Engineered antibodies through cell receptors as molecular degradation agents

Abstract

In one aspect, the present disclosure provides bifunctional compounds useful for promoting or enhancing degradation of certain circulating proteins. In certain embodiments, circulating proteins mediate a disease and / or disorder in a subject, while treating or managing the disease and / or disorder entails degradation, clearance, or reduced concentration of circulating proteins in the subject. Thus, in certain embodiments, administration of a compound of the present disclosure to a subject clears circulating proteins or reduces the circulating concentration of circulating proteins, thereby treating, ameliorating or preventing a disease and / or disorder.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Application No. 17 / 654,984, filed on March 15, 2022, which is incorporated herein by reference in its entirety.

[0003] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0004] This invention was made with government support under grant GM067543 from the National Institutes of Health. The government has certain rights in this invention.

[0005] Materials submitted as text files via the Office Electronic Filing System are incorporated by reference

[0006] The present invention contains one or more sequences in a computer-readable format in the accompanying text file entitled "047162-7249WO2_sequence_listing.xml", which is 114.2KB in size, created on March 14, 2022, the contents of which are incorporated herein by reference in their entirety. Background Art

[0007] One of the mechanisms regulating 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 this specific ligand) present outside the cell - this ligand may be a small molecule, metabolite, hormone, protein or even a virus. The binding process triggers 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, and the receptor is either degraded together with the ligand cargo bound to it, or the receptor is recycled to the cell surface for further harvesting of circulating ligands.

[0008] A type of such receptor is the asialoglycoprotein receptor (ASGPR). This receptor is a C-type lectin whose primary biological role is to bind, internalize, and subsequently remove glycoproteins (asialoglycoproteins) containing terminal galactose or N-acetylgalactosamine residues from the circulation. ASGPR removes target glycoproteins from the circulation by endocytosis and subsequent lysosomal degradation. ASGPR is highly expressed on the surface of hepatocytes, several human cancer cell lines, and hepatocarcinomas, and is also weakly expressed in the glandular cells of the gallbladder and stomach. It is known that these receptors are involved in the removal of IgG subtypes and other antibody isotypes from the circulation, the removal of apoptotic cells, the removal of low-density lipoproteins (LDL) and chylomicron remnants, and the processing of cellular fibronectin.

[0009] There is a need in the art for novel compounds and methods for inhibiting, clearing and / or degrading certain extracellular proteins that mediate disease and / or disorders in a subject. The present disclosure addresses this need. Summary of the invention

[0010] The present invention provides a compound comprising formula (I), or a salt, geometric isomer, stereoisomer or solvate thereof:

[0011] [Ab] k' —[CON] h —[Linking group] i —[CON] h' —[CRBM] j’ (I)

[0012] wherein Ab, CON, linker, CRBM, k', h, i, h' and j' are defined elsewhere herein.

[0013] The present disclosure further provides pharmaceutical compositions comprising at least one compound contemplated herein and at least one pharmaceutically acceptable excipient.

[0014] The present disclosure further provides methods of treating a disease or disorder in a subject, the methods comprising administering a therapeutically effective amount of at least one compound contemplated herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The drawings generally illustrate, by way of example and not by way of limitation, various embodiments of the present application.

[0016] As used herein, the term "REAG" refers to any agent including -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.

[0017] Figure 1 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0018] Figure 2 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0019] Figure 3 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0020] Figure 4 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0021] Figure 5Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0022] Figure 6 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0023] Figure 7 Non-limiting preparations of compounds of the disclosure comprising mannose receptor binding agents are shown.

[0024] Figure 8 A non-limiting preparation of a polymeric compound comprising a mannose-6-phosphate receptor binding agent is shown.

[0025] Fig. 9 shows that the ASGPRBM R 1 and / or R 3 Non-limiting examples of groups.

[0026] Fig.10 shows that the ASGPRBM R 2 Non-limiting examples of groups.

[0027] Figures 11A-11B A non-limiting synthesis of the ASGPRBM group is shown.

[0028] Figures 12A-12C The non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses a non-limiting Cbz protecting group, but any other suitable protecting group known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0029] Figures 13A-13L The non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses a non-limiting Cbz protecting group, but any other suitable protecting group known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0030] Figures 14A-14O The non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses a non-limiting Cbz protecting group, but any other suitable protecting group known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[0031] Fig.15 A non-limiting synthetic scheme that allows for labeling (derivatization) of antibodies (labeled Ab) with azide groups is shown.

[0032] Fig.16A non-limiting synthetic scheme that allows for labeling (derivatization) of CRBM groups with strained alkyne groups is shown. In certain non-limiting embodiments, any azide-containing compound (such as, but not limited to, Fig.15 ) can be combined with cycloalkyne-containing compounds (such as but not limited to Fig.16 ) to produce the compounds disclosed herein. DETAILED DESCRIPTION

[0033] In one aspect, the present disclosure provides bifunctional compounds that can be used to promote or enhance the degradation of extracellular proteins (e.g., which can be circulating proteins and / or cell surface proteins that can be attached to or embedded in cell membranes). In certain embodiments, extracellular proteins mediate diseases and / or disorders in subjects, and the treatment or management of diseases and / or disorders requires degradation, removal, or reduction in concentration of extracellular proteins in subjects. Therefore, in certain embodiments, administering compounds of the present disclosure to subjects removes extracellular proteins and / or reduces the circulating concentration of extracellular proteins, thereby treating, ameliorating, or preventing diseases and / or disorders in subjects.

[0034] In certain embodiments, the compounds of the present disclosure include antibodies, such as but not limited to monoclonal antibodies, which can bind 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 small molecules) that binds to a cell receptor, whereby the binding results in endocytosis of the compound (and / or the extracellular protein-compound complex). The receptor binding agent and the antibody can be connected by a linking group such as polyethylene glycol (PEG), any other length-adjustable linking group described herein, or other linking groups described herein and containing one or more linker molecules, which are referred to as CON herein. The conjugation of the antibody to the linker molecule can be achieved using any chemical method known to those skilled in the art, such as but not limited to lysine bioconjugation using activated esters such as NHS esters. Once the extracellular protein-compound complex undergoes endocytosis, the extracellular protein will eventually degrade, and the compound may be degraded or recycled outside the cell.

[0035] In certain embodiments, the receptor is the hepatocyte asialoglycoprotein receptor (ASGPR). In this case, the binding moiety is referred to herein as an ASGPR binding moiety or ASGPRBM. The present disclosure is not limited to receptors, but contemplates the use of other receptors described herein or any other endocytic receptor known in the art.

[0036] Furthermore, the present disclosure is not limited to degradation performed in hepatocytes. Rather, the present disclosure contemplates that non-hepatocytes in vivo display certain degradation receptors, and those receptors are contemplated within the present disclosure.

[0037] In one aspect, the compounds of the present disclosure bind to an extracellular target protein and cause it to be cleared from the circulation (and from the body) in vivo by the liver. Thus, the compounds of the present disclosure utilize the body's own machinery to degrade proteins. Without wishing to be bound by any theory, the compounds of the present disclosure bind to certain receptors located in certain cells, such as but not limited to liver cells, such as but not limited to ASGPR. This binding triggers degradation of the protein target by endolysosomal proteolysis. Due to this mechanism, the circulating levels of the extracellular protein target are reduced. As a result, the corresponding disease symptoms are reduced and / or eliminated from the subject to whom the compounds of the present invention are administered.

[0038] ASPGR has the function of clearing sialic acid glycoproteins with exposed non-reducing D-galactose (Gal) or N-acetylgalactosamine (GalNac) as terminal groups. The expression level of ASGPR in each hepatocyte is about 500,000, and its presence in other parts of the body is extremely low. The internalization half-life of ASGPR for target glycoproteins is about 3 minutes. The bifunctional compound claimed in the present invention selectively binds to extracellular proteins through the antibody part of the compound, thereby forming a protein complex. When this protein complex reaches the liver, the asialoglycoprotein receptor binding part (ASGPRBM) of the molecule is engaged by the terminal lysosomal pathway of the hepatocyte through ASGPR. Endosomally bound ASPGR releases extracellular protein ligands at pH 5.4, and the ligands are eliminated from the circulation by hepatocytes. However, ASPGR is still available for recycling, it is not degraded by lysosomes, and buds into the recycled endosomes. In fact, it can be recycled up to about 200 times, with a recovery rate of about 15-20 minutes, depending on the cell line. ASPGR has a very promiscuous ligand size requirement, most likely reaching a diameter of about 70nm. In comparison, the diameter of an IgM pentamer is about 20nm, so it meets the ligand size requirement for ASPGR.

[0039] The disclosures of International Patent Application No. PCT / US2019 / 026260, filed on April 8, 2019 (and published as WO 2019 / 199634 on October 17, 2019), and International Patent Application No. PCT / US2019 / 026239, filed on April 8, 2019 (and published as WO 2019 / 199621 on October 17, 2019), are incorporated herein by reference in their entireties.

[0040] Without wishing to be bound by any theory, the use of antibodies, such as but not limited to monoclonal antibodies, in the compounds of the present disclosure has distinct advantages over similar bifunctional compounds in the prior art.

[0041] In one aspect, the affinity of antibodies for their targets is typically in the pM to low nM range, which corresponds to particularly strong binding. In contrast, small molecule protein binders typically have affinities for their targets in the nM to μM range. Therefore, antibodies are expected to bind more tightly to the molecular target of interest.

[0042] On the other hand, antibodies, such as but not limited to monoclonal antibodies, are very specific for their intended target, which reduces their toxicity due to off-target interactions.

[0043] In still another aspect, the antibody interacts with the neonatal Fc receptor (FcRn) (also known as the Brambell receptor). In humans, FcRn regulates the turnover of IgG and serum albumin. FcRn prolongs 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 constantly internalized by pinocytosis and may be degraded in lysosomes. However, IgG and serum albumin are bound by FcRn at slightly acidic pH (<6.5) and circulate to the cell surface, and are released at neutral pH (>7.0) in the blood, thereby avoiding lysosomal degradation. Interestingly, both FcRn and ASGPR are expressed on hepatocytes, which are primary cell types where ASGPR-mediated degradation occurs. Therefore, the compounds of the present disclosure can bind to ASGPRBM, but escape ASGPR-mediated degradation by binding to FcRn.

[0044] The rescue of the compounds of the present disclosure by FcRn provides several therapeutic advantages. Typically, compounds comprising a circulating protein small molecule binding partner are degraded along with the circulating protein of interest. In contrast, due to their recovery by FcRn, the modified antibodies of the present disclosure can participate in multiple rounds of protein binding and targeted degradation. In addition, since the compounds of the present disclosure can participate in multiple rounds of degradation, they can be administered at lower doses, which is therapeutically advantageous. In addition, as the half-life of the compounds of the present disclosure is extended by FcRn rescue, the frequency of their administration is reduced relative to the frequency of administration required when using compounds comprising a circulating protein small molecule binding partner.

[0045] Indeed, the antibody-containing compounds of the present disclosure not only have advantageous properties over previously described compounds containing circulating protein small molecule binding partners, but also have advantageous properties over non-derivatized antibodies themselves. The primary function of unmodified antibodies is to bind and neutralize their protein targets - in this case, the unmodified antibodies can each participate in one binding event. In contrast, the antibody-containing compounds of the present disclosure act by degrading protein targets, and some percentage of these compounds are recycled by FcRn and can participate in another round of binding after the degradation event occurs. Therefore, these useful antibody-containing compounds of the present disclosure can participate in semi-catalytic protein degradation, a property promoted by FcRn-mediated recycling.

[0046] As another advantage, the present disclosure allows for the efficient generation of new antibody-containing compounds in which ASGPRBMs are attached to any selected antibody (without the need to change the amino acid sequence of these antibodies and / or extensively test the effects of these amino acid changes on FcRn binding, protein binding, and protein release). The ease of this synthesis lends itself to studying the degradation of various protein targets. In certain embodiments, using this approach is cheaper than traditional antibody modification methods. In certain embodiments, the less frequent dosing regimen of the antibody-containing compounds of the present disclosure (compared to other antibody therapies) reduces the overall cost of therapy, alleviating the financial burden on insurance companies and patients.

[0047] In light of the present disclosure, conventional chemical synthesis and pharmaceutical preparation methods within the skill of the art, as well as pharmacology, molecular biology, microbiology and recombinant DNA techniques may be employed. These techniques are well known and fully described in the literature.

[0048] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are partially illustrated in the accompanying drawings. Although the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0049] The values ​​expressed in range format throughout this article should be flexibly interpreted to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or sub-ranges included in the range, as if each value and sub-range were explicitly stated. For example, the range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3% and 4%) and sub-ranges within the specified range (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise specified, the statement "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise specified, the statement "about X, Y or about Z" has the same meaning as "about X, about Y or about Z".

[0050] In the methods described herein, unless a time or order of operations is explicitly stated, the actions may be performed in any order. In addition, specified actions may be performed simultaneously unless the language explicitly claimed provides that they should be performed separately. For example, a claimed action of performing X and a claimed action of performing Y may be performed simultaneously in a single step, and the resulting method will fall within the literal scope of the claimed method.

[0051] definition

[0052] As used herein, the term "about" may allow a value or range to vary to a certain degree, for example, within 10%, 5% or 1% of a stated limit of a stated value or range, and includes the exact stated value or range.

[0053] In this document, unless the context clearly dictates otherwise, the terms "a", "an" or "the" include one or more. Unless otherwise stated, "or" refers to a non-exclusive "or". 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". In addition, it should be understood that the phrases or terms used herein are for descriptive purposes only and not for limiting purposes unless otherwise defined. The use of any section headings is intended to aid in reading this document and should not be construed as limiting; information related to the section heading may appear within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0054] The term "abnormal" when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components thereof that differ from those that display the "normal" (expected) respective characteristic in at least one observable or detectable characteristic, such as age, treatment, time of day, etc. Characteristics that are normal or expected for one cell or tissue type may be abnormal for a different cell or tissue type.

[0055] The term "acyl" as used herein refers to a group containing a carbonyl moiety, wherein the group is bonded via a carbonyl carbon atom. The carbonyl carbon atom is bonded to hydrogen to form a "formyl" group, or to another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, etc. The acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may include double bonds or triple bonds within the meaning of this article. Acryloyl is an example of an acyl group. Acyl groups may also include heteroatoms within the meaning of this article. Nicotinoyl (pyridyl-3-carbonyl) is an example of an acyl group within the meaning of this article. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, etc. When a group containing a carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is trifluoroacetyl.

[0056] The term "alkyl" as used herein refers to straight and branched alkyl and 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 those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl and anteisoalkyl and other branched forms of alkyl. Representative substituted alkyl groups may be substituted once or multiple times by any group listed herein, for example, amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy and halogen groups.

[0057] The term "alkenyl" as used herein refers to straight and branched chains and cyclic alkyl groups as defined herein, except that there is at least one double bond 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, etc.

[0058] The term "alkoxy" as used herein refers to that an oxygen atom is connected to an alkyl group (including cycloalkyl) as defined herein. Examples of straight chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy groups may include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further include double bonds or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups within the meaning of this article, as methylenedioxy in the case where two adjacent atoms of the structure are replaced by them.

[0059] As used herein, the term "alkynyl" refers to straight and branched chain alkyl groups, except that there is at least one triple bond between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc.

[0060] The term "amine" as used herein refers to primary, secondary and tertiary amines having, for example, the formula N(group)3, wherein each group can independently be H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, RNH2, such as alkylamines, arylamines, alkarylamines; RNH, wherein each R is independently selected, such as dialkylamines, diarylamines, arylamines, heterocyclic amines, etc.; and RN, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" also includes ammonium ions as used herein.

[0061] 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 has at least about 70% homology, at least about 80% homology, at least about 90% homology, or at least about 95% homology with a native polypeptide. An amino acid sequence variant has substitutions, deletions, and / or insertions at certain positions within the amino acid sequence of a native amino acid sequence.

[0062] The term "amino group" as used herein refers to -NH2, -NHR, -NR2, -NR3 + (where each R is independently selected) forms, and except -NR3 + (which cannot be protonated). Therefore, any compound substituted with an amino group can be considered an amine. "Amino" within the meaning of this article can be a primary amino group, a secondary amino group, a tertiary amino group or a quaternary amino group. "Alkylamino" includes monoalkylamino, dialkylamino and trialkylamino.

[0063] The term "aminoalkyl" as used herein refers to an amine group attached to an alkyl group as defined herein. The amine group may be present at any suitable position in the alkyl chain, such as at the end of the alkyl chain or at any position in the alkyl chain.

[0064] The term "antibody" as used herein refers to an immunoglobulin molecule that specifically binds to an antigen. An antibody can be a complete immunoglobulin derived from a natural source or a recombinant source, or it can be an immunoreactive portion of a complete immunoglobulin. An antibody is typically a tetramer of an immunoglobulin molecule. The antibodies in the present disclosure can exist in a variety of forms, including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single-chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 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).

