiments 1-11, wherein the degradative cells comprise hepatocytes. Aspect 13 provides the following: The compound of any one of embodiments 1-12, wherein the CRBM is a folate receptor binder, a mannose receptor binder, a mannose-6-phosphate (M6P) receptor binder, a low density lipoprotein receptor-related protein 1 (LRP1) receptor binder, a low density lipoprotein receptor (LDLR) binder, an FcγRI receptor binder, a transferrin receptor binder, a macrophage scavenger receptor binder, a G protein-coupled receptor binder, or an asialoglycoprotein receptor (ASGPR) binder. Aspect 14 provides the following: The compound of any one of embodiments 1-13, wherein the CRBM is: (a) a folate receptor binder comprising at least one of folic acid, methotrexate, pemetrexed, or a biologically active fragment thereof; (b) a mannose receptor binder comprising at least one of the following: TIFF2025509733000367.tif18128 (wherein X is S or O and R is TIFF2025509733000368.tif16128, where 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); and Polymer molecules shown in Figures 1 to 7; (c) a mannose-6-phosphate (M6P) receptor binder comprising at least one of the following: TIFF2025509733000369.tif17128 (wherein X is O or S, and R 1 teeth, TIFF2025509733000370.tif48128; R 2 teeth, TIFF2025509733000371.tif38128, where 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); The polymer molecule shown in Figure 8; below Compounds selected from TIFF2025509733000372.tif106128; below Compounds selected from TIFF2025509733000373.tif121128; (d) a low density lipoprotein receptor-related protein 1 (LRP1) receptor binder comprising at least one amino acid sequence of SEQ ID NOs: 1-9; (e) a low density lipoprotein receptor (LDLR) binder comprising at least one amino acid sequence of SEQ ID NO:10-35; (f) an FcγRI receptor binder comprising at least one amino acid sequence of SEQ ID NO:36-52; (g) a transferrin receptor binder comprising at least one amino acid sequence of SEQ ID NOs:53-59 and 67; (h) a macrophage scavenger receptor binder comprising at least one amino acid sequence of SEQ ID NO:60-65; (i) less than or equal to TIFF2025509733000374.tif33128, wherein each occurrence of R is independently H or C1-C6 alkyl; (j) an asialoglycoprotein receptor (ASGPR) binder, comprising: TIFF2025509733000375.tif22128 (in the formula, X is a linker 1 to 4 atoms in length, and If X is a linker one atom long, X can be O, S, N(R N1 ), or C(R N1 )(R N1 ) and If X is a linker two atoms long, not more than one atom of X may be O, S, or N(R N1 ) and When X is a linker three or four atoms in length, no more than two atoms of X are independently O, S, or N(R N1 ) As such, O, S, N(R N1 ), or C(R N1 )(R N1 ) group, Here, R N1 each occurrence is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R 1 and R 3 are each independently H, -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, -(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (Alkynyl), -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; or R 1 and R 3 are each independently Ph(CH2) K-, which is optionally substituted with 1-3 independently selected halogens; C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or C1-C4 alkoxy optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or R 1 and R 3 each independently has the following structure: -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 Based on During the ceremony, R 7 is a C1-C4 alkoxy optionally substituted with 1 to 3 independently selected halogens and / or 1 to 2 hydroxy groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2; K is 0, 1, 2, 3, or 4; K' is 1, 2, 3, or 4; R N3 each occurrence is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N4 each occurrence is independently H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, or Ph-(CH2) K -is; or R 1 and R 3 are each independently TIFF2025509733000376.tif25128, wherein CYC is selected from the group consisting of TIFF2025509733000377.tif103132; During the ceremony, The bond shown in TIFF2025509733000378.tif2128 is -(CH2) K indicates the site on CYC where the link is made; L 1 is a bond, -linker, -CON-linker, or -CON-linker-CON; R C is absent, H, C1-C4 alkyl optionally substituted with 1-3 optionally substituted halogens and / or 1-2 hydroxyl groups, or the following structure: Based on TIFF2025509733000379.tif57128, During the ceremony, R 4 , R 5 , and R 6 are independently H, F, Cl, Br, I, CN, or NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1 to 3 independently selected halogens, C1-C3 alkoxy optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens, or -C(=O)-(C1-C4 alkyl) optionally substituted with 1-3 independently selected halogens; R N each occurrence is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; R N2 each occurrence of is independently H, or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups; or R 1 and R 3 are each independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocycle is -L 1 and -R C is further substituted with; R 2 Ha-(CH2) K -N(R N1 )-C(=O)R AM where: R AM is H, C1-C4 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) K -NR N3 R N4 or R 2 teeth TIFF2025509733000380.tif15128, wherein R TA H, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1 to 3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens 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; or R TA is C3~C 10 an aryl group or a 3- to 10-membered heteroaryl group containing 1 to 5 non-carbon ring atoms, each of which is selected from the group consisting of CN, NR N1 R N2 , -(CH2) K OH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups, -(C1-C3-alkoxy) optionally substituted with 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted with 1 to 3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted with 1 to 3 independently selected halogens, or -(CH2) optionally substituted with 1 to 3 independently selected halogens. K C(=O)-(C1-C4 alkyl), or R TA teeth TIFF2025509733000381.tif44128, which is optionally substituted with 1 to 3 C1-C3 alkyl groups, each of which is optionally substituted with 1 to 3 independently selected halogens; or R TA teeth TIFF2025509733000382.tif26128, wherein each -(CH2) K The group is optionally substituted with 1 to 4 C1 to C3 alkyl groups, which may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups. Aspect 15 provides the following: If X is two atoms long, then X in the ASGPRBM is -OC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-S-, -N(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-N(R N1 )-, or -C(R N1 )(R N1 )-C(R N1 )(R N1 )-is; If X is 3 atoms long, then X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(RN1 )(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 ) or If X is four atoms long, then X in the ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-, -SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1)-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, -C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-, -N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, or -C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-is, A compound according to any one of embodiments 1 to 14. Aspect 16 provides the following: X is OCH2 and R N1 is H, or X is CHO and R N1 The compound of any one of embodiments 1-15, wherein Aspect 17 provides the following: ASGPRBM has the following structure: 17. The compound of any one of embodiments 14-16, comprising TIFF2025509733000383.tif20128. Aspect 18 provides the following: A compound of any one of embodiments 14-17, wherein the ASGPRBM group comprises: TIFF2025509733000384.tif71128 (in the formula, R A is a C1-C3 alkyl optionally substituted with 1 to 5 independently selected halogens; Z A Ha-(CH2) IM -, -O-(CH2) IM -, -S-(CH2) IM -, -NR M -(CH2) IM -, -C(=O)-(CH2) IM -, a PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH2) IM NR M - and Z B is absent, -(CH2) IM -, -C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M - and R M is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups; each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6); TIFF2025509733000385.tif90136TIFF2025509733000386.tif195111 (where R = CH3, CF3, or CH2CF3); TIFF2025509733000387.tif237139TIFF2025509733000388.tif113143. Aspect 19 provides the following: The compound of any one of embodiments 1-18, wherein the linker is a polyethylene glycol-containing linker having 1-12 ethylene glycol residues. Aspect 20 provides the following: The linker has the following structure: -CH2CH2(OCH2CH2) m OCH2-, -(CH2) m CH2-, -[N(R a )-CH(R b )(C=O)] m - or a polypropylene glycol group or a polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units, Each R a are independently H, C1-C3 alkyl, or C1-C6 alkanol, or R b together with to form a pyrrolidine or hydroxypyrroline group; Each R b is independently selected from the group consisting of hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole, or -(CH2)phenol; m is an integer ranging from 1 to 15; or The linker has the following structure: -[N(R ' -(CH2) 1~15 -C(=O)]- (wherein R' is H or C1-C3 alkyl optionally substituted with 1-2 hydroxyl groups, and m is an integer ranging from 1 to 100). contains; or The linker has the following structure: -ZD-Z'- (In the formula, Z and Z' are each independently a bond; TIFF2025509733000389.tif16148; each R is independently H, C1-C3 alkyl, or C1-C6 alkanol; Each R 2 is independently H or C1-C3 alkyl; each Y is independently a bond, O, S, or N(R); each i is independently between 0 and 100; D is a bond, -(CH2) i-YC(=O)-Y-(CH2) i -, -(CH2) m' - or -[(CH2) n -X1)] j - with the proviso that Z, Z', and D are not each simultaneously a bond; X 1 is O, S, or N(R); j is an integer ranging from 1 to 100; m' is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100. contains; or The linker has the following structure: -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n' CH2CH2- or -(CH2CH2CH2O) n - (wherein each n and n' is independently an integer ranging from 1 to 25). contains; or The linker has the following structure: -PEG-CON-PEG- wherein each PEG is independently a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and CON is a triazole group. TIFF2025509733000390.tif13128) Including, The compound of any one of embodiments 1 to 19. Aspect 21 provides the following: CON has the following structure: TIFF2025509733000391.tif79144 (wherein R' and R'' are each independently H, methyl, or a bond). contains; or CON has the following structure: -C(=O)-N(R 1 )-(CH2) n'' -N(R 1 )C(=O)-, -N(R 1)-C(=O)(CH2) n'' -C(=O)N(R 1 )-,or -N(R 1 )-C(=O)(CH2) n'' -N(R 1 )C(=O)- (In the formula, each R 1 is independently H or C1-C3 alkyl, and n'' is independently an integer from 0 to 8, in certain embodiments from 1 to 7, and in certain embodiments, 1, 2, 3, 4, 5, or 6. contains; or CON has the following structure: TIFF2025509733000392.tif13128 (in the formula, R 1a , R 2a , and R 3a are each independently H, -(CH2) M1 -, -(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -, -(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 - or -(CH2) M2 O-(CH2) M1 -C(O)NR 4 -, where R 1a , R 2a , and R 3a but not simultaneously H; each M1 is independently 1, 2, 3, or 4; each M2 is independently 0, 1, 2, 3, or 4; each M3 is independently 0 or 1; Each R 4 are independently H, C1-C3 alkyl, C1-C6 alkanol, or -C(=O)(C1-C3 alkyl), provided that the same R 1a , R 2a , and R 3a (M2 and