[0065] The term "antibody fragment" refers to a portion of an intact antibody, and refers to the antigen-determining variable region of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, linear antibodies, scFv antibodies, single domain antibodies such as sdAb (VL or VH), such as camelid antibodies (Riechmann, 1999, J. Immunol. Meth. 231: 25-38), camelid VHH domains, consisting of VL or VH domains that exhibit sufficient affinity for the target, and multispecific antibodies formed by antibody fragments, such as a bivalent fragment comprising two Fab fragments linked by a disulfide bond at the hinge region, and an isolated complementary determining region (CDR) or other epitope binding fragment of an antibody. Antigen binding fragments can also be incorporated into single domain antibodies, maxi-antibodies, mini-antibodies, nano-antibodies, intrabodies, diabodies, tri-antibodies, tetra-antibodies, v-NARs and bi-scFvs (see, e.g., Hollinger & Hudson, 2005, Nature Biotech. 23: 1126-1136). Antigen binding fragments can also be transplanted into polypeptide-based scaffolds, such as type III fibronectin (Fn3) (U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide mini-antibodies). Antibody fragments also include human antibodies or humanized antibodies or a portion of a human antibody or a humanized antibody.

[0066] The term "antigen" or "Ag" as used herein is defined as a molecule that triggers an immune response. This immune response may involve the production of antibodies, or the activation of specific immunocompetent cells, or both. It will be understood by those skilled in the art that any macromolecule, including almost all proteins or peptides, can serve as an antigen. In addition, antigens can be derived from recombinant or genomic DNA. It will be understood by those skilled in the art that any DNA, which contains a nucleotide sequence or a partial nucleotide sequence encoding a protein that triggers an immune response, therefore encodes the term "antigen" used herein. In addition, it will be understood by those skilled in the art that antigens do not need to be encoded only by the full-length nucleotide sequence of a gene. It is clear that the present disclosure includes, but is not limited to, the use of partial nucleotide sequences of more than one gene, and these nucleotide sequences are arranged in various combinations to trigger the desired immune response. In addition, it will be understood by those skilled in the art that antigens do not need to be encoded by a "gene" at all. It is clear that antigens can be produced, synthesized or can be derived from biological samples. Such biological samples can include, but are not limited to, tissue samples, tumor samples, cells or biological fluids.

[0067] As used herein, the term "aralkyl" refers to an alkyl group as defined herein wherein a hydrogen bond or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl, phenethyl, and fused (cycloalkylaryl)alkyl groups, such as 4-ethylindenyl. Aralkenyl groups are alkenyl groups as defined herein wherein a hydrogen bond or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0068] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Thus, aryl includes, but is not limited to, phenyl, azulenyl, heptadenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthacenyl, In some embodiments, the aryl group contains about 6 to about 14 carbon atoms in the ring portion of the group. As defined herein, the aryl group can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or multiply substituted, such as but not limited to phenyl substituted at any one or more positions in the 2-, 3-, 4-, 5- or 6-positions of the phenyl ring, or naphthyl substituted at any one or more positions in its 2-8 positions.

[0069] As used herein, the term "asialoglycoprotein receptor binding moiety" or "ASGPRBM" refers to a group that is capable of binding to at least one hepatocyte asialoglycoprotein receptor on the surface of a cell, such as, but not limited to, a hepatocyte. Once the ASGPRBM and any additional moieties attached thereto bind to a receptor on the surface of a hepatocyte, the molecule comprising the ASGPRBB is taken up into the hepatocyte via an endocytic mechanism, where the molecule is degraded at least in part by lysosomal degradation.

[0070] As used herein, the term “ 6-10 -C 6-10 Biaryl)" refers to C 6-10 The aryl moiety is bonded to another C 6-10 The aromatic moiety is covalently bonded. 6-10 The aryl moiety may be any suitable aryl group described herein. 6-10 -C 6-10 Non-limiting examples of biaryl groups include biphenyl and binaphthyl.

[0071] As used herein, the term "coding sequence" refers to a sequence of a nucleic acid or its complement or a portion thereof that can be transcribed and / or translated to produce mRNA and / or a polypeptide or a fragment thereof. The coding sequence includes exons in genomic DNA or immature primary RNA transcripts that are linked together by the biochemical machinery of the cell to provide mature mRNA. The antisense strand is the complement of this nucleic acid, from which the coding sequence can be inferred. In contrast, as used herein, the term "non-coding sequence" refers to a sequence of a nucleic acid or its complement or a portion thereof that is not translated into amino acids in vivo, or tRNA does not interact to place or attempt to place amino acids. Non-coding sequences include intron sequences in genomic DNA or immature primary RNA transcripts, and gene-related sequences such as promoters, enhancers, silencers, etc.

[0072] As used herein, the terms "complementary" or "complementarity" are used to refer to polynucleotides (i.e., sequences of nucleotides) that are related by the base pairing rules. For example, the sequence "AGT" is complementary to the sequence "TCA". Complementarity may be "partial", in which only some of the bases of the nucleic acids 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 chains has a significant effect on the efficiency and intensity of hybridization between nucleic acid chains. This is particularly important in amplification reactions and detection methods that rely on binding between nucleic acids.

[0073] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate administration of the compound to a patient or subject. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0074] As used herein, the term "conservative variation" or "conservative substitution" refers to the replacement of an amino acid residue with another biologically similar residue. Conservative variations or substitutions are less likely to change the shape of the peptide chain. Examples of conservative variations or substitutions include replacing one hydrophobic residue such as isoleucine, valine, leucine or methionine with another, or replacing one polar residue with another, such as replacing lysine with arginine, replacing aspartic acid with glutamic acid, or replacing asparagine with glutamine.

[0075] 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, the cycloalkyl group may have 3 to about 8-12 ring members, and in other embodiments, the number of ring carbon atoms is in the range of 3 to 4, 5, 6, or 7. Cycloalkyl further includes polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, and fused rings, such as, but not limited to, decalinyl, etc. Cycloalkyl groups also include rings substituted with straight or branched alkyl groups as defined herein. Representative substituted cycloalkyl groups may be monosubstituted or multiply substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl or mono-, di- or tri-substituted norbornyl or cycloheptyl, which may be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy and halogen groups. The term "cycloalkenyl" alone or in combination refers to cyclic alkenyl groups.

[0076] "Disease" refers to a health condition in an animal in which the animal is unable to maintain homeostasis and in which the animal's health will continue to deteriorate if the disease is not ameliorated.

[0077] In contrast, a "disorder" in an animal is a health state in which the animal is able to maintain homeostasis, but in which state its health is worse than it would be without the disorder. If left untreated, a disorder does not necessarily lead to further deterioration of the animal's health.

[0078] A disease or disorder is "alleviated" if there is a decrease in the severity of the symptoms of the disease or disorder, the frequency with which a patient experiences such symptoms, or both.

[0079] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic but sufficient amount of a pharmaceutical agent to provide a desired biological result. Such a result may be a reduction and / or alleviation of symptoms, signs or causes of a disease, or any other desired change in a biological system. One of ordinary skill in the art can determine the appropriate therapeutic amount in any individual case by routine experimentation.

[0080] As used herein, the term "efficacy" refers to the maximum effect (E max ).

[0081] "Encoding" refers to the inherent properties of a specific nucleotide sequence in a polynucleotide (such as a gene, cDNA or mRNA) that serves as a template for the synthesis of other polymers and macromolecules in biological processes, which have a defined nucleotide sequence (i.e., rRNA, tRNA and mRNA) or a defined amino acid sequence, and the resulting biological properties. Therefore, if the transcription and translation of the mRNA corresponding to the gene produces a protein in a cell or other biological system, the gene encodes the protein. Both the coding strand (whose nucleotide sequence is the same as the mRNA sequence and is usually provided in the sequence listing) and the non-coding strand (used as a template for transcription of the gene or cDNA) can be referred to as encoding the protein or other product of the gene or cDNA.

[0082] As used herein, the term "fragment" when applied to nucleic acids refers to a subsequence of a larger nucleic acid. A "fragment" of a nucleic acid can be at least about 15 nucleotides in length; for example, at least about 50 nucleotides to about 100 nucleotides; at least about 100 to about 500 nucleotides, at least about 500 to about 1000 nucleotides; at least about 1000 nucleotides to about 1500 nucleotides; about 1500 nucleotides to about 2500 nucleotides; or about 2500 nucleotides (and any integer value therebetween). As used herein, the term "fragment" 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; for example, 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).

[0083] As used herein, the term "GN3" refers to the following group:

[0084]

[0085] As used herein, unless otherwise stated, the terms "halo," "halogen," or "halide" group, by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0086] As used herein, the term "haloalkyl" includes monohaloalkyl, polyhaloalkyl (wherein all halogen atoms may be the same or different) and perhaloalkyl (wherein all hydrogen atoms are substituted by halogen atoms (such as fluorine atoms). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0087] As used herein, the term "heavy chain antibody" or "heavy chain antibodies" includes immunoglobulin molecules derived from species of the Camelidae family by immunization with an antigen and subsequent isolation of serum, or by cloning and expressing nucleic acid sequences encoding such antibodies. The term "heavy chain antibody" or "heavy chain antibodies" further includes immunoglobulin molecules isolated from animals with heavy chain diseases, or by cloning and expressing the V H (variable heavy chain immunoglobulin) gene produced by the immunoglobulin molecule.

[0088] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing 5 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 5 to about 8-12 ring members. Heteroaryls are various heterocyclic groups with aromatic electronic structures. A heteroaryl designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms, and the like. Similarly, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and the like. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl includes but is not limited to the following groups: for example pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, phenylthio, benzophenylthio, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolepyridyl, thiapyridine, purinyl, xanthinyl, adeninyl, guanidyl, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalinyl and quinazolinyl. Heteroaryl can be unsubstituted, or can be substituted by the groups discussed herein. Representative substituted heteroaryl can be substituted once or multiple by the groups listed herein.

[0089] Additional examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthryl, 2-anthryl, 3-anthryl), phenylthio (2-phenylthio, 3-phenylthio), furanyl (2-furanyl, 3-furanyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, 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), phenylthio (2-benzo[b]phenylthio, 3-benzo[b]phenylthio, 4-benzo[b]phenylthio, 5-benzo[b]phenylthio, 6-benzo[b]phenylthio, 7-benzo[b]phenylthio), 2,3-dihydro-benzo[b]phenylthio, (2-(2,3-dihydro-benzo[b]phenylthio), 3-(2,3-dihydro-benzo[b]phenylthio), 4-(2,3-dihydro-benzo[b]phenylthio), 5-(2,3-dihydro-benzo[b]phenylthio), 6-(2,3-dihydro-benzo[b]phenylthio), 7-(2,3-dihydro-benzo[b]phenylthio),3-dihydro-benzo[b]phenylthio), 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, imidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepine, (5H-dibenzo[b,f]azepine -1-yl, 5H-dibenzo[b,f]azepine -2-yl, 5H-dibenzo[b,f]azepine -3-yl, 5H-dibenzo[b,f]azepine -4-yl, 5H-dibenzo[b,f]azepine -5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepine (10,11-dihydro-5H-dibenzo[b,f]azepine -1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine -5-yl) etc.

[0090] The term "heteroarylalkyl" as used herein refers to an alkyl group as defined herein wherein a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0091] The term "C 6-10 -5-6 membered heterobiaryl (C 6-10 -5-6 membered heterobiaryl)" refers to a C-5-6 membered heterobiaryl covalently bonded to a 5- or 6-membered heterobiaryl moiety via a single bond. 6-10 Aryl. C 6-10 The aryl and 5-6 membered heteroaryl groups may be any suitable aryl and heteroaryl groups described herein. 6-10Non-limiting examples of 5-6 heterobiaryl groups include:

[0092]

[0093] When C 6-10 -5-6 membered heterobiaryl is listed as a substituent (e.g., "R" group), C 6-10 -5-6 membered heterobiaryl groups through C 6-10 part is bonded to the rest of the molecule.

[0094] As used herein, the term "5-6-membered-C 6-10 Heteroaryl" and C 6-10 -5-6 membered heterobiaryl, except that when the 5-6 membered -C 6-10 When a heterobiaryl group is listed as a substituent (e.g., as an "R" group), the 5-6 membered -C 6-10 The heterobiaryl group is bonded to the rest of the molecule via the 5-6 membered heteroaryl moiety.

[0095] The term "heterocyclyl" as used herein refers to aromatic and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms, such as but not limited to N, O and S. Therefore, the heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or if it is a polycyclic ring, any combination thereof. In some embodiments, the heterocyclyl group includes 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. The heterocyclyl group named C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms, etc. Similarly, the C4-heterocyclyl group can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms is equal to the total number of ring atoms. The heterocyclyl ring can also include one or more double bonds. The heteroaryl ring is an embodiment of the heterocyclyl group. The phrase "heterocyclyl" includes fused ring materials, including those of fused aromatic and non-aromatic groups. For example, dioxolane and benzodioxolane systems (methylenedioxyphenyl ring systems) are both heterocyclic groups within the meaning herein. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclic groups may be unsubstituted or may be substituted as discussed herein. Heterocyclic 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, thiazolyl, purinyl, xanthinyl, adeninyl, guanidinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclic groups may be mono-substituted or multiply substituted, such as, but not limited to, piperidinyl or quinolinyl, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed herein.

[0096] The term "heterocyclylalkyl" as used herein refers to an alkyl group as defined herein, wherein a hydrogen bond or carbon bond of the alkyl group as defined herein is replaced by a bond to a heterocyclyl group as defined herein. Representative heterocycloalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl and indol-2-ylpropyl.

[0097] The term "immunoglobulin" or "Ig" as used herein is defined as a class of proteins that function as antibodies. Antibodies expressed by B cells are sometimes referred to as BCRs (B cell receptors) or antigen receptors. The five members included in this class of proteins are IgA, IgG, IgM, IgD, and IgE. IgA is the main antibody present in body secretions (such as saliva, tears, breast milk, gastrointestinal secretions, and mucous secretions of the respiratory and urogenital tracts). IgG is the most common circulating antibody. IgM is the main immunoglobulin produced in the primary immune response in most subjects. It is the most effective immunoglobulin in agglutination, complement fixation, and other antibody reactions, and is important in defending against bacteria and viruses. IgD is an immunoglobulin with no known antibody function, but can act as an antigen receptor. IgE is an immunoglobulin that mediates immediate hypersensitivity reactions by causing the release of mediators from mast cells and basophils after exposure to allergens.

[0098] Unless the context clearly indicates otherwise, the term "independently selected from" as used herein means that the groups referred to are the same, different, or a mixture thereof. Thus, according to this definition, the phrase "X 1 , X 2 and X 3 "independently selected from inert gases" would include, for example, 1 , X 2 and X 3 All the same, where X 1 , X 2 and X 3 All different, including X 1 and X 2 Same but X 3 Different and other similar arrangements.

[0099] An "inducible" promoter is a nucleotide sequence that, when operably linked to a polynucleotide encoding or specifying a gene product, will produce the gene product in a cell essentially only when an inducing agent corresponding to the promoter is present in the cell.

[0100] "Isolated" means changed or removed from its natural state. For example, a nucleic acid or polypeptide naturally present in a living animal is not "isolated", but the same nucleic acid or polypeptide partially or completely separated from the coexisting materials of its natural state is "isolated". An isolated nucleic acid or protein can exist in a substantially purified form or can exist in a non-natural environment, such as a host cell.

[0101] As used herein, the term "modulating" refers to a detectable increase or decrease in the activity and / or level of an mRNA, polypeptide, or reaction in a subject compared to the activity and / or level of the mRNA, polypeptide, or reaction in the absence of a treatment or compound, and / or compared to the activity and / or level of an mRNA, polypeptide, or reaction in an otherwise identical but untreated subject. The term includes activating, inhibiting, and / or otherwise affecting a natural signal or reaction, thereby mediating a beneficial therapeutic response in a subject (preferably a human).

[0102] As used herein, the term "monovalent" refers to a substituent that is attached to the substituted molecule via a single bond. When a substituent is monovalent, such as F or Cl, it is bonded to the substituted atom via a single bond.

[0103] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include oxygen-containing groups, such as alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylates; sulfur-containing groups, such as alkyl and aryl thioether groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, SO2N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N (R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R and substituted or unsubstituted (C1-C 100 )alkyl, wherein R can be hydrogen (in examples including other carbon atoms) or a carbyl moiety, and wherein the carbyl moiety can be substituted or unsubstituted.

[0104] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal or cell thereof in vitro or in situ suitable for use in the methods described herein. In non-limiting embodiments, the patient, subject, or individual is a human.

[0105] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not diminish the biological activity or properties of the compound and is relatively non-toxic, i.e., such material can be administered to a subject without causing adverse biological effects or interacting in a deleterious manner with any of the ingredients of the composition.

[0106] As used herein, the language "pharmaceutically acceptable salt" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solubilities, hydrates or clathrates thereof.

[0107] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and hydrogen sulfates) and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharinic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid.

[0108] 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 N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-meglumine) and procaine. All of these salts can be prepared from the corresponding compounds by reacting, for example, a suitable acid or base with the compound.

[0109] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle that participates in carrying or transporting a compound described herein into the body or to a patient so that it can perform its intended function, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material. Typically, such a compound will be 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 (including the compound(s) described herein) and not causing harm to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein and that are physiologically acceptable to the patient. Supplementary active compounds may also be added to the composition. A "pharmaceutically acceptable carrier" may also include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in pharmaceutical compositions for use with the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0110] As used herein, the term "polypeptide" refers to a polymer consisting of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof connected by peptide bonds. For example, an automatic peptide synthesizer can be used to synthesize synthetic polypeptides. As used herein, the term "protein" generally refers to large polypeptides. As used herein, the term "peptide" generally refers to short polypeptides. Conventional symbols are used herein to represent polypeptide sequences: the left-hand end of a polypeptide sequence is the amino terminus, and the right-hand end of a polypeptide sequence is the carboxyl terminus.

[0111] As used herein, the term "efficacy" refers to the effect of producing a half-maximal response (ED 50 ) required dose.