M3 in the contains; or CON has the following structure: Including TIFF2025509733000393.tif42128, The compound of any one of embodiments 1 to 20. Aspect 22 provides the following: Extracellular proteins include 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide α, Canis lupus familiaris IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clumping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli (E.coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, episialin, FGF 23, fibrin II, beta chain, fibronectin extra domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon gamma, interferon Ron gamma-inducing protein, interleukin 1α, interleukin 13, interleukin 17α, interleukin 17α, TNF, interleukin 17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch 22. The compound of any one of embodiments 1-21, comprising: 1, NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, tectal plate specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus alpha toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A, and Ang-2, VEGFA, or VWF. Aspect 23 provides the following: The compound of any one of embodiments 1-22, wherein Ab is a monoclonal antibody. Aspect 24 provides the following: The antibody is selected from the group consisting of abagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, afelimomab, alirocumab, altumomab, and altumomab pentetate. pentetate, Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Biciromab, Bimetazumab, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine, Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumab pegol, Cibisatamab, Clazakizumab, Clivatuzumab, Clivatuzumab tetraxetanTetraxetan, Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab-alitox Aritox, Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomab-sitaxetan cituxetan, Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Firivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Furunevetomab Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, IndatuximabRavtansine, Infliximab, Istiratumab, Ixekizumab, Labetuzumab, Lacnotuzumab, Lampalizumab, Lanadelumab, Landogrozumab, Lebrikizumab, Remalesomab, Lendalizumab, Lenzilumab, Lerdelimumab Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab butafenatox Tafenatox, Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab Merpentanemerpentan, obiltoxaximab, oleclumab, olendalizumab, olokizumab, omalizumab, OMS, onartuzumab, olegovomab, orticumab, otilimab, ozanezumab, ozoralizumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, pemtumomab, perakizumab, pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab b), Raxibacumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab govitecan govitecan, Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab vedotinvedotin, solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvratoxumab, tabalumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritoxumab 24. The compound of any one of embodiments 1-23, comprising: aritox, Tesidolumab, Tezepelumab, Tiburizumab, Tildrakizumab, Timolumab, Tisotumab, Tisotumab vedotin, Tralokinumab, Trevogrumab, Urtoxazumab, Ustekinumab, Vanucizumab, Vapaliximab, Varisacumab, Vepalimomab, Vesencumab, Vobarilizumab, Bunakizumab, or Xentuzumab. Aspect 25 provides the following: A pharmaceutical composition comprising at least one pharma- ceutically acceptable excipient and at least one compound according to any one of embodiments 1-24. Aspect 26 provides the following: The pharmaceutical composition of embodiment 25, further comprising another therapeutically active compound. Aspect 27 provides the following: TIFF2025509733000394.tif119137TIFF2025509733000395.tif205142TIFF2025509733000396.tif185141TIFF2025509733000397.tif148140TIFF2025509733000398.tif156138TIFF2025509733000399.tif175136TIFF2025509733000400.tif218140TIFF2025509733000401.tif198141, or a salt, stereoisomer, or solvate thereof. Aspect 28 provides the following: The formula: TIFF2025509733000402.tif183128TIFF2025509733000403.tif219130TIFF2025509733000404.tif177128TIFF2025509733000405.tif202131TIF F2025509733000406.tif224124TIFF2025509733000407.tif201138TIFF2025509733000408.tif198132TIFF2025509733000409.tif168139TIFF20 25509733000410.tif196131TIFF2025509733000411.tif210130TIFF2025509733000412.tif218129TIFF2025509733000413.tif206138TIFF2025509733000414.tif191130TIFF2025509733000415.tif166140TIFF2025509733000416.tif73128, or a pharma- ceutically acceptable salt thereof. During the ceremony, An extracellular protein targeting ligand is a circulating protein binding moiety [CPBM] that binds to a circulating protein in a subject, where the circulating protein mediates a disease state or condition and is to be cleared by the action of hepatocytes or other cells of the subject; X 1 is O, S, N(R 6 ), and C(R 4 )(R 4 ) independently selected from 1 to 5 groups, 1 When is one group, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1 When there are two groups, X 1 Not more than one group in 6 ) and X 1 When X has 3, 4, or 5 groups, 1 Up to two groups in 6 ) and; R 2 teeth (i) aryl, heterocycle, and heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, each of the aryl, heterocycle, and heteroaryl being optionally substituted with 1, 2, 3, or 4 substituents; (ii) TIFF2025509733000417.tif31128; (iii) -NR, each of which is optionally substituted with 1, 2, 3, or 4 substituents. 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)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ; and (iv) hydrogen, R 10 , alkyl-C(O)-R3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 More selected; R 10 is aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl with 1, 2 or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 , alkyl-NR 6 R 8 , N.R. 8 -NR 6 -C(O)R 3 , N.R. 8 -S(O)2-R 3 , alkenyl, aryl, alkynyl, -NR 6 -Alkenyl, -O-Alkenyl, -NR 6 -Alkynyl, -NR 6 -heteroaryl, -NR 6 -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl; R 10 each of which is optionally substituted with 1, 2, 3, or 4 substituents; R 1 and R 5 are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -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 alkylN3, 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), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 More selected; R 4 is independently at each occurrence hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, 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 More selected; R 6 and R 7 is independently at each occurrence hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; The ring is a 3- to 8-membered fused ring group optionally substituted with 1, 2, 3, or 4 substituents; Each linker A is a bond or a linker connecting the ASGPR ligand B is a moiety that covalently links to; Linker B is a bond or a linker A a moiety that covalently links the to an extracellular protein targeting ligand; Linker C Each linker A is a chemical group that links the to an extracellular protein targeting ligand; Linker D Each linker A is a chemical group that links the to an extracellular protein targeting ligand; Here, R 2 NR 6 -Alkenyl, -NR 6 -Alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl, or -NR 6 -aryl, then the extracellular protein targeting ligand does not comprise an oligonucleotide; The optional substituents, where valences permit, may be any group that results in a stable compound, such as alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 , F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , Selected from TIFF2025509733000418.tif14128. Aspect 29 provides the following: A method for treating, ameliorating, and / or preventing a disease or disorder in a subject, comprising administering a therapeutically effective amount of at least one compound of any one of embodiments 1-24 and 27-29, and / or at least one pharmaceutical composition of any one of embodiments 25-26. Aspect 30 provides the following: The method of embodiment 29, wherein the disease or disorder comprises an autoimmune disease, cancer, or inflammation. Aspect 31 provides the following: Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoproliferative syndrome (AML), and autoimmune thyroiditis (AD). Globulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful adiposity, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatism, Parry-Romberg syndrome, Parsonage-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, Barrault concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, childhood autoimmune streptococcal-associated neuropsychiatric disorder (PANDAS), progressive Diachronic inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),The method of embodiment 30, comprising IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immune deficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immune deficiency, or pyoderma gangrenosum. Aspect 32 provides the following: 31. The method of embodiment 30, wherein the cancer comprises prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, or lymphoma. Aspect 33 provides the following: The method of embodiment 30, wherein the inflammation comprises inflammatory neurodegenerative diseases, immune response diseases causing inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes (type I and type II), pancreatic beta cell death and related hyperglycemic disorders, liver disease, kidney disease, cardiovascular disease, muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis. Aspect 34 provides the following: The method of any one of embodiments 29-33, wherein at least one additional therapeutic agent that treats or prevents said disease or disorder is further administered to the subject. Embodiment 35 provides the following: The method of any one of embodiments 29 to 34, wherein the subject is a mammal. Aspect 36 provides the following: The method of any one of embodiments 29 to 35, wherein the subject is a human. Aspect 37 provides the following: A method of treating, preventing or preventing an autoimmune disease, cancer or inflammation, comprising administering a composition comprising a therapeutically effective amount of at least one compound of claim 27 or 28 and at least one pharma- ceutically acceptable carrier or excipient; Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoproliferative syndrome (AML), and autoimmune thyroiditis (AD). Globulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful adiposity, adult Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatism, Parry-Romberg syndrome, Parsonage-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, Barrault concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran syndrome, childhood autoimmune streptococcal-associated neuropsychiatric disorder (PANDAS), progressive Diachronic inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, lignified conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),including IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum; Cancer includes prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, renal cancer, or lymphoma; The method, wherein the inflammation comprises inflammatory neurodegenerative diseases, immune response disorders causing inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes (type I and type II), pancreatic beta cell death and related hyperglycemic disorders, liver disease, kidney disease, cardiovascular disease, muscle degeneration and muscle atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis.