[0112] As used herein, the term "REAG" refers to any reagent comprising -CON, -linker, -CON-linker, -linker-CON, -CON-linker-CON, -CRBM, -CON-CRBM, -linker-CRBM, -CON-linker-CRBM, -linker-CON-CRBM, and / or -CON-linker-CON-CRBM. As described herein, REAG reacts with a protein binder to add the protein binder to a compound of the disclosure, or a fragment, derivative, or intermediate thereof.

[0113] As used herein, the term "room temperature" refers to a temperature of about 15°C to 28°C.

[0114] For antibodies, the term "specific binding" as used herein refers to antibodies that recognize a specific antigen but do not substantially recognize or bind to other molecules in the sample. For example, an antibody that specifically binds to an antigen of one species may also bind to antigens of one or more species. However, this cross-species reaction itself does not change the specific classification of the antibody. In another example, an antibody that specifically binds to an antigen may also bind to different allele forms of the antigen. However, this cross-reactivity itself does not change the specific classification of the antibody. In some cases, the term "specific binding" or "specific binding" can be used to refer to the interaction of an antibody, protein or peptide with a second chemical substance, meaning that this interaction depends on the presence of a specific structure (such as an antigenic determinant or epitope) on the chemical substance; for example, an antibody recognizes and binds to a specific protein structure, rather than a common protein. If the antibody is specific to epitope "A", then in a reaction containing labeled "A" and an antibody, the presence of a molecule containing epitope A (or free, unlabeled A) will reduce the amount of labeled A bound to the antibody.

[0115] As used herein, the term "solvent" refers to a liquid that can dissolve solids, liquids, or gases. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0116] As used herein, the term "standard temperature and pressure" refers to 20°C and 101 kPa.

[0117] As used herein, the term "substantially" refers to a majority or a majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term "substantially free of" may mean free of or containing only a very small amount of material such that the amount of material present does not affect the material properties of the composition including the material, such that the material in the composition is from about 0 wt % to about 5 wt %, or from about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt % or less. The term "substantially free" can mean having an insignificant amount such that the material in the composition is from about 0 wt % to about 5 wt %, or from about 0 wt % to about 1 wt %, or about 5 wt % or less, or less than, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt % or less, or about 0 wt %.

[0118] The term "substituted" used herein in conjunction with a molecule or organic group as defined herein refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" used herein refers to a group that can be or is substituted onto a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in the following groups, such as hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, carboxyl groups (including carboxylic acids, carboxylates, and carboxylates); sulfur atoms in the following groups, such as thiol groups, alkyl and aryl thioether groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in the following groups, such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be bonded to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O(oxo), S(thiocarbonyl), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, S02N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R and C(=NOR)R, wherein R can be hydrogen or a carbonyl moiety; for example, R can be hydrogen, (C1-C 100 ) is a hydrocarbon group, an alkyl group, an acyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group, a heteroaryl group or a heteroaralkyl group; or wherein the two R groups bonded to a nitrogen atom or adjacent nitrogen atoms may form a heterocyclic group together with one or more nitrogen atoms.

[0119] The term "synthetic antibody" as used herein refers to an antibody produced using recombinant DNA technology, such as a phage-expressed antibody as described herein. The term should also be interpreted as referring to an antibody produced by synthesizing a DNA molecule encoding the antibody, which expresses the antibody protein, or specifies the amino acid sequence of the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology available and well known in the art.

[0120] "Therapeutic" treatment refers to treatment administered to a subject experiencing pathological symptoms with the intent to alleviate or eliminate those symptoms.

[0121] The term "thioalkyl" as used herein refers to a sulfur atom connected to an alkyl group as defined herein. The alkyl group in the thioalkyl group can be straight or branched. Examples of straight chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, etc. Examples of branched chain alkoxy groups include, but are not limited to, isothiopropyl, secondary thiobutyl, tertiary thiobutyl, isothiopentyl, isothiohexyl, etc. The sulfur atom can appear in any suitable position in the alkyl chain, such as at the end of the alkyl chain or at any position in the alkyl chain.

[0122] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0123] As used herein, the term "wild-type" refers to a gene or gene product isolated from a naturally occurring source. A wild-type gene is a gene that is most common in a population and is therefore arbitrarily designed to be the "normal" or "wild-type" form of a gene. In contrast, the term "modified" or "mutant" refers to a gene or gene product that displays modifications (i.e., altered characteristics) in sequence and / or functional properties when compared to a wild-type gene or gene product. It is noteworthy that naturally occurring mutants can be isolated; these are identified by the fact that they have altered characteristics (including altered nucleic acid sequences) when compared to a wild-type gene or gene product.

[0124] 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.

[0125] A more complete list of autoimmune diseases that can be treated by the compounds and pharmaceutical compositions according to the present disclosure includes Addison's disease, autoimmune polyendocrine syndrome (APS) types 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune bowel disease, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome, syndrome (APlS), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed cold agglutininemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesin-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry-Romberg syndrome, Parsonage-Turner syndrome syndrome), psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndromesyndrome), undifferentiated connective tissue disease (UCTD) in systemic lupus erythematosus, dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eatonmyasthenic syndrome, multiple sclerosis, pattern II, Oshtoran Syndrome, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus Streptococcus (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Syndenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate teuveitis, ligneous conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmitisophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease (AIED), Méniére's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki's disease, leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency and pyoderma gangrenosum, etc.

[0126] Throughout this specification, the term "cancer" or "neoplasia" refers to a pathological process that leads to the formation and growth of cancerous or malignant neoplasms, i.e., an abnormal tissue that grows by cell proliferation, usually growing faster than normal tissue, and continuing to grow after the stimulus that initiates new growth stops. Malignant neoplasms are characterized by a partial or complete lack of structural organization and functional coordination with normal tissues, most of which invade surrounding tissues, metastasize to multiple sites, and may recur after attempted resection, and may cause death of the patient unless adequately treated. As used herein, the term neoplasm is used to describe all cancerous disease states, and includes or comprises pathological processes associated with malignant hematogenous, ascites, and solid tumors. Neoplasms include, but are not limited to, irregular morphology of cells in a subject or host tissue, and pathological proliferation of cells in a subject's tissue compared to normal proliferation in the same type of tissue. In addition, neoplasms include invasive or non-invasive benign and malignant tumors (such as colon tumors). Malignant neoplasms (cancers) are distinguished from benign neoplasms in that the former exhibit a greater degree of anaplasia, or loss of cellular differentiation and orientation, and possess the properties of invasion and metastasis.Examples of neoplasms or tumor formations from which target cells of the present disclosure may be derived include, but are not limited to, cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), in particular bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, in particular Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliogliomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and schwannomas); of the germ line (e.g., intestinal, breast, prostate, cervical, uterine, lung, ovarian, testicular, thyroid, astrocytomas, esophageal, pancreatic, gastric, liver, colon, and melanoma); mixed tumors, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinoma (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms can be treated using the compounds of the present disclosure.

[0127] Representative common cancers treated with compounds according to the present disclosure include, for example, prostate cancer, metastatic prostate cancer, stomach, colon, rectum, liver, pancreas, lung, breast, cervix, uterine body, ovary, testis, bladder, kidney, brain / CNS, head and neck, larynx, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal, esophageal, laryngeal, renal cancer and lymphoma, etc., which can be treated by one or more compounds according to the present disclosure. Because of the activity of the compounds of the invention, the present disclosure has general applicability to the treatment of virtually any cancer in any tissue, and thus the compounds, compositions and methods of the present disclosure are generally useful for the treatment of cancer and for reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0128] In certain specific aspects of the present disclosure, the cancer treated is a metastatic cancer, a recurrent cancer, or a drug-resistant cancer, particularly including a drug-resistant cancer. In addition, metastatic cancers can be found in almost all tissues of cancer patients at the advanced stage of the disease, and typical metastatic cancers can be found in the lymphatic system / lymph nodes (lymphoma), bones, lungs, bladder tissue, kidney tissue, liver tissue, and almost any tissue (including brain (brain cancer / tumor)). Therefore, the present disclosure is generally applicable and can be used to treat any cancer in any tissue, regardless of the cause.

[0129] The term "anticancer agent" or "additional anticancer agent" refers to a compound other than a chimeric compound according to the present disclosure that can be used in combination with a compound for treating cancer according to the present disclosure. Exemplary anticancer agents that can be co-administered in combination with one or more chimeric compounds according to the present disclosure include, for example, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (such as paclitaxel), among others. Exemplary anticancer compounds for use in the present disclosure may include everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA744, 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 antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, cottonpol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanthone, LY317615, neuradiab, vitespan, Rta744, Sdx102, talampanel, atrasentan, Xr311, 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-pyrrole[2,3 -d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (ethylestradiol), estradiol, estrogen, estrogen conjugate, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperidinylmethyl)-indole-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C 59 H 84 N 18Oi4-(C2H4O2)x, wherein 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; amifortin, NVP-LAQ824, suberoylanilide isothiocyanate Hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BCG, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin D, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin , mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis retinoic acid, phenylalanine mustard, uramustine, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, nefatinib statin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitamin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, interleukin fusion toxin (denileukindiftitox), gefitinib, bortezomib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, paclitaxel without polyoxyethylene castor oil, epothilone B, BMS-247550, BMS-310705, droloxifene,4-Hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK222584, VX-745, PD184352, 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, zoledronic acid, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab tuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan tiuxetan), androgens, decitabine, hexamethonium, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposomal, 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, filgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, and the like, including immunotherapeutic agents such as IDO inhibitors (indoleamine 2, 3-dioxygenase (IDO) pathway inhibitors), such as Indoximod (NLG-8187), Navoximod (GDC-0919) and NLG802, PDL1 inhibitors (inhibitors of programmed death ligand 1) (including, for example, nivolumab, durvalumab and atezolizumab), PD1 inhibitors such as pembrolizumab (Merck) and CTLA-4 inhibitors (inhibitors of cytotoxic T lymphocyte-associated protein 4 / cluster of differentiation 152) (including ipilimumab and tremelimumab, etc.).

[0130] In addition to anticancer agents, many other drugs can be co-administered with the chimeric compounds according to the present disclosure in the treatment of cancer. These include active agents, minerals, vitamins and nutritional supplements that show some efficacy in inhibiting cancer tissue or its growth, or are otherwise useful in treating cancer. For example, one or more dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids and phytoestrogens, including beta-sitosterol, can be combined with the compounds of the present invention for the treatment of cancer.

[0131] The term "inflammatory disease" is used to describe diseases or conditions in which acute but more commonly chronic inflammation is the primary manifestation of the disease or condition. Inflammatory diseases include neurodegenerative diseases (including, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease; other ataxias), diseases of impaired immune responses that cause inflammation (e.g., dysregulation of T cell maturation, B cell and T cell homeostasis, destruction of antagonists of inflammation), chronic inflammatory diseases, such as inflammatory bowel disease, including Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjögren's disease; hyperglycemia, diabetes (type I and II), pancreatic islet function and / or structure affecting lipid metabolism, pancreatic beta cell death and its related hyperglycemia, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g., Mendenhall's Syndrome, Werner Syndrome, and others). Syndrome, leprechaun syndrome and lipoatrophic diabetes) and dyslipidemia (e.g., hyperlipidemia, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome exhibited by obese subjects, liver disease, kidney disease (cell apoptosis in plaques, glomerular disease), cardiovascular disease (especially including complications during infarction, ischemia, stroke, pressure overload and reperfusion), muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, such as cardiac and neurological (both central and peripheral) manifestations, including stroke, age-related dementia and sporadic Alzheimer's disease, and psychiatric disorders including depression), stroke and spinal cord injury, arteriosclerosis, etc. In these diseases, MIF is often observed to be elevated, making these disease states and / or conditions responsive to treatment with compounds and / or pharmaceutical compositions according to the present disclosure. It is noteworthy that, as described herein, there is some overlap between certain autoimmune diseases and inflammatory diseases.

[0132] Throughout this disclosure, various aspects of the disclosure may be represented in range format. It should be understood that the description in range format is only for convenience and brevity, and should not be construed as a rigid limitation on the scope of the disclosure. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and single values ​​within the range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and single values ​​within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the width of the range.

[0133] Compound

[0134] The present disclosure provides a compound comprising formula (I), or a salt, geometric isomer, stereoisomer or solvate thereof:

[0135] [Ab] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (I).

[0136] In certain embodiments, the compound comprises formula (Ia) or a salt, geometric isomer, stereoisomer or solvate thereof:

[0137] [Ab]—[CON] 0-1 —[Linking group]—[CON] 0-1 —[CRBM] ’ (Ia).

[0138] In (I) or (Ia), Ab is an antibody, such as but not limited to a monoclonal antibody, which binds to a biological target, such as but not limited to an extracellular protein, such as but not limited to a circulating protein and / or a cell surface protein. In certain embodiments, the circulating protein mediates a disease and / or disorder in a subject, and the treatment or management of the disease and / or disorder requires degradation, clearance, 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 or substantially similar affinity as the Ab itself.

[0139] In (I) or (Ia), the CRBM is a cell receptor binding moiety that binds to at least one receptor on the surface of a hepatocyte or other degradative cell in a subject, whereby the binding results in the endocytosis and degradation of (I) and / or (Ia) and / or a biological target. In certain embodiments, the CRBM is an ASGPRBM, which is a cell receptor binding moiety that binds to at least one asialoglycoprotein receptor on the surface of a hepatocyte or other degradative cell in a subject.

[0140] In (I) or (la), each CON is independently a bond or group that covalently links Ab to the CRBM, covalently links Ab to the linking group, and / or covalently links the linking group to the CMBM.

[0141] In (I) or (Ia), the linking group is a group with a valence ranging from 1 to 15. In certain embodiments, the linking group has a valence of 1 to 10. In certain embodiments, the linking group has a valence of 1 to 5. In certain embodiments, the linking group has a valence of 1, 2, or 3. In certain embodiments, the linking group is covalently linked to one or more CRBM and / or Ab groups, optionally through CON, wherein the linking group optionally itself comprises one or more CON groups.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] In certain embodiments, at least one of h, h', and i is at least 1.

[0148] In certain embodiments, k', j', h, h' and i are each independently 1, 2 or 3.

[0149] In certain embodiments, k' is 1 and j' is 1, 2 or 3.

[0150] CRBM

[0151] Folic Acid (Folate) Receptor:

[0152] In certain embodiments, the CRBM is folic acid, or any fragment or derivative thereof that can bind to a folic acid (folate) receptor. The folic acid receptor binds to folic acid and reduced folic acid derivatives and mediates the delivery of tetrahydrofolate to the interior of the cell, whereupon tetrahydrofolate is converted from monoglutamate to a polyglutamate form (such as 5-methyltetrahydrofolate) because only the monoglutamate form can be transported across the cell membrane. Human proteins in this family include folate receptor 1 (adult), folate receptor 2 (fetal), and folate receptor gamma.

[0153] In certain embodiments, the folate CRBM comprises methotrexate or a biologically active fragment thereof:

[0154]

[0155] In certain embodiments, the folate CRBM comprises a pre-processed or biologically active fragment thereof:

[0156]

[0157] In certain embodiments, the folate CRBM can be added to the compounds of the present disclosure via one of its carboxylic acids. In other embodiments, the folate CRBM can be added to the compounds of the present disclosure using N-hydroxysuccinamido (NHS) activated folate (similar chemistry is applicable to methotrexate and is pre-treated).

[0158]

[0159] Mannose receptor:

[0160] In some embodiments, CRBM is a group that binds to a mannose receptor. In some embodiments, CRBM includes the following groups:

[0161]

[0162] In certain embodiments, the mannose receptor CRBM can be attached to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (which can optionally be protected with an appropriate protecting group):

[0163]

[0164] Wherein X is S or O, and wherein R is selected from the following:

[0165]

[0166] and wherein 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.

[0167] In some embodiments, the mannose receptor CRBM is part of a polymer molecule. Such a molecule may include one or more independently selected mannose receptor CRBMs as part of a polymeric chain. In some embodiments, the CRBM is incorporated into a polymer molecule using a CRBM reagent described elsewhere herein.

[0168] Mannose-6-phosphate (M6P) receptor:

[0169] In certain embodiments, CRBM is a group that binds to mannose-6-phosphate (M6P) receptor. In certain embodiments, CRBM includes the following groups:

[0170]

[0171] Where X is O or S and where R 1 Select from the following:

[0172]

[0173] In certain embodiments, a CRBM can be attached to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (which can optionally be protected with an appropriate protecting group):

[0174]

[0175] Where X and R 1 As defined elsewhere herein, where R 2 Selected from:

[0176]

[0177] and wherein 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.

[0178] In some embodiments, the M6P receptor CRBM is part of a polymer molecule. Such a molecule may include one or more independently selected M6P receptor CRBMs as part of a polymer chain. In some embodiments, the CRBM is incorporated into a polymer molecule using a CRBM reagent described elsewhere herein. Figure 1-8 Exemplary mannose receptor binding agents and their preparation are shown.