[0551] The disclosures of all patents, patent applications, and publications cited in this specification are incorporated herein by reference in their entirety. Although the present disclosure has been disclosed with reference to certain embodiments, it is clear that those skilled in the art can devise other embodiments and variations of the present disclosure without departing from the spirit and scope of the present disclosure. The appended claims are intended to be interpreted to include all such embodiments and equivalent variations.

Claims

1. Compounds with the following chemical formulas, or their salts, geometric isomers, stereoisomers, or solvates: [Ab] k' -[CON] h -[Linker] i -[CON] h' -[CRBM] j' (I) During the ceremony, Ab is an antibody that binds to extracellular proteins. CRBM is a cell receptor binding portion that binds to at least one receptor on the surface of a degradable cell in question, and the binding of (I) by it leads to endocytosis and degradation of extracellular proteins. Each CON is independently a bond, or a group that covalently links Ab to CRBM, Ab to a linker, and / or a linker to CRBM. A linker is a group having a valency in the range of 1 to 15. k' is an integer in the range of 1 to 15. h is an integer in the range of 0 to 15. i is an integer in the range of 0 to 15. h' is an integer in the range of 0 to 15. j is an integer in the range of 1 to 15; Here, the compound is Or selected from the group consisting of those pharmaceutically acceptable salts, During the ceremony, Extracellular protein targeting ligands are antibodies (Abs) that bind to extracellular proteins; X 1 is one to five groups independently selected from O, S, N(R 6 ), and C(R 4 )(R 4 ), where when X 1 is one group, X 1 is O, S, N(R 6 ), or C(R 4 )(R 4 ), and when X 1 is two groups, one or less of the groups of X 1 is O, S, or N(R 6 ), and when X 1 is three, four, or five groups, two or less of the groups of X 1 is O, S, or N(R 6 ); R 2 teeth, (i) Heteroaryls comprising an aryl, a heterocyclic, and one or two heteroatoms independently selected from N, O, and S, where each of the aryl, heterocyclic, and heteroaryl may be substituted with one, two, three, or four substituents; (ii) ; (iii) Each may be substituted with one, two, three, or four substituents, -NR 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 ) 2 , -NR 8 C(O)NR 9 S(O) 2 R 3 , -NR 8 -S(O) 2 -R 10 , and -NR 8 -C(NR 6 )-R 3 ; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8 -C(O)R 10 More selected; R 10 These are aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 Alkyl-NR 6 R 8 , NR 8 -NR 6 -C(O)R 3 , NR 8 -S(O) 2 R 3 , alkenyl, allyl, alkinyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, R 10 Each of these may be substituted with one, two, three, or four substituents; R 1 and R 5 are independently hydrogen, heteroalkyl, C 0 -C 6 -alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C 0 -C 6 -alkyl-OR 6 、C 0 -C 6 -alkyl-SR 6 、C 0 -C 6 -alkyl-NR 6 R 7 、C 0 -C 6 -alkyl-C(O)R 3 、C 0 -C 6 -alkyl-S(O)R 3 、C 0 -C 6 -alkyl-C(S)R 3 、C 0 -C 6 -alkyl-S(O) 2 R 3 、C 0 -C 6 -alkyl-N(R 8 )-C(O)R 3 、C 0 -C 6 -alkyl-N(R 8 )-S(O)R 3 、C 0 -C 6 -alkyl-N(R 8 )-C(S)R<000,0102>、C 0 -C 6 -alkyl-N(R 8 )-S(O) 2 R 3 、C 0 -C 6 -alkyl-O-C(O)R 3 、C 0 -C 6 -alkyl-O-S(O)R 3 、C 0 ~C 6 Alkyl-OC(S)R 3 -N=S(O)(R 3 ) 2 , C 0 ~C 6 Alkyl N 3 , and C 0 ~C 6 Alkyl-OS(O) 2 R 3 More selections may be made, each of which may be substituted with one, two, three, or four substituents; R 3 Each instance independently produces hydrogen, alkyl, heteroalkyl, and haloalkyl (-CF). 3 , -CHF 2 ,-CH 2 F, -CH 2 CF 3 ,-CH 2 CH 2 F and -CF 2 CF 3 (including), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 8 , and -NR 8 R 9 More selected; R 4 Each of these independently appears as hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 6 and R 7 Each of these independently appears as hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O) 2 R 3 More selected; R 8 and R 9 Each instance is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic; The ring is a 3- to 8-membered fused cyclic group which may be substituted with one, two, three, or four substituents; Each linker A This is either binding to or linking the ASGPR ligand. B It is the part that is covalently connected to it; Linker B This is either a binding or a portion that covalently links linker A to an extracellular protein targeting ligand; Linker C Each linker A It is a chemical group that links to an extracellular protein targeting ligand; and Linker D Each linker A It is a chemical group that links to an extracellular protein targeting ligand; and Here, R 2 NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O) 2 -Alkenyl, -NR 8 -S(O) 2 -alkynyl, -NR 6 -heteroaryl, or -NR 6 -If it is an aryl, the extracellular protein targeting ligand does not contain an oligonucleotide; and The optional substituents can be alkyl, alkenyl, alkynyl, haloalkyl, or -OR, as long as their valence is acceptable, to obtain a stable compound. 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , More likely to be selected.