[0179] In certain embodiments, the M6P receptor CRBM is one of the following (Yamaguchi, et al., 2016, J. Am. Chem. Soc. 138(38): 12472-12485):

[0180]

[0181] In certain embodiments, the M6P receptor CRBM is one of the following (US 2011 / 0110960 to Platenburg):

[0182]

[0183]

[0184] Low-density lipoprotein receptor-related protein 1 (LRP1) receptor:

[0185] In certain embodiments, the CRBM is an LRP1 [low-density lipoprotein receptor-related protein 1; also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER), or cluster of differentiation 91 (CD91)] binding group comprising one of the following amino acid sequences:

[0186] Ac-VKFNKPFVFLNleIEQNTK-NH2 (SEQ ID NO: 1), Toldo et al., 2017, JACC: Basic to Translational Science 2.5:561-574;

[0187] VKFNKPFVFLMIEQNTK(SEQ ID NO:2), Toldo et al., 2017, JACC: Basic to Translational Science 2.5:561-574;

[0188] TWPKHFDKHTFYSILKLGKH-OH (SEQ ID NO:3), Sakamoto, et al., 2017, Biochemistryand biophysics reports 12:135-139;

[0189] Angiopep-2: TFFYGGSRGKRNNFKTEEY-OH (SEQ ID NO: 4), Sakamoto, et al., 2017, Biochemistry and biophysics reports 12:135-139;

[0190] LRKLRKRLLRDADDLLRKLRKRLLRDADDL (SEQ ID NO: 5), Croy, et al., 2004, Biochemistry 43.23:7328-7335;

[0191] TEELRVRLASHLRKLRKRLL (SEQ ID NO:6), Croy, et al., 2004, Biochemistry43.23:7328-7335;

[0192] Rap12: EAKIEKHNHYQK (SEQ ID NO:7), Ruan, et al., 2018, Journal of ControlledRelease279:306-315;

[0193] Rap22: EAKIEKHNHYQKQLEIAHEKLR (SEQ ID NO:8), Ruan, et al., 2018, Journal of Controlled Release 279:306-315; or

[0194] ANG: TFFYGGSRGKRNNFKTEEY (SEQ ID NO: 9) Kim, et al., 2016, Scientific reports 6:34297.

[0195] Low-density lipoprotein receptor (LDLR):

[0196] In certain embodiments, the CRBM is a LDLR (low-density lipoprotein receptor) binding group comprising one of the following amino acid sequences:

[0197] VH4127: cM-Thz-RLRG-Pen (cyclized c-Pen) (SEQ ID NO: 10), Molino, et al., 2017, The FASEB Journal 31.5: 1807-1827;

[0198] VH434: CMPRLRGC (cyclized CC) (SEQ ID NO: 11), Molino, et al., 2017, The FASEB Journal 31.5: 1807-1827;

[0199] VH101: HLDCMPRGCFRN (cyclized CC) (SEQ ID NO: 12), David, et al., 2018, PloSone 13.2: 0191052;

[0200] VH202: CQVKSMPRC (cyclized CC) (SEQ ID NO: 13), David, et al., 2018, PloS one 13.2: 0191052;

[0201] VH203: CTTPMPRLC (cyclized CC) (SEQ ID NO: 14), David, et al., 2018, PloS one 13.2: 0191052;

[0202] VH204: CKAPQMPRC (cyclized CC) (SEQ ID NO: 15), David, et al., 2018, PloS one 13.2: 0191052;

[0203] VH205: CLNPSMPRC (cyclized CC) (SEQ ID NO: 16), David, et al., 2018, PloS one 13.2: 0191052;

[0204] VH306: CLVSSMPRC (cyclized CC) (SEQ ID NO: 17), David, et al., 2018, PloS one 13.2: 0191052;

[0205] VH307: CLQPMPRLC (cyclized CC) (SEQ ID NO: 18), David, et al., 2018, PloS one 13.2: 0191052;

[0206] VH308: CPVSSMPRC (cyclized CC) (SEQ ID NO: 19), David, et al., 2018, PloS one 13.2: 0191052;

[0207] VH309: CQSPMPRLC (cyclized CC) (SEQ ID NO: 20), David, et al., 2018, PloS one 13.2: 0191052;

[0208] VH310: CLTPMPRLC (cyclized CC) (SEQ ID NO: 21), David, et al., 2018, PloS one 13.2: 0191052;

[0209] VH411: DSGLCMPRLRGCDPR (cyclized CC) (SEQ ID NO: 22), David, et al., 2018, PloS one 13.2: 0191052;

[0210] VH549: TPSAHAMALQSLSVG (SEQ ID NO: 23), David, et al., 2018, PloS one 13.2: 0191052;

[0211] AcVH411: Ac-DSGLCMPRLRGCDPR-NH2 (cyclized CC) (SEQ ID NO: 24), David, et al., 2018, PloS one 13.2: 0191052;

[0212] PrVH434: Pr-CMPRLRGC-NH2 (cyclized CC) (SEQ ID NO: 25), David, et al., 2018, PloSone 13.2: 0191052;

[0213] VH445: Pr-cMPRLRGC-NH2 (cyclized CC) (SEQ ID NO: 26), David, et al., 2018, PloSone 13.2: 0191052;

[0214] VH4127: Pr-cMThzRLRG-Pen-NH2 (cyclized C-Pen) (SEQ ID NO: 27), David, et al., 2018, PloS one 13.2: 0191052;

[0215] AcVH434: Ac-CMPRLGC-NH2 (cyclized CC) (SEQ ID NO: 28), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0216] AcVH445: Ac-cMPRLRGC-NH2 (cyclized CC) (SEQ ID NO: 29), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0217] VH4106: Ac-D-Pen-M-Thz-RLRGC-NH2 (cyclized Pen-C) (SEQ ID NO: 30), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0218] VH4127: Pr-cM-Thz-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO: 31), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0219] VH4128: Pr-cM-Thz-RLR-Sar-Pen-NH2 (cyclized C-Pen) (SEQ ID NO: 32), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0220] VH4129: Pr-cM-Pip-RLR-Sar-C-NH2 (cyclized CC) (SEQ ID NO: 33), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105;

[0221] VH4130: Pr-cM-Pip-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO: 34), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105; or

[0222] VH4131: Pr-cM-Pip-RLR-Sar-Pen-NH2 (cyclized c-Pen) (SEQ ID NO: 35), Jacquot, et al., 2016, Molecular pharmaceutics 13.12: 4094-4105.

[0223] FcγRI receptors:

[0224] In certain embodiments, the CRBM is an FcγRI binding group comprising one of the following amino acid sequences:

[0225] Cp22: TDT C LMLPLLLG C DEE (cyclized CC) (SEQ ID NO: 36), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0226] Cp21: DPI C WYFPRLLG C TTL (cyclized CC) (SEQ ID NO: 37), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0227] Cp23: WYP C YIYPRLLG C DGD (cyclized CC) (SEQ ID NO: 38), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0228] Cp24: GNI C MLIPGLLG C SYE (cyclized CC) (SEQ ID NO: 39), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0229] Cp33: VNS C LLLPNLLG C GDD (cyclized CC) (SEQ ID NO: 40), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0230] Cp25: TPV C ILLPSLLG C DTQ (cyclized CC) (SEQ ID NO: 41), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0231] Cp26: TVL C SLWPELLG C PPE (cyclized CC) (SEQ ID NO: 42), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0232] Cp27: TFS C LMWPWLLG C ESL (cyclized CC) (SEQ ID NO: 43), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0233] Cp32: FGT C YTWPWLLG C EGF (cyclized CC) (SEQ ID NO: 44), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0234] Cp34: SLF C RLLLTPVG C VSQ (cyclized CC) (SEQ ID NO: 45), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0235] P35: HLL V LPRGLLG C TTLA (cyclized CC) (SEQ ID NO: 46), Bonetto, et al., 2009, TheFASEB Journal 23.2:575-585;

[0236] Cp28: TSL C SMFPDLLG C FNL (cyclized CC) (SEQ ID NO: 47), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0237] Cp29: SHP C GRLPMLLG C AES (cyclized CC) (SEQ ID NO: 48), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0238] P37: TST C SMVPGPLGAV STW (cyclized CC) (SEQ ID NO: 49), Bonetto, et al., 2009, TheFASEB Journal 23.2:575-585;

[0239] Cp30: KDP C TRWAMLLG C DGE (cyclized CC) (SEQ ID NO: 50), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585;

[0240] Cp31: IMT C SVYPFLLG C VDK (cyclized CC) (SEQ ID NO: 51), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585:

[0241] Cp36: IHS C AHVMRLLG C WSR (cyclized CC) (SEQ ID NO: 52), Bonetto, et al., 2009, The FASEB Journal 23.2: 575-585.

[0242] Transferrin Receptor:

[0243] In certain embodiments, the CRBM is a transferrin receptor binding group comprising one of the following amino acid sequences:

[0244] Tf1: CGGGPFWWWP (SEQ ID NO:53), Santi, et al., 2016, Bioconjugatechemistry28.2:471-480;

[0245] Tf2: CGGGHKYLRW (SEQ ID NO:54), Santi, et al., 2016, Bioconjugatechemistry28.2:471-480;

[0246] Tf3: CGGGKRIFMV (SEQ ID NO:55), Santi, et al., 2016, Bioconjugatechemistry28.2:471-480;

[0247] Tf2-scr: CGGGKWHYLR (SEQ ID NO: 56), Santi, et al., 2016, Bioconjugate chemistry 28.2: 471-480;

[0248] TfR-T12 :THRPPMWSPVWP (SEQ ID NO: 57), Mu, et al., 2017, Scientific reports 7.1: 3487;

[0249] HAIYPRH (SEQ ID NO: 67), Lee, et al., 2001, European journal of biochemistry 268.7: 2004-2012);

[0250] THRPPMWSPVWP (SEQ ID NO:58), Lee, et al., 2001, European journal of biochemistry268.7:2004-2012);

[0251] THRPPMWSPVWP (SEQ ID NO: 59), et al., 2011, Molecular Imaging and Biology 13.2: 332-341.

[0252] Macrophage scavenger receptors:

[0253] In certain embodiments, CRBM is a macrophage scavenger receptor binding portion comprising one of the following amino acid sequences:

[0255] PP1: LSLERFLRCWSDAPA (SEQ ID NO: 60), Segers, et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0256] PP1-13: LERFLRCWSDAPA (SEQ ID NO:61), Segers, et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0257] PP1-11: RFLRCWSDAPA (SEQ ID NO:62), Segers, et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0258] PP1-9: LRCWSDAPA (SEQ ID NO: 63), Segers, et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0259] PP1-7: CWSDAPA (SEQ ID NO: 64), Segers, et al., 2012, Arteriosclerosis, thrombosis, and vascular biology 32.4:971-978;

[0260] 4F: DWFKAFYDKVAEKFKEAF (SEQ ID NO: 65), Neyen, et al., 2009, Biochemistry 48.50: 11858-11871);

[0261] 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.

[0262] G protein coupled receptors:

[0263] In some embodiments, the CRBM is a G protein coupled receptor (GPCR) binding moiety. In some embodiments, the binding moiety binds to the GPCR and induces receptor internalization. In some embodiments, the receptor is CXCR7 (e.g., see Nalawansha, et al., 2019, ACS Cent. Sci. 5(6): 1079-1084). In some embodiments, the binding moiety includes the following:

[0264]

[0265] wherein each occurrence of R is independently H or C1-C6 alkyl. In certain embodiments, CRBM can be attached to a compound of the disclosure (such as, but not limited to, REAG) using one of the following reagents (which can optionally be protected with an appropriate protecting group):

[0266]

[0267] wherein at least one occurrence of R is REAG and wherein the remaining occurrences of R are independently H or C1-C6 alkyl.

[0268] Asialoglycoprotein receptor (ASGPR):

[0269] The present disclosure contemplates the use of ASGPR binding moieties (ASGPRBMs).

[0270] In certain embodiments, the ASGPRBM group is any such group described in Huang et al., 2017, Bioconjugate Chem. 28:283-295, the contents of which are incorporated herein by reference in their entirety.

[0271] In certain embodiments, the ASGPRBM group comprises the following structure:

[0272]

[0273] Where X is a linking group of 1-4 atoms in length and contains O, S, N (R N1 ) or C(R N1 )(R N1 ) groups such that:

[0274] When X is a linking group of 1 atom in length, X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[0275] When X is a linking group of 2 atoms in length, no more than 1 atom in X is O, S or N (R N1 ),

[0276] When X is a linking group of 3 or 4 atoms in length, no more than 2 atoms in X are independently O, S or N (R N1 ).

[0277] In certain embodiments, R N1 Each occurrence of is independently H or 1-3 independently selected halogens and / or 1-2 hydroxy optionally substituted C1-C3 alkyl.

[0278] In certain embodiments, when X is 2 atoms in length, X in ASGPRBM is -OC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-O-、-SC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-S-、-N(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-N(RN1 )-or-C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[0279] In certain embodiments, when X is 3 atoms in length, X in ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-、-OC(R N1 )(R N1 )-O-、-OC(R N1 )(R N1 )-S-、-OC(R N1 )(R N1 )-N(R N1 )-、-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1 )(R N1 )-S、-SC(R N1 )(R N1 )-S-、-SC(R N1 )(R N1 )-O-、-SC(R N1 )(R N1 )-N(R N1 )-、-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1)(R N1 )-N(R N1 )-、-N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-or-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ).

[0280] In certain embodiments, when X is 4 atoms in length, X in ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-N(R N1 )-C(R N1 )(R N1)-C(R N1 )(R N1 )-C(R N1 )(R N1 )-or-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[0281] In certain embodiments, X is OCH2, R N1 It's H.

[0282] In certain embodiments, X is CH2O, R N1 It's H.

[0283] In certain embodiments, the ASGPRBM comprises the following structure:

[0284]

[0285] In certain embodiments, the ASGPRBM comprises the following structure:

[0286]

[0287] In certain embodiments, R 1 yes Fig. 9 In certain embodiments, R 3 yes Fig. 9 In certain embodiments, R 1 and R 3 Each independently Fig. 9 The groups shown.

[0288] In certain embodiments, R 1 and R 3 Each independently represents H, -(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 independently selected halogens, -(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (Alkynyl), -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens KC(═O)O(C1-C4 alkyl), -OC(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -C(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens.

[0289] In certain embodiments, R 1 and R 3 Each independently is Ph(CH2) K -, which is optionally substituted by the following groups; 1-3 independently selected halogens; C1-C4 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxy groups; or C1-C4 alkoxy optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxy groups.

[0290] In certain embodiments, R 1 and R 3 Each is independently a group of the following structure:

[0291] -O-(CH2) K’ -CH(OH)-(CH2)K'-R 7 ,

[0292] Where R 7 is: C1-C4 alkoxy optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxyl groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2.

[0293] 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.

[0294] In certain embodiments, K' is 1. In certain embodiments, K' is 2. In certain embodiments, K' is 3. In certain embodiments, K' is 4.

[0295] 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;

[0296] In certain embodiments, R N4 Each occurrence of is independently H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyls, or Ph-(CH2) K -.

[0297] In certain embodiments, R 1 and R 3 Each independently selected from:

[0298] -(CH2) K OH, L 1 -≡-, L 1 -(CH2) K - and CYC-(CH2) K -,

[0299] Where CYC is selected from:

[0300]

[0301]

[0302] Among them The key marked indicates CYC on and -(CH2) K The site of connection.

[0303] In certain embodiments, L 1 is a bond, a -linker, a -CON-linker or a -CON-linker-CON.

[0304] In certain embodiments, R C is absent, H, C1-C4 alkyl optionally substituted by 1-3 optionally substituted halogens and / or 1-2 hydroxy groups, or a group of the following structure:

[0305]

[0306] Where R 4 , R 5 and R 6 Each independently represents H, F, Cl, Br, I, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 independently selected halogens, C1-C3 alkoxy optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens KC(═O)O-(C1-C4 alkyl), OC(═O)-(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -C(═O)-(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens.

[0307] In certain embodiments, R N2 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyl groups.

[0308] In certain embodiments, R C yes

[0309]

[0310] In certain embodiments, R 1 and R 3 Each is independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, where the carbocyclic ring is further separated by -L 1 and -R C replace.

[0311] 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.

[0312] In certain embodiments, R 2 yes Fig.10 The groups shown in .

[0313] In certain embodiments, R 2 Yes - (CH2) K -N(R N1 )-C(=O)R AM .

[0314] In certain embodiments, R AM is H, C1-C4 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxy groups, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -(CH2) K -NR N3 R N4 .

[0315] In certain embodiments, R 2 yes in:

[0316] R TA It is H, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(═O)O(C1-C4 alkyl), —OC(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or —C(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens,

[0317] or

[0318] R TA It is C3-C 10 Aryl or 3-membered or 10-membered heteroaryl containing 1-5 non-carbon ring atoms, each aryl or heteroaryl is optionally substituted by 1-3 groups independently selected from the following groups: CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydrocarbon groups, -(C1-C3-alkoxy) optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -(CH2) optionally substituted by 1-3 independently selected halogens K C(=O)-(C1-C4 alkyl),

[0319] or

[0320] R TA is optionally substituted by 1-3 C1-C3 alkyl groups optionally substituted by 1-3 independently selected halogen groups

[0321]

[0322] or

[0323] R TA yes Each -(CH2) K The group is optionally substituted with 1 to 4 C1-C3 alkyl groups which are optionally substituted with 1 to 3 fluoro groups or 1 to 2 hydrocarbon groups.

[0324] In certain embodiments, the ASGPRBM group comprises the following structure:

[0325]

[0326] Where: R A is C1-C3 alkyl optionally substituted by 1-5 independently selected halogens;

[0327] Z A Yes - (CH2) IM -、-O-(CH2) IM -、-S-(CH2) IM -、-NR M -(CH2) IM -、-C(=O)-(CH2) IM -, containing 1 to

[0328] PEG group with 8 ethylene glycol residues or -C(O)(CH2) IM NR M -;

[0329] Z B Does not exist, -(CH2) IM -、-C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M -;

[0330] R M is H or C1-C3 alkyl optionally substituted by 1-2 hydrocarbon groups; and

[0331] Each occurrence of IM is independently 0, 1, 2, 3, 4, 5 or 6.

[0332] In certain embodiments, R A is methyl or ethyl, either of which is optionally substituted by 1 to 3 fluorine groups.

[0333] In certain embodiments, Z A A PEG group containing 1 to 4 ethylene glycol residues.

[0334] In certain embodiments, the ASGPRBM group includes one of the following (Mamidyala, et al., 2012, J. Am.

[0335] Chem. Soc. 134: 1978-1981):

[0336]

[0337]

[0338]

[0339] In certain embodiments, the ASGPRBM group includes one of the following (Sanhueza et al., 2017, J. Am. Chem. Soc. 139:3528-3536):

[0340]

[0341]

[0342] Connector & CON

[0343] In certain embodiments, the linking group is a polyethylene glycol-containing linking group having 1-12 ethylene glycol residues.

[0344] In certain embodiments, the linking group comprises the following structure:

[0345] -CH2CH2(OCH2CH2) m OCH2-、-(CH2) m CH2-、-[N(R a )-CH(R b (C=O)] m - or a polypropylene glycol or polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units;

[0346] Each R a independently H, C1-C3 alkyl or C1-C6 alkanol, or with R b combine to form a pyrrolidine or hydroxypyrroline group;

[0347] Each R bindependently selected from hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole or -(CH2)phenol; and

[0348] wherein m is an integer ranging from 1 to 15.

[0349] In certain embodiments, the linking group comprises the structure -[N(R'-(CH2) 1-15 -C(=O)] m -, wherein R' is H or a C1-C3 alkyl group optionally substituted with 1-2 hydroxyl groups, and

[0350] m is an integer from 1 to 100.

[0351] In certain embodiments, the linking group comprises the following structure:

[0352] -ZD-Z'-,

[0353] in:

[0354] Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, -(CH2) i -C(R 2 )=C(R 2 )-(cis or trans), -(CH2) i -≡- or -YC(=O)-Y-;

[0355] Each R is independently H, C1-C3 alkyl or C1-C6 alkanol;

[0356] Each R 2 are independently H or C1-C3 alkyl;

[0357] Each Y is independently a bond, O, S or N(R);

[0358] 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;

[0359] D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m’ -or-[(CH2) n -X1)] j -, provided that Z, Z' and D are not each simultaneously a bond;

[0360] X 1 is O, S or N(R);

[0361] 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, 1, 2, 3, 4, or 5;

[0362] 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, 1, 2, 3, 4, or 5;

[0363] 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; in certain embodiments, 1, 2, 3, 4, or 5.

[0364] In certain embodiments, the linking group comprises the following structure:

[0365] -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n’ CH2CH2-or-(CH2CH2CH2O) n -,

[0366] wherein 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, 2 or 3; in certain embodiments, 1, 2, 3, 4, 5, 6, 7, or 8.

[0367] In certain embodiments, the linking group comprises the following structure:

[0368] -PEG-CON-PEG-

[0369] wherein each PEG is independently a polyethylene glycol group containing 1-12 ethylene glycol residues and CON is a triazole group

[0370] In certain embodiments, CON comprises the following structure:

[0371] wherein R' and R" are each independently H, methyl or a bond.

[0372] In certain embodiments, CON comprises a diamide structure:

[0373] -C(=O)-N(R 1 )-(CH2) n” -N(R 1 )C(=O)-,

[0374] -N(R 1 )-C(=O)(CH2) n” -C(=O)N(R 1 )-,or

[0375] -N(R 1 )-C(=O)(CH2) n” -N(R 1 )C(=O)-;

[0376] 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.

[0377] In certain embodiments, CON comprises the following structure:

[0378]

[0379] in:

[0380] R 1a , R 2a and R 3a Each independently represents H, -(CH2) M1 -、-(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -、-(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 -or-(CH2) M2 O-(CH2) M1 -C(O)NR 4 -, the condition is R 1a , R 2a and R 3a Not at the same time H;

[0381] Each M1 is independently 1, 2, 3 or 4; in certain embodiments, 1 or 2;

[0382] Each M2 is independently 0, 1, 2, 3 or 4; in certain embodiments, 0, 1 or 2;

[0383] Each M3 is independently 0 or 1; and

[0384] Each R 4are 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 Both M2 and M3 cannot be 0 at the same time.

[0385] In certain embodiments, CON comprises the following structure:

[0386]

[0387] Ab

[0388] Any antibody (Ab) that binds an extracellular protein is useful in the present disclosure. In certain non-limiting embodiments, the antibody is a monoclonal antibody.

[0389] Non-limiting examples of extracellular proteins contemplated in the present disclosure include: 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, Canis lupusfamiliaris)IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, aggregation factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli Shiga toxin type 1, Escherichia coli Shiga toxin type 2, EGFL7, endotoxin, epithelial sialoprotein, FGF 23, fibrin II, beta chain, fibronectin ectodomain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid protein, human scatter factor receptor kinase, human TNF, IFN-α, IFN-γ, IgE, IgEFc 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, hepatitis A virus hemagglutinin HA, interferon gamma, interferon gamma-induced 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), neural apoptosis regulating proteinase 1, NGF, NOGO-A, Notch 1. NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, root plate-specific spondin 33), RTN4, sclerostin, SDC1, serum amyloid A, 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.

[0390] Non-limiting examples of antibodies useful in the present disclosure include: Abagovomab, Abrezekimab, Adalimumab, Aducanumab, Afasevikumab, Afelimomab, Alirocumab, Altumomab, Atumomab, Atumomab Pentetate, and pentetate), Andecaliximab, Anrukinzumab, Arcitumomab, Ascrinvacumab, Atezolizumab, Atidortoxumab, Atinumab, Avelumab, Bapineuzumab, Bavituximab, Belimumab, Bermekimab, Besilesomab, Bevacizumab, Bisciclovir Biciromab, Bimekizumab, Birtamimab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumab, Cantuzumab ravtansine), Caplacizumab, Carlumab, Cergutuzumab, Cergutuzumab amunaleukin, Certolizumab, Certolizumabpegol, Cibisatamab, Clazakizumab, Clivatuzumab, Titan-Clivatuzumabtetraxetan), Concizumab, Crenezumab, Dectrekumab, Denosumab, Dezamizumab, Diridavumab, Domagrozumab, Dorlimomab, Dorlimomab aritox), Durvalumab, Dusigitumab, Eculizumab, Edobacomab, Efungumab, Eldelumab, Elezanumab, Elsilimomab, Emactuzumab, Emapalumab, Emicizumab, Enokizumab, Epitumomab, Epitumomabcituxetan), Eptinezumab, Erenumab, Evinacumab, Evolocumab, Faricimab, Fasinumab, Fezakinumab, Ficlatuzumab, Firivumab, Fletikumab, Fontolizumab, Fremanezumab, Fresolimumab, Frovocimab, Frunevetmab, Fulanuzumab Fulranumab, Galcanezumab, Gantenerumab, Gatipotuzumab, Gedivumab, Gevokizumab, Gimsilumab, Girentuximab, Golimumab, Gosuranemab, Guselkumab, Idarucizumab, Igovomab, Imalumab, Indatuximab, Indatuximabravtansine), infliximab, istiratumab, ixekizumab, labetuzumab, lacnotuzumab, lambalizumab, lanadelumab, landogrozumab, lebrikizumab, lemalesomab, lendalizumab, lenzlumab enzilumab, Lerdelimumab, Lesofavumab, Ligelizumab, Lodelcizumab, Lokivetmab, Lutikizumab, Marstacimab, Mepolizumab, Metelimumab, Mirikizumab, Nacolomab, Nacolomab tafenatox), Namilumab, Narnatumab, Navivumab, Naxitamab, Nebacumab, Nemolizumab, NEOD, Nerelimomab, Nesvacumab, Netakimab, Nofetumomab, Nofetumomabmerpentan), Obiltoxaximab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, OMS, Onartuzumab, Oregovomab, Orticumab, Otilimab, Ozannezumab zanezumab, Ozoralizumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Pemtumomab, Perakizumab, Pexelizumab, Placulumab, Ponezumab, Prasinezumab, Pritoxaximab, Quilizumab, Radretumab, Ralpancizumab, Ranevetmab, Ranibizumab, Ravulizumab, Raxibacumab, REGN- EB, Remtolumab, Reslizumab, Rilotumumab, Risankizumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Sacituzumab, Sacituzumab govitecan, Samrotamab, Vitin-Samrotamabvedotin), Sarilumab, Secukinumab, Setoxaximab, Setrusumab, Sifalimumab, Siltuximab, Simtuzumab, Sirukumab, Sofituzumab, Sofituzumab, Vedotin-Sofituzumab vedotin), Solanezumab, Sontuzumab, Stamulumab, Sulesomab, Sutimlimab, Suvizumab, Suvratoxumab, Tabalumab, Tacatuzumab, Tacatuzumab tetraxetan, Talizumab, Tanezumab, Tefibazumab, Telimomab, Telimomab aritox), Tesidolumab, Tezepelumab, Tibulizumab, Tildrakizumab, Timolumab, Tisotumab, Vitin-Tisotumab vedotin, tralokinumab, trevogrumab, urtoxazumab, ustekinumab, vanucizumab, vapaliximab, varisacumab, vepalimomab, vesencumab, vobarilizumab, vunakizumab, and xentuzumab.

[0391] Any method known in the art and / or any technique described or illustrated herein can be used to incorporate the antibody of interest into the compounds of the present disclosure. For example, the antibody can be attached to the linking group through the carboxylic acid group on the antibody surface, such as using amide or ester formation chemistry. For example, the antibody can be attached to the linking group through the amine group on the antibody surface, such as using amide formation chemistry. For example, the antibody can be attached to the linking group through the sulfhydryl group on the antibody surface, such as using nucleophilic substitution chemistry. In this case, the surface cysteine ​​residues can exist in the wild-type form of Ab and / or can be introduced by mutation (e.g., using site-directed mutagenesis). The linking group useful in the present disclosure can be any linking group known in the art, as long as the presence of the linking group does not significantly interfere with the ability of Ab to bind to circulating proteins.

[0392] As a non-limiting example, antibodies useful in the context of the present invention can bind to circulating proteins. As will be appreciated by those skilled in the art, any antibody that can recognize and specifically bind to a circulating protein is useful in the present disclosure. The present disclosure should not be construed as being limited to any one type of antibody, whether known or heretofore unknown, as long as the antibody can specifically bind to a circulating protein and prevent or minimize the biological activity of the circulating protein.

[0393] Methods for preparing and using such antibodies are well known in the art. For example, the production of polyclonal antibodies can be achieved by inoculating the desired animal with an antigen and isolating the antibody that specifically binds to the antigen therefrom. Monoclonal antibodies directed against the full length or peptide fragments of a protein or peptide can be prepared using any well-known monoclonal antibody preparation procedure, such as the methods described in Harlow et al. (1989, Antibodies, A Laboratory Manual, Cold Spring Harbor, New York) and Tuszynski et al. (1988, Blood 72: 109-115). The amount of the desired peptide can also be synthesized using chemical synthesis techniques. Alternatively, DNA encoding the desired peptide can be cloned and expressed from an appropriate promoter sequence in a cell suitable for producing a large amount of peptides. Using the standard procedures cited herein, monoclonal antibodies directed against the peptide are produced from mice immunized with the peptide. However, the present disclosure should not be interpreted as being limited to methods and compositions including these antibodies, but should be interpreted as including other antibodies, as defined elsewhere herein for the term.

[0394] 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. Descriptions of techniques for preparing such 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. Pat. Nos. 5,693,762, 5,693,761, 5,585,089 and 6,180,370.

[0395] The nucleic acids encoding antibodies obtained using the procedures described herein can be cloned and sequenced using techniques available in the art, such as those described in Wright et al. (Critical Rev. Immunol. 1992, 12: 125-168) and references cited therein. In addition, antibodies useful in the present disclosure can be "humanized" using techniques described in Wright et al. (above) and references cited therein, and Gu et al. (Thrombosis and Hematocyst 1997, 77: 755-759).

[0396] Alternatively, phage display technology can be used to produce antibodies. In order to produce a phage antibody library, first a cDNA library is obtained from the mRNA separated from a cell (e.g., a hybridoma), and the cell expresses the desired protein to be expressed on the phage surface, such as the desired antibody. Reverse transcriptase is used to produce a cDNA copy of the mRNA. The cDNA of the immunoglobulin fragment is obtained by PCR, and the resulting DNA is cloned into a suitable phage vector to generate a phage DNA library comprising the DNA of the prescribed immunoglobulin gene. The program for preparing a phage library comprising heterologous DNA is well known in the art, and is described, for example, in Sambrook et al. (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York).

[0397] The phage encoding the desired antibody can be modified so that the protein is displayed on its surface in a manner that can be used to bind to its corresponding binding protein (e.g., the antigen to which the antibody is directed). Therefore, when the phage expressing a specific antibody is incubated in the presence of a cell expressing the corresponding antigen, the phage will bind to the cell. Phage that does not express the antibody will not bind to the cell. This panning technique is well known in the art, for example, as described in Wright et al. (Critical Rev. Immunol. 1992, 12: 125-168).

[0398] A method for producing human antibodies using M13 phage display has been developed, as described herein (Burton et al., 1994, Adv. Immunol. 57: 191-280). In essence, a cDNA library is produced from mRNA obtained from an antibody-producing cell population. The mRNA encodes rearranged immunoglobulin genes, so the cDNA encodes the same genes. The amplified cDNA is cloned into an M13 expression vector to create a phage library, and the phage expresses human Fab fragments on its surface. Phages that display the antibody of interest are selected by antigen binding and propagated in bacteria to produce soluble human Fab immunoglobulins. Therefore, compared with traditional monoclonal antibody synthesis, this procedure immortalizes the DNA encoding human immunoglobulins instead of immortalizing the cells expressing human immunoglobulins.

[0399] The procedure just introduced describes the generation of phages encoding the Fab part of antibody molecules. However, the present disclosure should not be construed as being limited to the generation of phages encoding Fab antibodies. Rather, phages encoding single-chain antibodies (scFv / phage antibody libraries) are also included in the present disclosure. Fab molecules include the entire Ig light chain, that is, they include the variable region and constant region of the light chain, but only include the variable region and the first constant region domain (CH1) of the heavy chain. Single-chain antibody molecules include single-chain proteins, which include Ig Fv fragments. The Ig Fv fragments only include the variable regions of the antibody heavy chain and light chain, wherein the constant region is not contained. The phage library comprising scFv DNA can be produced according to the procedure described in Marks et al. (1991, J Mol Biol 222: 581-597). The panning of the phages thus produced is carried out in a manner similar to that described in the phage library comprising Fab DNA, for separating the desired antibodies.

[0400] The present disclosure should also be interpreted as including synthetic phage display libraries, in which heavy and light chain variable regions can be synthesized such that they include nearly all possible specificities (Barbas, 1995, Nature Medicine 1:837-839; deKruif et al., 1995, J Mol Biol 248:97-105).

[0401] Additional galactose- and talose-based ASGPR binding moieties

[0402] In one embodiment, the present invention is directed to compounds useful for clearing circulating proteins associated with a disease state or condition in a patient or subject according to the general chemical structure of Formula II, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof:

[0403]

[0404] 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 asiaglycoprotein receptor (ASGPR) binding moiety as defined herein.

[0405] In the compounds of formula II, each [CON] is an optional linker chemical moiety which, when present, directly links [CPBM] or [CRBM] or links [LINKER-2] to [CPBM] or [CRBM].

[0406] In the compound of formula II:

[0407] [LINKER-2] is a chemical moiety with a valence of 1 to 15, which is covalently attached to one or more [CRBM] and / or [CPBM] groups, optionally via a [CON] comprising a [MULTICON] group, wherein the [LINKER-2] itself optionally contains one or more [CON] or [MULTICON] groups;

[0408] k' is an integer from 1 to 15;

[0409] j' is an integer from 1 to 15;

[0410] h and h' are each independently an integer from 0 to 15;

[0411] i L is an integer from 0 to 15;

[0412] The conditions are h, h' and i L At least one of is at least 1.

[0413] The [MULTICON] group may link one or more [CRBM] or [CPBM] to one or more [LINKER-2]. In various embodiments, the valence of [LINKER-2] is from 1 to 10. In various embodiments, the valence of [LINKER-2] is from 1 to 5. In various embodiments, the valence of [LINKER-2] is 1, 2, or 3. In various embodiments, in the compounds of Formula II, [LINKER-2] comprises a linking group as defined herein A , Linking group B , Linking group C , Linking group D and / or one or more of their combinations.

[0414] In the 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.

[0415] In the 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.

[0416] In the 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.