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

2. .

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

3. .

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

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

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

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

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

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

10. Extracellular proteins include 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, α-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide α, canine (Canis lupus familiaris) IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, clamping factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, and Escherichia coli (E. coli).E. coli Shiga toxin type 1, E. coli Shiga toxin type 2, EGFL7, endotoxin, epicyalin, FGF 23, fibrin II, β chain, fibronectin extradomain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth and differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human β-amyloid, human cell dispersion factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgE Fc region, IGF1, IGF2, IGHE, IL 17A, IL 17A and IL 17F, IL 20, IL-1, IL-12, IL-23, IL-13, IL-17, IL-1β, IL-22, IL-4, IL-5, IL-6, IL17A and IL17F, IL1A, IL2, IL23, IL23A, IL31RA, IL6, IL6R, IL9, ILGF2, influenza A hemagglutinin, influenza A virus hemagglutinin, influenza A virus hemagglutinin HA, interferon γ, interferon Ron-γ-inducing protein, interleukin-1α, interleukin-13, interleukin-17α, interleukin-17α, TNF, interleukin-17A, kallikrein, LOXL2, LRRC15, LTA, MASP-2, MCP-1, MIF, MST1R (also known as RON), MUC1, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, Notch The compound according to claim 1, which is NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, lid-specific spongein 3, RTN4, sclerostin, SDC1, serum amyloid A protein, serum amyloid P component, SOST, Staphylococcus aureus α toxin, tau protein, TFPI, TGFβ1, TGFβ2, TGF-β, TNF-α, TROP-2, TSLP, VEGF-A, VEGF-A and Ang-2, VEGFA, or VWF.