[0417] In the compound of formula II, X 1 is 1 to 5 independently selected from O, S, N(R b ) and C(R 4 )(R 4 ) of consecutive atoms, where if X 1 is 1 atom, then X 1 O, S, N (R 6 ) or C(R 4 )(R 4 ); if X 1 is 2 atoms, then X 1 No more than one atom in the 6 ); if X 1 is 3, 4 or 5 atoms, then X 1 No more than 2 atoms are O, S or N (R 6 );

[0418] R 3is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaralkyl, alkenyl, alkynyl and heteroaryl, heterocycle, -OR 8 and-NR 8 R 9 ;

[0419] R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 ,

[0420] R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, 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 ;

[0421] R 8 and R 9 and alkyl. Each occurrence of is independently selected from the group consisting of hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[0422] A. Galactose-based ASGPR-binding cell receptor binding moiety of Formula II

[0423] In certain embodiments, the compound of Formula II is selected from:

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443] In one embodiment, the compound of Formula II has one of the following structures:

[0444]

[0445] In various embodiments, the ASGPR ligand is present in C 1 or C 5 (R 1 or R 5 ) position to form a degradation compound. In various embodiments, the ASGPR ligand is attached at C 6 The ASGPR ligand is connected to the target site to form a degradation compound. For example, when the ASGPR ligand is the following structure:

[0446]

[0447] Then, non-limiting examples of ASGPR binding compounds of Formula II include:

[0448]

[0449] or a di-substituted or tri-substituted form or a pharmaceutically acceptable salt thereof, wherein the di-substituted or tri-substituted refers to the number of additional galactose derivatives attached to the linking group moiety.

[0450] In any embodiment described herein where an ASGPR ligand is used as a degrader, the ASGPR ligand is typically in the C 5 The position of the extracellular protein targeting ligand is connected (for example, this can refer to the adjacent C 6 When the linker and the extracellular protein targeting ligand are connected by C 1 When attachment is made at the position of the carbon, the carbon may be appropriately functionalized for attachment, for example, to a hydroxyl, amino, allyl, alkynyl or hydroxy-allyl group.

[0451] In various embodiments, the ASGPR ligand is not in C 3 or C 4 In some embodiments, the ASGPR ligands that can be incorporated into the compounds of Formula II are selected from:

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] In certain embodiments, the compound of Formula II is selected from:

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] B. Talose-Based ASGPR Binding Cell Receptor Binding Moieties of Formula II

[0470] In certain embodiments, the compound of Formula II is selected from:

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] In one embodiment, the compound of Formula II is an extracellular protein degradation compound wherein the ASGPR ligand is a ligand described herein

[0511]

[0512] In one embodiment, in the compound of Formula II, the ASGPR ligand is at C1 or C5 (R 1 or R 5 ) position to form a degradation compound. In one embodiment, in the compound of Formula II, the ASGPR ligand is attached at C6. In various embodiments, when the ASGPR ligand is

[0513]

[0514] Non-limiting examples of ASGPR binding compounds of Formula II include:

[0515]

[0516] or a disubstituted or trisubstituted form or a pharmaceutically acceptable salt thereof, wherein disubstituted or trisubstituted refers to the number of additional galactose derivatives attached to the linking moiety. In certain embodiments, the compound of Formula II is selected from:

[0517]

[0518] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0519] In certain embodiments, the compound of Formula II is selected from:

[0520]

[0521]

[0522] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0523] In certain embodiments, the compound of Formula II is selected from:

[0524]

[0525]

[0526] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0527] In certain embodiments, the compound of Formula II is selected from:

[0528]

[0529]

[0530] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0531] In certain embodiments, the compound of Formula II is selected from:

[0532]

[0533]

[0534] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0535] In certain embodiments, the compound of Formula II is selected from:

[0536]

[0537]

[0538] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6-(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0539] In certain embodiments, the compound of Formula II is selected from:

[0540]

[0541]

[0542] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 3 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0543] In certain embodiments, the compound of Formula II is selected from:

[0544]

[0545]

[0546] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0547] In certain embodiments, the compound of Formula II is selected from:

[0548]

[0549]

[0550] Wherein in certain embodiments, R 2 Selected from -NR b COR 10 、-NR 6-(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0551] In certain embodiments, the compound of Formula II is selected from:

[0552]

[0553]

[0554]

[0555] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0556] In certain embodiments, the compound of Formula II is selected from:

[0557]

[0558]

[0559] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0560] In certain embodiments, the compound of Formula II is selected from:

[0561]

[0562]

[0563] Wherein in certain embodiments, R2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0564] In certain embodiments, the compound of Formula II is selected from:

[0565]

[0566]

[0567] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0568] In certain embodiments, the compound of Formula II is selected from:

[0569]

[0570]

[0571] Wherein in certain embodiments, R 2 Selected from -NR 6 COR 10 、-NR 6 -(5-membered heteroaryl) and -NR 6 -(6-membered heteroaryl), wherein each R 2 The group is optionally substituted with 1, 2, 3 or 4 independent substituents described herein, for example 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0572] In certain embodiments, the compound of Formula II is selected from:

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584] In certain embodiments, the ASGPR ligands useful for incorporation into the compounds of Formula II are selected from:

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598] C. ASGPR Ligand / Binding Moiety in Compounds of Formula II

[0599] In certain embodiments, in the compound of Formula II, R1 It's hydrogen.

[0600] In certain embodiments, in the compound of Formula II, R 1 yes

[0601] In certain embodiments, in the compound of Formula II, R 1 yes

[0602] In certain embodiments, in the compound of Formula II, R 1 yes

[0603] In certain embodiments, in the compound of Formula II, R 1 yes

[0604] In certain embodiments, in the compound of Formula II, R 1 yes

[0605] In certain embodiments, in the compound of Formula II, R 1 yes

[0606] In certain embodiments, in the compound of Formula II, R 1 is C0-C6 alkyl-cyano which is optionally substituted by 1, 2, 3 or 4 substituents.

[0607] In certain embodiments, in the compound of Formula II, R 1 is alkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0608] In certain embodiments, in the compound of Formula II, R 1 is an alkenyl group 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 a haloalkyl group optionally substituted with 1, 2, 3 or 4 substituents. 1 It's F.

[0609] In certain embodiments, in the compound of Formula II, R 1 It is Cl.

[0610] In certain embodiments, in the compound of Formula II, R 1 It's Br.

[0611] In certain embodiments, in the compound of Formula II, R 1 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0612] In certain embodiments, in the compound of Formula II, R 1 is aralkyl optionally substituted by 1, 2, 3 or 4 substituents.

[0613] In certain embodiments, in the compound of Formula II, R 1 is heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0614] In certain embodiments, in the compound of Formula II, R 1 is heteroaralkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0615] In certain embodiments, in the compound of Formula II, R 1 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0616] In certain embodiments, in the compound of Formula II, R 1 is heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents.

[0617] In certain embodiments, in the compound of Formula II, R 1 is haloalkoxy optionally substituted with 1, 2, 3 or 4 substituents.

[0618] In certain embodiments, in the compound of Formula II, R 1 is -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 、C0-C6 alkyl-C(S)R 3 、C0-C6 alkyl-S(O)2R 3 、C0-C6 alkyl-N(R 8 )-C(O)R 3 、C0-C6 alkyl-N(R 8 )-S(O)R 3 、C0-C6 alkyl-N(R 8 )-C(S)R 3 、C0-C6 alkyl-N(R 8 )-S(O)2R 3、C0-C6 alkyl-OC(O)R 3 、C0-C6 alkyl-OS(O)R 3 、C0-C6 alkyl-OC(S)R 3 、-N=S(O)(R 3 )2, C0-C6 alkyl N3 or C0-C6 alkyl-OS(O)2R 3 , wherein each is optionally substituted with 1, 2, 3 or 4 substituents.

[0619] In certain embodiments, in the compound of Formula II, R 2 is aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0620] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0621] In certain embodiments, in the compound of Formula II, R 2 is a heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O and S optionally substituted by 1, 2, 3 or 4 substituents.

[0622] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0623]

[0624] In certain embodiments, in the compound of Formula II, R 2 is a heterocycle optionally substituted by 1, 2, 3 or 4 substituents.

[0625] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)-R 3 .

[0626] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -C(S)-R 3 .

[0627] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)(NR 6 )-R 3 .

[0628] In certain embodiments, in the compound of Formula II, R 2 is -N=S(O)(R 3 )2.

[0629] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 C(O)NR 9 S(O)2R 3 .

[0630] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -S(O)2-R 10 .

[0631] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 8 -C(NR 6 )-R 3 .

[0632] In certain embodiments, in the compound of Formula II, R 2 It's hydrogen.

[0633] In certain embodiments, in the compound of Formula II, R 2 YesR 10 .

[0634] In certain embodiments, in the compound of Formula II, R 2 is alkyl-C(O)-R 3 .

[0635] In certain embodiments, in the compound of Formula II, R 2 Yes-C(O)-R 3 .

[0636] In certain embodiments, in the compound of Formula II, R 2 It is an alkyl group.

[0637] In certain embodiments, in the compound of Formula II, R 2 It is a haloalkyl group.

[0638] In certain embodiments, in the compound of Formula II, R 2 Yes-OC(O)R 3 .

[0639] In certain embodiments, in the compound of Formula II, R 2 Yes - NR 8 -C(O)R 10 .

[0640] In certain embodiments, in the compound of Formula II, R 2 is alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0641] In certain embodiments, in the compound of Formula II, R 2 is allyl optionally substituted with 1, 2, 3 or 4 substituents.

[0642] In certain embodiments, in the compound of Formula II, R 2 is alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0643] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkenyl.

[0644] In certain embodiments, in the compound of Formula II, R 2 is -O-alkenyl optionally substituted with 1, 2, 3 or 4 substituents.

[0645] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -alkynyl.

[0646] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -heteroaryl.

[0647] In certain embodiments, in the compound of Formula II, R 2 is -NR optionally substituted with 1, 2, 3 or 4 substituents 6 -Aryl.

[0648] In certain embodiments, in the compound of Formula II, R 2 is -O-heteroaryl optionally substituted with 1, 2, 3 or 4 substituents.

[0649] In certain embodiments, in the compound of Formula II, R 2 is -O-aryl optionally substituted with 1, 2, 3 or 4 substituents.

[0650] In certain embodiments, in the compound of Formula II, R 2 is -O-alkynyl optionally substituted with 1, 2, 3 or 4 substituents.

[0651] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0652]

[0653] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0654]

[0655] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0656]

[0657] wherein R is an optional substituent as defined herein.

[0658] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0659]

[0660] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0661]

[0662] wherein R is an optional substituent as defined herein.

[0663] In certain embodiments, in the compound of Formula II, R 2A Selected from

[0664]

[0665] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0666]

[0667]

[0668] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0669]

[0670] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0671] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0672] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0673]

[0674] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0675]

[0676] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0677]

[0678] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0679]

[0680] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0681]

[0682] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0683]

[0684] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0685]

[0686] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0687]

[0688] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0689]

[0690] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0691]

[0692] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0693]

[0694] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0695]

[0696] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0697]

[0698] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0699]

[0700] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0701]

[0702] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0703]

[0704] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0705]

[0706] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0707]

[0708] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0709]

[0710] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0711]

[0712] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0713]

[0714] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0715]

[0716] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0717]

[0718] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0719]

[0720] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0721]

[0722] In certain embodiments, in the compound of Formula II, R 2 or R 2A Selected from

[0723]

[0724] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0725]

[0726] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0727]

[0728] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0729]

[0730] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0731]

[0732] In certain embodiments, in the compound of Formula II, R 2 Selected from

[0733] In certain embodiments, in the compound of Formula II, R 2 is a spiro heterocycle, such as but not limited to,

[0734] In certain embodiments, in the compound of Formula II, R 2 is a silicon-containing heterocycle, such as but not limited to,

[0735] In certain embodiments, in the compound of Formula II, R 2 Replaced by SF5, such as but not limited to,

[0736]

[0737] In certain embodiments, in the compound of Formula II, R 2 Substituted with sulfoxime, such as but not limited to,

[0738]

[0739] In certain embodiments, in the compound of Formula II, R 10 is selected from bicyclic heterocycles.

[0740] In certain embodiments, in the compound of Formula II, R 10 is selected from spiro heterocycles.

[0741] In certain embodiments, in the compound of Formula II, R 10 Selected from -NR 6 -Heterocyclic ring.

[0742] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0743] In certain embodiments, in the compound of Formula II, R10 Selected from

[0744]

[0745] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0746]

[0747] In certain embodiments, in the compound of Formula II, R 10 Selected from

[0748]

[0749] In certain embodiments, in the compound of Formula II, the ring is selected from

[0750]

[0751] In certain embodiments, in the compound of Formula II, R 30 Selected from

[0752]

[0753] In certain embodiments, in the compound of Formula II, R 200 yes

[0754]

[0755] In certain embodiments, in the compound of Formula II, R 200 yes

[0756] In certain embodiments, in the compound of Formula II, R 200 yes

[0757] In certain embodiments, in the compound of Formula II, R 200 yes

[0758] In certain embodiments, in the compound of Formula II, R 200 yes

[0759] In certain embodiments, in the compound of Formula II, R 200 yes In certain embodiments, in the compound of Formula II, R 200 yes

[0760] In certain embodiments, in the compound of Formula II, R200 yes

[0761] In certain embodiments, in the compound of Formula II, R 200 yes

[0762] In certain embodiments, in the compound of Formula II, R 200 yes

[0763] In certain embodiments, in the compound of Formula II, R 200 yes

[0764] In certain embodiments, in the compound of Formula II, R 200 yes

[0765] Linking group

[0766] In a non-limiting embodiment, in the compound of Formula II, the linking group A and linking groups B Independently selected from:

[0767]

[0768] in:

[0769] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 is independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -、-NR 6 C(O)-, -O-, -S-, -NR 6 -、-C(R 21 R 21 )-、-P(O)(R 3 )O-、-P(O)(R 3 )-, divalent residues of natural or unnatural amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, and heterocyclic, heteroaryl, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR6 -、-CH2CH2-[O-(CH2)2] n -、-[-(CH2)2-O-] n -、-[O-(CH2)2] n -、-[O-CH(CH3)C(O)] n -、-[C(O)-CH(CH3)-O] n -、-[O-CH2C(O)] n -、-[C(O)-CH2-O] n -, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated monocarboxylic acid or a divalent residue of a dicarboxylic acid; each of which is independently selected from R 21 1, 2, 3 or 4 substituents of are optionally substituted;

[0770] n is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0771] R 21 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxy, alkoxy, azide, amino, cyano, -NR 6 R 7 、-NR 8 S02R 3 、-NR 8 S(O)R 3 , haloalkyl, heteroalkyl, and heteroaryl, and heterocycle;

[0772] and the remaining variables are as defined herein.

[0773] In one embodiment, in the compound of formula II, the linking group A are bonds and linking groups B yes

[0774]

[0775] In one embodiment, in the compound of formula II, the linking group B are bonds and linking groups A yes

[0776]

[0777] In one embodiment, in the compound of formula II, the divalent amino acid residue is selected from

[0778]

[0779]

[0780] Therein the amino acids may be oriented in either direction and therein the amino acids may be in the L- or D-form or a mixture thereof.

[0781] In one embodiment, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated by a nucleophilic addition reaction:

[0782]

[0783] Non-limiting embodiments of the divalent residue of a dicarboxylic acid generated by a nucleophilic addition reaction include:

[0784]

[0785] In one embodiment, in the compound of formula II, the divalent residue of a dicarboxylic acid is formed by the condensation reaction:

[0786]

[0787] Non-limiting embodiments of the divalent residue of a dicarboxylic acid produced by the condensation include:

[0788]

[0789] Non-limiting embodiments of the divalent residue of a saturated dicarboxylic acid include:

[0790]

[0791] Non-limiting embodiments of the divalent residue of a saturated dicarboxylic acid include:

[0792]

[0793] Non-limiting embodiments of the divalent residue of a saturated monocarboxylic acid are selected from butyric acid (-OC(O)(CH2)2CH2-), hexanoic acid (-OC(O)(CH2)4CH2-), octanoic 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 tetracosanoic acid (-OC(O)(CH2) 22 CH2-);

[0794] Non-limiting embodiments of divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid:

[0795]

[0796] Non-limiting embodiments of the divalent fatty acid residue are selected from 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-), linolenic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), y- Linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), arachidonic acid (-C(O)(CH2)3(CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), eicosenoic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), eicos-11-enoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), cis-9-eicosenoic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), tetracosenoic acid (-C(O)(CH2) 13 CHCH(CH2)3CH2-), eicosatrienoic acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0797] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0798]

[0799] in:

[0800] R 22 is independently selected at each occurrence from alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 )N-, alkenyl, haloalkyl, aryl, heterocyclic and heteroaryl, each of which is independently selected from R 21 1, 2, 3 or 4 substituents of are optionally substituted;

[0801] and the remaining variables are as defined herein.

[0802] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0803]

[0804] in:

[0805] R 32 is independently selected at each occurrence from alkyl, N + X-, -C-, alkenyl, haloalkyl, aryl, heterocyclic and heteroaryl, each of which is independently selected from R 21 1, 2, 3 or 4 substituents of are optionally substituted;

[0806] X- is an anionic group, such as Br- or Cl - ;and

[0807] All other variables are as defined herein.

[0808] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0809]

[0810] Each of the heteroaryl, heterocycle, cycloalkyl and aryl groups may be optionally substituted with 1, 2, 3 or 4 halogen, alkyl, haloalkyl, and any combination of heteroaryl, heterocycle or cycloalkyl groups as valence permits.

[0811] In certain embodiments, in the compound of Formula II, the linking groupA Selected from:

[0812]

[0813] Each heteroaryl, heterocycle, cycloalkyl group may be optionally substituted with any combination of 1, 2, 3 or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl groups as allowed by valence.

[0814] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0815]

[0816] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0817]

[0818] In certain embodiments, in the compound of Formula II, the linking group B , Linking group C or linking group D Selected from:

[0819]

[0820] wherein tt is independently selected from 1, 2 or 3 and ss is 3 minus tt (3-tt).

[0821] In certain embodiments, in the compound of Formula II, the linking group B , Linking group C or linking group D Selected from:

[0822]

[0823] wherein tt and ss are as defined herein.

[0824] In certain embodiments, in the compound of Formula II, the linking group B , Linking group C or linking group D Selected from:

[0825]

[0826]

[0827]

[0828]

[0829] wherein each heteroaryl, heterocycle, cycloalkyl and aryl may be optionally substituted with any combination of 1, 2, 3 or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl, as valence permits; and tt and ss are as defined herein.

[0830] In certain embodiments, in the compound of Formula II, the linking group B , Linking group C or linking group D Selected from:

[0831]

[0832]

[0833] wherein each heteroaryl, heterocycle, cycloalkyl and aryl may be optionally substituted with any combination of 1, 2, 3 or 4 halogen, alkyl, haloalkyl, heteroaryl, heterocycle or cycloalkyl, as valence allows: and tt and ss are as defined herein.

[0834] In certain embodiments, in the compound of Formula II, the linking group B , Linking group C or linking group D Selected from:

[0835]

[0836] wherein each heteroaryl and aryl may be optionally substituted with any combination of 1, 2, 3 or 4 halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle or cycloalkyl, as valence permits; and tt and ss are as defined herein.

[0837] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0838]

[0839] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0840]

[0841] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0842]

[0843] In certain embodiments, in the compound of Formula II, the linking group ASelected from:

[0844]

[0845] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0846]

[0847] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0848]

[0849] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0850]

[0851]

[0852] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0853]

[0854]

[0855] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0856]

[0857] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0858]

[0859] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0860]

[0861] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0862]

[0863] In certain embodiments, in the compound of Formula II, the linking groupC Selected from:

[0864]

[0865] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0866]

[0867] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0868]

[0869] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0870]

[0871] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0872]

[0873] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0874]

[0875]

[0876] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0877]

[0878] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0879]

[0880] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0881]

[0882] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0883]

[0884] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0885]

[0886] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0887]

[0888] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0889]

[0890] In certain embodiments, in the compound of Formula II, the linking group A Selected from:

[0891]

[0892] In certain embodiments, the linking group A Selected from

[0893]

[0894]

[0895] Each of which is selected from R 21 1, 2, 3 or 4 substituents are optionally substituted. In certain embodiments, in the compound of formula II, the linking group A Selected from:

[0896]

[0897] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0898]

[0899] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0900]

[0901] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0902]

[0903] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0904]

[0905] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0906]

[0907] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0908]

[0909]

[0910] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0911]

[0912]

[0913] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0914]

[0915] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0916]

[0917] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0918]

[0919] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0920]

[0921] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0922]

[0923] In certain embodiments, in the compound of Formula II, the linking group A Selected from

[0924]

[0925] In certain embodiments, in the compound of Formula II, the linking group B Selected from

[0926]

[0927] In certain embodiments, in the compound of Formula II, the linking group B Selected from

[0928]

[0929] In certain embodiments, in the compound of Formula II, the linking group B Selected from

[0930]

[0931] In certain embodiments, in the compound of Formula II, the linking group B Selected from, where each is selected from R 21 1, 2, 3 or 4 substituents are optionally substituted.

[0932] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0933]

[0934] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0935]

[0936] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0937]

[0938] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0939]

[0940] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0941]

[0942] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0943]

[0944] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0945]

[0946] In certain embodiments, in the compound of Formula II, the linking group B Selected from:

[0947]

[0948] In certain embodiments, in the compound of Formula II, the linking group B -Linking group A Selected from:

[0949]

[0950] In certain embodiments, in the compound of Formula II, the linking group B -Linking group A Selected from:

[0951]

[0952] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0953]

[0954] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0955]

[0956] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0957]

[0958] In certain embodiments, in the compound of Formula II, the linking groupC Selected from:

[0959]

[0960] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0961]

[0962] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0963]

[0964] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0965]

[0966]

[0967] In certain embodiments, in the compound of Formula II, the linking group C Selected from: Each of which is selected from R 21 1, 2, 3 or 4 substituents are optionally substituted.

[0968] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0969]

[0970] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0971]

[0972] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0973] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0974]

[0975] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0976]

[0977] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0978]

[0979] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0980]

[0981] In certain embodiments, in the compound of Formula II, the linking group C Selected from:

[0982]

[0983] In certain embodiments, in the compound of Formula II, the linking group C -(Linking Group A )2Selected from:

[0984]

[0985] In certain embodiments, in the compound of Formula II, the linking group C -(Linking Group A )2Selected from:

[0986]

[0987] In certain embodiments, in the compound of Formula II, the linking group C -(Linking Group A )2Selected from:

[0988]

[0989] In certain embodiments, in the compound of Formula II, the linking group C -(Linking Group A )2Selected from:

[0990]

[0991] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0992]

[0993] In certain embodiments, in the compound of Formula II, the linking group D Selected from:

[0994]

[0995] Each of which is selected from R 21 1, 2, 3 or 4 substituents are optionally substituted.

[0996] In certain embodiments, in the compound of Formula II, the linking group B -(Linking Group A )

[0997]

[0998] In certain embodiments, in the compound of Formula II, the linking group C -(Linking Group A )

[0999]

[1000] In certain embodiments, in the compound of Formula II, the linking group D -(Linking Group A )

[1001]

[1002] In various embodiments, R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 .

[1003] In various embodiments, in the compound of Formula II, R 5 are independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 、C0-C6 alkyl-C(S)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 alkyl N3 and C0-C6 alkyl-OS(O)2R 3 , wherein each is optionally substituted with 1, 2, 3 or 4 substituents.

[1004] In various embodiments, in the compound of Formula II, R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, 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 .

[1005] In various embodiments, in the compound of Formula II, R 8 and R 9 and alkyl. Each occurrence of is independently selected from the group consisting of hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.

[1006] 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.

[1007] A compound of formula II-A having the following structure or a salt, stereoisomer or solvate thereof:

[1008]

[1009] in:

[1010] [Ab] is an antibody that binds to extracellular proteins;

[1011] [ASGPBM] is an asialoglycoprotein receptor binding moiety having a structure selected from the group consisting of

[1012]

[1013]

[1014] Each [CON] is an optional linker chemical moiety which, when present, links [LIN] to [CPBM] or [ASGPBM];

[1015] [LIN] is [LINKER] or [LINKER-2], each of which is a chemical moiety with a valence of 1 to 15, which is covalently attached to one or more [ASGPBM] or [CPBM] groups, optionally via [CON], wherein [LIN] itself optionally contains one or more [CON] groups;

[1016] Z B Does not exist, (CH2) IM 、C(O)-(CH2) IM - or C(O)-(CH2) IM -NR M ;

[1017] R M is H or C1-C3 alkyl optionally substituted by one or two hydroxy groups;

[1018] R2 is

[1019] Where R AM is H, C1-C4 alkyl optionally substituted by up to 3 halo groups and 1 or 2 hydroxy groups, -(CH2) K COOH, -(CH2) optionally substituted by 1 to 3 halo groups K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halo groups, -C(O)-(C1-C4 alkyl) optionally substituted by 1-3 halo groups, or -(CH2) K -NR N3 R N4 ,or

[1020] R2 is

[1021] in

[1022] R TA It is H, CN, NRN1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1 to 3 halo groups K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 halo groups, -(CH2) K COOH, -(CH2) optionally substituted by 1 to 3 halo groups K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halo groups, or -C(O)-(C1-C4 alkyl) optionally substituted by 1-3 halo groups, or

[1023] R TA It is C3-C 10 Aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each aryl or heteroaryl group being optionally substituted by up to 3 of the following groups: CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1 to 3 halo groups K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 halo groups or 1-2 hydroxyl groups, -O-(C1-C3-alkyl) optionally substituted by 1-3 halo groups, -(CH2)KCOOH, -(CH2) optionally substituted by 1-3 halo groups K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) optionally substituted by 1-3 halo groups, or -(CH2) optionally substituted by 1-3 halo groups K C(O)-(C1-C4 alkyl), or

[1024] R TA yes which is optionally substituted with up to three C1-C3 alkyl groups, which are optionally substituted with up to three halo groups; or

[1025] R TA yes

[1026] R N , R N1 , R N2 , R N3 , R N4 are each independently H or C1-C3 alkyl optionally substituted by 1 to 3 halo groups or 1 or 2 hydroxyl groups, and each -(CH2) KThe group is optionally substituted by 1-4 C1-C3 alkyl groups, and these C1-C3 alkyl groups are optionally substituted by 1-3 fluoro groups or 1-2 hydroxyl groups;

[1027] IM is independently an integer from 0 to 6 at each occurrence;

[1028] K is independently an integer from 0 to 4 at each occurrence;

[1029] k' is an integer ranging from 1 to 15;

[1030] j' is an integer ranging from 1 to 15;

[1031] h and h' are each independently an integer ranging from 0 to 15;

[1032] i L 0 to 15;

[1033] The conditions are h, h' and i L At least one of is at least 1.

[1034] In various embodiments, in the compound of Formula II-A, R2 is -NC(=O)CH3.

[1035] D. Based on other ASGPR binding moieties

[1036] In some embodiments, the ASGPR binding moiety can be any of the moieties described 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; 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., "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, volume 69, issue 1, pages 158-163, January 2020; Yamansarov, E. Yu. et al., “New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids,” Russian Chemical Bulletin, International Edition, volume 68, issue 12, pages 2331-2338, December 2019; Congdon, M.D. 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 invitro assessment", Carbohydrate Research 509(2021)108417, doi: 10.1016 / j.carres.2021.108417. The following ASGPR binding moieties are illustrative and not intended to be limiting. .

[1037] 1. GalNAc-tyrosine based moiety

[1038] In some embodiments, the ASGPR binding moiety can be a moiety having a structure of M1, M2, M3, or M4, or a combination thereof. In the structures of M1, M2, M3, and M4, X is independently O, NH, or S at each occurrence. In various embodiments, the compound of Formula I or Formula II can have one, two, or three ASGPR binding moieties having a structure of M1, M2, M3, or M4.

[1039]

[1040] In various embodiments, the ASGPR binding moieties M1 to M4 can be conjugated to any suitable [CON], [Linker] or [Linker-2] 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.

[1041] 2. Trivalent triazole-based moieties

[1042] In some embodiments, the ASGPR binding moiety can be a moiety having the structure M5:

[1043]

[1044] In Structure M5, each R at each occurrence is independently R1 or R2,

[1045]

[1046] In various embodiments, the compound of Formula I or Formula II contains an ASGPR binding portion having the structure of M5. In various embodiments, each R in M5 is R1. In various embodiments, each R in M5 is R2.

[1047] In various embodiments, the ASGPR binding moiety M5 can be conjugated / bonded to any suitable [CON], [Linker] or [Linker-2] 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.

[1048] 3. Galactose and agarose derivatized behenate moieties

[1049] In various embodiments, the ASGPR binding moiety can be a galactosylbehenate-derivatized moiety M7:

[1050]

[1051] In structure M7, Y is OH or NHAc.

[1052] In various embodiments, the ASGPR binding moiety can be agarose behenate-derivatized moiety M8:

[1053]

[1054] In various embodiments, the ASGPR binding moieties M7 and M8 can be conjugated to any suitable [CON], [Linker] or [Linker-2] 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.

[1055] 4. Other small molecule ASGPR binding moieties

[1056] In various embodiments, the ASGPR binding moiety can be any of the following compounds 2-18:

[1057]

[1058] In various embodiments, in compounds 15 and 16, R is CH2OAc, COOH or CH2OH. Compounds 2-18 can be used in this article and in Majouga, AG et al., "Identification of Novel Small-Molecule ASGP-RL ligands", Current Drug Delivery, 2016, 13, 1303-1312, doi: 10.2174 / 1567201813666160719144651; 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, any suitable [CON], [Linker] or [Linker-2] conjugation / bonding. Compound 2-18 can be attached via any suitable reactive group contained therein. Without limitation, compound 2-13 can be attached to [CON], [Linker] or [Linker-2] via or by reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone or aromatic halogen contained in compound 2-18. Suitable reaction modes for attaching compound 2-18 to [CON], [Linker] or [Linker-2] described herein include, but are not limited to, substitution (e.g., alkylation of OH or NH groups), esterification (ester formation), amidation (amide formation), transesterification (exchanging one ester for another ester), transamidation (exchanging one amide for another amide), azide-alkyne cycloaddition, and other reactions capable of forming CC, NC or OC bonds with vinyl and alkynyl groups, such as cycloadditions, aminations, oxidations, alkylations, rearrangements (e.g., Claisen, Cope, etc.), and the like.

[1059] The present disclosure includes polyclonal antibodies, monoclonal antibodies, synthetic antibodies, etc. Based on the disclosure provided herein, one of ordinary skill in the art will appreciate that an important feature of antibodies useful in the present disclosure is that the antibodies specifically bind to circulating proteins.

[1060] The compounds described herein may have one or more stereocenters, and each stereocenter may exist independently in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. It should be understood that the compounds described herein include racemic, optically active, regioisomers, and stereoisomeric forms or combinations thereof having therapeutically useful properties as described herein. The preparation of optically active forms is achieved in any suitable manner, including, as non-limiting examples, by resolving the racemic form with recrystallization techniques, synthesizing from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as a therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The resolution of compounds and their isomers may be achieved by any means, including but not limited to chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[1061] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound (one or more) described herein, as well as metabolites and active metabolites of these compounds having the same active type. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[1062] In certain embodiments, the compound(s) described herein may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[1063] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into a parent drug in vivo. In certain embodiments, after in vivo administration, the prodrug is chemically converted into a biological, pharmaceutical or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical or therapeutically active form of the compound by one or more steps or processes.

[1064] In certain embodiments, sites on the aromatic ring portion of compounds described herein are susceptible to various metabolic reactions. Addition of appropriate substituents to the aromatic ring structure can reduce, minimize or eliminate such metabolic pathways. In certain embodiments, by way of example only, appropriate substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are deuterium, halogen or alkyl.

[1065] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 36 Cl, 18 F. 123 I. 125 I. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P and 35 S. In certain embodiments, isotope-labeled compounds can be used for drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N substitution is useful in positron emission topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process by using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed.

[1066] In certain embodiments, 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.

[1067] The compounds described herein and other related compounds having various substituents are prepared using the methods described herein and, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition, (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry, 4th Edition, Vols. A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis, 3rd Edition, (Wiley 1999) (all of which are incorporated into the present disclosure by reference). The general methods for preparing compounds as described herein are modified by using appropriate reagents and conditions to introduce the various moieties present in the formulae as provided herein.

[1068] The compounds described herein are synthesized using any suitable procedures starting from compounds available from commercial sources or prepared using the procedures described herein.

[1069] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, sulfenyl or carboxyl, are protected to avoid them from undesirably participating in reactions. Protective groups are used to block some or all of the reactive moieties, and prevent these groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group can be removed by different means. The protective group cracked under completely different reaction conditions meets the requirement of difference removal.

[1070] In certain embodiments, the protecting group is removed by acid, base, reducing conditions (e.g., hydrogenolysis) and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid-labile and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by Cbz groups and base-labile Fmoc groups that can be removed by hydrogenolysis. Carboxylic acid and hydroxyl reactive moieties are blocked by base-labile groups (e.g., methyl, ethyl, and acetyl) in the presence of amines blocked by acid-labile groups (e.g., tert-butyl carbamate) or acid- and base-stable but hydrolyzable carbamates.

[1071] In certain embodiments, carboxylic acid and hydroxyl reactive moieties are blocked by hydrolytically removable protecting groups such as benzyl, while amine groups capable of forming hydrogen bonds with acids are blocked by 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 blocking with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride-labile silylcarbamates.

[1072] 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 π-acid catalysts. For example, in the presence of acid-labile tert-butyl carbamate or base-labile acetamine protecting groups, allyl-blocked carboxylic acids are deprotected using palladium-catalyzed reactions. Another form of protecting group is a resin connected to a compound or intermediate. As long as the residue is connected to the resin, the functional group will be blocked and will not react. Once released from the resin, the functional group can react.

[1073] Typically blocking / protecting groups may be selected from:

[1074]

[1075] Other protecting groups, as well as a detailed description of techniques suitable for the creation of protecting groups and their removal, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are hereby incorporated by reference for such disclosures.

[1076] Composition

[1077] Compositions containing the compound (one or more) described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for administration routes such as oral or parenteral, such as transdermal, transmucosal (e.g., sublingual, lingual, oral, urethral, ​​vaginal (e.g., vaginal and perivaginal), nasal (intra) and rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[1078] Treatment

[1079] The compounds of the present disclosure may 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.