11. The compound according to claim 1, wherein Ab is a monoclonal antibody.

12. The antibodies include avagovomab, abrezekimab, adalimumab, aducanumab, afasevikumab, aferimomab, alirocumab, altumomab, and altumomab pentetate. pentetate), andecaliximab, anrukinzumab, alsitumomab, ascrinvacumab, atezolizumab, atidortoxumab, atinumab, avelumab, bapineuzumab, bavituximab, belimumab, bermekimab, besilesomab, bevacizumab, bicilomab, bime Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumabrabutansine ravtansine), caplacizumab, carlumab, cergutuzumab, cergutuzumab amunaleukin, certolizumab, certolizumab pegol, cibisatamab, clazakizumab, cribatuzumab, cribatuzumab tetraxetantetraxetan), concizumab, crenezumab, dectrekumab, denosumab, dezamizumab, diridavumab, domagrozumab, dorlimomab, dorlimomab aritox aritox), durvalumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, elezanumab, elsilimomab, emactuzumab, emapalumab, emicizumab, enokizumab, epitumomab, epitumomab situxetan cituxetan), eptinezumab, erenumab, evinacumab, evolocumab, faricimab, facinumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, fontrizumab, fremanezumab, fresolimumab, phlovocimab, flunebetomab ( Frunevetmab, Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gebokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, Indatuximab tansineravtansine), infliximab, istiratumab, ixekizumab, rabetsumab, lacnotuzumab, lampalizumab, lanadelumab, landogrozumab, lebrikizumab, lemalesomab, lensalizumab, lensilumab, reldelimumab ( Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomabutafenatox Tafenatox), Namilumab, Narnatumab, Navivumab, Naxitamab, Nevacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomab merpentanMerpentan), Obiltoxaximab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, OMS, Onartuzumab, Olegobomab, Orticumab, Otilimab, Ozanezumab, Ozoralizumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Pemtumomab, Perakizumab, Pexelizumab, Placulumab, ponezumab, prasinezumab, pritoxaximab, quilizumab, radretumab, ralpancizumab, ranevetmab, ranibizumab, ravulizumab b) Laxibakumab, REGN-EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab-Govitecan govitecan), Samrotamab, Samrotamab vedotin, Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Silkumab, Sofituzumab, Sofituzumab, Sofituzumab vedotinVedotin), solanezumab, sontuzumab, stamulumab, sulesomab, sutimlimab, suvizumab, supratoxumab, tabarumab, tacatuzumab, tacatuzumab tetraxetan, talizumab, tanezumab, tefibazumab, telimomab, telimomab aritox The compound according to claim 1, which is aritox, tesidolumab, tezeperumab, tibrizumab, tildrakizumab, timolumab, tisotumab, tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, bapariximab, valisacumab, bepalimomab, besencumab, vobarilizumab, vunakizumab, or xentuzumab.

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

14. The pharmaceutical composition according to claim 13, further comprising a further therapeutically active compound.

15. A pharmaceutical composition for treating, relieving, and / or preventing a disease or disorder in a subject, comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 12.

16. The pharmaceutical composition according to claim 15, wherein the disease or disorder includes autoimmune disease, cancer, or inflammation.

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

18. The pharmaceutical composition according to claim 16, wherein the cancer includes prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, or lymphoma.

19. The pharmaceutical composition according to claim 16, wherein the inflammation comprises inflammatory neurodegenerative diseases, immunocompromised immune response diseases that cause inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes mellitus (type I and type II), pancreatic β-cell death and associated hyperglycemic disorders, liver diseases, kidney diseases, cardiovascular diseases, muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis.

20. The pharmaceutical composition according to claim 15, administered to a subject in combination with at least one additional therapeutic agent for treating, relieving, and / or preventing the aforementioned disease or disorder.

21. The pharmaceutical composition according to claim 15, wherein the target is a mammal.

22. The pharmaceutical composition according to claim 15, wherein the target is human.

23. A pharmaceutical composition for treating, relieving, and / or preventing an autoimmune disease, cancer, or inflammation, comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 12 and at least one pharmaceutically acceptable carrier or excipient, Autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, and essential mixed cryoplasmosis. Globulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult Still's disease, ankylosing spondylitis, Crest syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, Undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenia dysthesia, multiple sclerosis, pattern II, Oshtoran syndrome, childhood autoimmune streptococcal neuropsychiatric disorders (PANDAS), Inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mollen's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA),This includes IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency disorders, or pyoderma gangrenosum; Cancer includes prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, or lymphoma; and Inflammation is a symptom of inflammatory neurodegenerative diseases, immunocompromised immune response disorders that cause inflammation, chronic inflammatory diseases, hyperglycemic disorders, diabetes mellitus (type 1 and type 2), pancreatic β-cell death and associated hyperglycemic disorders, liver diseases, kidney diseases, cardiovascular diseases, muscle degeneration and muscular atrophy, mild inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury, or arteriosclerosis. Pharmaceutical composition.

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