[1080] Non-limiting examples of diseases and / or disorders include acute sciatica, advanced solid tumors, allergic asthma, allergic reactions, ALS and multiple sclerosis, Alzheimer's disease, amyloidosis, progressive large cell lymphoma, angioedema, angiogenesis, angiogenesis, ocular vascular diseases, ankylosing spondylitis, psoriasis, anthrax (prevention and treatment), arthritis, asthma, asthma and white blood cell diseases, asthma, atopic dermatitis, atypical hemolytic uremic syndrome, autoimmune diseases, autoimmune disorders, B cell cancer, B Cellular malignancies, Anthrax spores, Bleeding, Hemophilia Bleeding, Cancer, Cancer (diagnosis), Cancer, etc., Cancer, Viral infections, Chronic myeloid leukemia and juvenile myeloid leukemia, Clear cell renal cell carcinoma, Clinical signs of canine atopic dermatitis, Cold agglutinin disease, Colorectal cancer, Crohn's disease, Psoriasis, Psoriatic arthritis and asthma, Rheumatoid arthritis, Axial spondyloarthritis, Psoriatic arthritis, Ulcerative colitis, Cryopyrin-associated periodic syndromes syndrome), diabetes, diagnostic agents, diarrhea caused by Escherichia coli, Duchenne muscular dystrophy, dyslipidemia, eczema, fibrosis, gastric cancer or gastroesophageal junction adenocarcinoma, gastrointestinal cancer, geographic atrophy secondary to age-related macular degeneration, hemophilia A, hemophagocytic lymphohistiocytosis, high-risk neuroblastoma and refractory myeloid disease, Hodgkin lymphoma, hypercholesterolemia, idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis , cancer, immune-mediated inflammatory disorders, infectious diseases / influenza A, inflammation, respiratory, skin and gastrointestinal tract inflammation, inflammatory autoimmune diseases, inflammatory lesions and metastases (detection), influenza A, invasive candidal infections, macular degeneration (wet), metastatic cancer, retinopathy of prematurity, metastatic pancreatic cancer, migraine, migraine and cluster headaches, multiple sclerosis, multiple sclerosis, psoriasis, psoriatic arthritis, muscle atrophy due to orthopedic disuse and sarcopenia, muscle wasting disorders, muscular dystrophy, nosocomial pneumoniapneumonia), oncology / immune indications, canine osteoarthritis, osteoarthritis, rheumatoid arthritis, osteomyelitis, osteoporosis, 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 uremic syndrome, paroxysmal nocturnal hemoglobinuria, atypical HUS, plaque psoriasis, primary systemic amyloidosis, progressive supranuclear palsy, psoriasis, inflammatory bowel disease, multiple sclerosis, scar reduction after glaucoma surgery, side effect reduction 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, neonatal hemolytic disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, sepsis, sepsis caused by gram-negative bacteria, severe asthma and chronic spontaneous urticaria, SLE, dermatomyositis, polymyositis, solid malignancies, solid tumors, spinal cord injury and multiple sclerosis, Staphylococcus aureus infection, systemic lupus erythematosus, systemic lupus erythematosus without renal or central nervous system involvement, systemic lupus erythematosus, lupus nephritis, acute graft-versus-host disease, systemic scleroderma, thromboembolism, thrombotic thrombocytopenic purpura, thrombosis, triple-negative breast cancer, uveitis, rheumatoid arthritis psoriasis, viral infections, wet age-related macular degeneration, X-linked hypophosphatemia.

[1081] The methods described herein include administering to a subject a therapeutically effective amount of at least one compound described herein, optionally formulated in a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further includes administering to the subject an additional therapeutic agent for treating the disease or disorder.

[1082] In certain embodiments, administering a compound described herein to a subject may allow for administration of a lower dose of an additional therapeutic agent than would be required to achieve a similar effect when the additional therapeutic agent is administered alone in treating a disease or disorder in the subject. For example, in certain embodiments, a compound described herein may enhance the activity of an additional therapeutic compound, thereby allowing the use of a lower dose of the additional therapeutic compound to provide the same effect.

[1083] In certain embodiments, a compound described herein and a therapeutic agent are co-administered to a subject. In other embodiments, a compound described herein and a therapeutic agent are co-formulated and co-administered to a subject.

[1084] In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human.

[1085] Combination therapy

[1086] The compounds useful in the methods described herein can be used in combination with one or more additional therapeutic agents for treating a disease or disorder, and / or can be used in combination with additional therapeutic agents that can alleviate or ameliorate the symptoms and / or side effects of the therapeutic agents used to treat a disease or disorder. These additional therapeutic agents can include compounds that are commercially available or synthesizable by those skilled in the art. When additional therapeutic agents useful for treating a disease or disorder are used, these additional therapeutic agents are known to treat or alleviate the symptoms of the disease or disorder.

[1087] In various embodiments, a synergistic effect is observed when the compounds described herein are administered with one or more additional therapeutic agents or compounds. For example, a suitable method such as, for example, Sigmoid-E max The synergistic effect is calculated using the equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453), the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). Each of the equations mentioned above can be applied to experimental data to generate a corresponding curve to help evaluate the effect of the drug combination. The corresponding curves associated with the equations mentioned above are concentration-effect curves, isobologram curves, and combination index curves, respectively.

[1088] Administration / dosage / formulation

[1089] The administration regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered to the subject before or after the disease or disorder occurs. In addition, several separate doses and staggered doses may be administered daily or sequentially, or the dose may be infused continuously, or may be a bolus injection. In addition, the dose of the therapeutic formulation may be increased or decreased in proportion to the urgency of the treatment or prevention situation.

[1090] The compositions described herein can be administered to a patient, preferably a mammal, more preferably a human, in a dosage and for a time effective to treat a disease or disorder in the patient using known procedures. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary according to factors such as the disease or disorder state of 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 dosage regimen can be adjusted to provide the best therapeutic response. For example, several divided doses may be administered daily, or the dosage may be reduced proportionally as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dosage range for the therapeutic compounds described herein is between about 1 and 5,000 mg / kg body weight / day. One of ordinary skill in the art will be able to study the relevant factors and make a decision on the effective amount of the therapeutic compound without undue experimentation.

[1091] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[1092] In particular, the selected dosage level will depend upon a variety of factors, including the activity of the particular compound employed, the time of administration, the excretion rate of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[1093] A physician, such as an internist or veterinarian, having ordinary skills in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start with a dose of the compound described herein employed in the pharmaceutical composition that is lower than the dose required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[1094] In certain embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit dosages for patients to be treated; each unit containing a predetermined quantity of the therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The dosage unit form of the compound(s) described herein is determined by and directly dependent on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such therapeutic compounds.

[1095] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein include a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[1096] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. For example, a coating such as lecithin can be used, and suitable fluidity can be maintained by maintaining the required particle size and using a surfactant in the case of dispersion. The effect of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents are preferably included in the composition, such as sugar, sodium chloride or polyols, such as mannitol and sorbitol. By including an agent that delays absorption in the composition, such as aluminum monostearate or gelatin, the absorption time of the composition for injection can be extended.

[1097] In certain embodiments, the compositions described herein are administered to patients at a dosage of 1-5 times per day or more. In other embodiments, the compositions described herein are administered to patients at a dosage range including, but not limited to, once a day, once every two days, every three days to once a week, and once every two weeks. It is apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual, depending on many factors, including, but not limited to, age, the disease or disorder to be treated, sex, overall health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be understood to be limited to any specific dosage regimen, and the precise dosage and composition administered to any patient is determined by the attending physician after considering all other factors of the patient.

[1098] The compound(s) for administration described herein may be 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, 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 whole or partial increments therebetween.

[1099] In some embodiments, the dose of the compounds described herein is between about 1 mg and about 2,500 mg. In some embodiments, the dose of the compounds described herein for use 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 whole or partial increments thereof.

[1100] In certain embodiments, the composition described herein is a packaged pharmaceutical composition comprising a container containing 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 or alleviate one or more symptoms of a disease or disorder in a patient.

[1101] The preparation can be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other suitable administration known in the art. The pharmaceutical preparation can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure buffers, colorants, flavorings and / or aromatic substances. They can also be combined with other active agents, such as other analgesics, when necessary.

[1102] The administration route of any composition described herein includes oral, rectal, intravaginal, parenteral, oral, sublingual or topical. The compound used in the composition described herein can be formulated to be administered by any suitable route, such as oral or parenteral, such as transdermal, transmucosal (e.g., sublingual, lingual, (through) oral, (through) urethral, ​​vaginal (e.g., transvaginal and perivaginal), nasal (intra) and (through) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.

[1103] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, pastes, lozenges, creams, ointments, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosols 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.

[1104] Oral administration

[1105] For oral administration, tablets, lozenges, liquids, drops, suppositories or capsules, caplets and gel capsules are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group of inert non-toxic pharmaceutical excipients, which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, such as lactose; granulating agents and disintegrants, such as corn starch; binders, such as starch; and lubricants, such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques to achieve a delicate effect or to delay the release of the active ingredient. Preparations for oral use may also appear in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert diluent.

[1106] For oral administration, the compound (s) described herein can be in the form of tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients, such as binders (e.g., polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, the tablets can be coated using suitable methods and coating materials, such as OPADRY available from Colorcon, West Point, Pa. TM Film coating systems (eg, OPADRY TM OY type, OYC type, organic enteric-coated OY-P type, aqueous enteric-coated OY-A type, OY-PM type and OPADRY TMWhite, 32K18400). Liquid preparations for oral administration may be in the form of solutions, syrups or suspensions. Liquid preparations may be prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethanol); and preservatives (e.g., methylparaben or propylparaben or sorbic acid).

[1107] Parenteral administration

[1108] For parenteral administration, the compounds described herein can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or administered as a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles may be used, optionally containing other formulating agents, such as suspending agents, stabilizers and / or dispersing agents.

[1109] The sterile injectable form of the composition described herein can be a water-based or oil-based suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 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 generally used as solvents or suspension 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 can be used to prepare injections, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially its polyoxyethylene form. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[1110] Other forms of administration

[1111] Additional dosage forms suitable for use with the compounds (one or more) and compositions described herein include dosage forms as described in U.S. Pat. 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 (one or more) and compositions described herein also include dosage forms as described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Additional dosage forms suitable for use with the compounds (one or more) and compositions described herein also 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.

[1112] Controlled release formulations and drug delivery systems

[1113] In certain embodiments, the formulations described herein may be, but are not limited to, short-term, rapid-release, and controlled, such as sustained-release, delayed-release, and pulsatile-release formulations.

[1114] The term sustained release in its conventional sense refers to a pharmaceutical formulation that releases a drug gradually over an extended period of time, although not necessarily, resulting in substantially constant blood levels of the drug over the extended period of time. This period of time may be as long as a month or more, and should be longer than the release of the same amount administered as a bolus injection.

[1115] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained release properties. Thus, the compound for use in the method (s) described herein can be administered in microparticle form, for example by injection, or in wafer or disc form, by implantation.

[1116] In some cases, the dosage form to be used can be provided as a sustained or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, liposomes, or microspheres or combinations thereof, thereby providing the desired release profile in different proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be easily selected for use in the pharmaceutical compositions described herein. Therefore, single unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and caplets suitable for controlled release are included in the compositions and dosage forms described herein.

[1117] Most controlled-release pharmaceutical products share the common goal of improving drug therapy relative to that achieved by their non-controlled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical therapy is characterized by the use of the least amount of drug substance in the shortest amount of time to cure or control a condition. Advantages of controlled-release formulations include prolonged activity of the drug, reduced frequency of dosing, and improved patient compliance. In addition, controlled-release formulations can be used to affect the onset of action or other characteristics of a drug, such as blood concentrations of the drug, and thus can affect the occurrence of side effects.

[1118] Most controlled-release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and to gradually and continuously release additional amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body.

[1119] The controlled release of active ingredients 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 one or more compounds, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes or microspheres or combinations thereof that promote the controlled release of active ingredients. In one embodiment, a sustained-release formulation is used to administer the compound (one or more) described herein alone or in combination with another pharmaceutical formulation to a patient. In one embodiment, a sustained-release formulation is used to administer the compound (one or more) described herein alone or in combination with another pharmaceutical formulation to a patient.

[1120] The term delayed release is used herein in its conventional sense to refer to drug formulations that provide initial release of the drug after a certain delay after drug administration, and although not necessarily, may include from about 10 minutes up to about 12 hours.

[1121] The term pulsatile release is used herein in its conventional sense to refer to drug formulations that provide for release of the drug in a manner that produces a pulsatile plasma profile following drug administration.

[1122] The term immediate release in its conventional sense refers to a pharmaceutical formulation that provides for release of the drug immediately after administration of the drug.

[1123] As used herein, short-term refers to any time period following drug administration, up to and including 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 following drug administration and any or all full or partial increments thereof.

[1124] As used herein, rapid compensation refers to any time period after drug administration, up to and including 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 full and partial increments thereof.

[1125] Drug administration

[1126] The therapeutically effective amount or dosage 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. A skilled person will be able to determine the appropriate dosage based on these and other factors.

[1127] Suitable doses of the compounds described herein may be in the range of about 0.01 mg to about 5,000 mg per day, such as about 0.1 mg to about 1,000 mg, for example, about 1 mg to about 500 mg per day, such as about 5 mg to about 250 mg. The dose may be administered in a single dose or multiple doses, for example 1 to 4 times or more per day. When multiple doses are used, the amount of each dose may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with an interval of about 12 hours between each dose.

[1128] It is understood that, in non-limiting examples, the amount of compound administered daily can be administered every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, in the case of administration every other day, a daily dose of 5 mg can be initiated on Monday, the first subsequent daily dose of 5 mg can be administered on Wednesday, the second subsequent daily dose of 5 mg can be administered on Friday, etc.

[1129] In the event that the patient's condition does improve, the compound(s) described herein may optionally be administered continuously, at the discretion of the physician; alternatively, the dosage of the drug administered may be temporarily reduced or suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday may be selected to vary between 2 days and 1 year, including, 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%-100%, including, 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%.

[1130] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dose or frequency of administration or both are reduced to a level that maintains the improved disease. In certain embodiments, the patient requires intermittent treatment on a long-term basis upon recurrence of any symptoms and / or infection.

[1131] The compounds described herein can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for patients receiving treatment, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, optionally used together with a suitable pharmaceutical carrier. The unit dosage form can be used for one of a single daily dose or multiple daily doses (e.g., about 1 to 4 times or more per day). When multiple daily doses are used, the unit dosage form of each dose may be the same or different.

[1132] The toxicity and efficacy of such treatment regimens are optionally determined in cell cultures or experimental animals, including but not limited to determining the LD 50 (a dose that is lethal to 50% of the population) and ED 50 (The dose that has a therapeutic effect on 50% of the population). The dose ratio between toxicity and efficacy is the therapeutic index, which is expressed as LD 50 and ED 50 The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED with minimal toxicity. 50 Within this range the dosage may vary depending upon the dosage form employed and the route of administration utilized.

[1133] Those skilled in the art will recognize, or can determine using routine experiments, that the specific steps, embodiments, claims and examples described herein have many equivalents. These equivalents are considered to be within the scope of the present disclosure and are covered by the appended claims. For example, it should be understood that modifications to reaction conditions, including but not limited to reaction time, reaction scale / volume and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmosphere) and reducing agents / oxidants, are within the scope of the present application using art-recognized alternative methods and using only routine experimental methods.

[1134] It should be understood that, wherever numerical values ​​and ranges are provided herein, all numerical values ​​and ranges included in these numerical values ​​and ranges are included in the scope of the present disclosure. In addition, all numerical values ​​within these ranges and the upper or lower limits of the numerical ranges are also within the consideration scope of the application.

[1135] The following examples further illustrate various aspects of the present disclosure. However, they are in no way limiting to the teachings or disclosures of the present disclosure set forth herein.

[1136] Experimental Examples

[1137] The present disclosure will now be described with reference to the following examples. These examples are for illustrative purposes only, and the present disclosure should in no way be construed as being limited to these examples, but rather should be construed to include any and all variations that are obvious as a result of the teachings provided herein.

[1138] Without further explanation, it is believed that one of ordinary skill in the art can utilize the foregoing description and the following examples to prepare and use the compounds of the present disclosure and to practice the claimed methods. Therefore, the following working examples indicate specific embodiments of the present disclosure and should not be construed as limiting the remainder of the disclosure in any way.

[1139] The materials and methods used in the experiments presented in this experimental example are now described in this application.

[1140] Figures 11A-11B A non-limiting synthesis of the ASGPRBM group is shown.

[1141] Figures 12A-12C The non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses non-limiting Cbz protecting groups, but any other suitable protecting groups known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[1142] Figures 13A-13LThe non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses non-limiting Cbz protecting groups, but any other suitable protecting groups known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[1143] Figures 14A-14O The non-limiting synthesis of certain ASGPRBM groups is shown. This example discloses non-limiting Cbz protecting groups, but any other suitable protecting groups known to those of ordinary skill in the art may also be used for synthesis. The protecting groups in each intermediate and / or final product may be deprotected as appropriate.

[1144] Fig.15 A non-limiting synthetic scheme allowing for the labeling (derivatization) of antibodies (labeled Ab) with an azide group is shown, where pBpa represents p-benzoylphenylalanine.

[1145] Fig.16 A non-limiting synthetic scheme that allows for labeling (derivatization) of a CRBM group with a cycloalkyne-containing group is shown. In certain non-limiting embodiments, any azide-containing compound (such as, but not limited to, Fig.15 ) can be combined with cycloalkyne-containing compounds (such as but not limited to Fig.16 ) to produce the compounds disclosed herein.

[1146] Examples of implementations:

[1147] The following enumerated embodiments are provided, the numbering of which should not be construed as designating a level of importance.

[1148] Embodiment 1 provides a compound comprising formula (I), or a salt, geometric isomer, stereoisomer or solvate thereof:

[1149] [Ab] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (I)

[1150] in:

[1151] The Ab is an antibody that binds to extracellular proteins;

[1152] 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 the extracellular protein;

[1153] Each CON is independently a bond or group that covalently links Ab to CRBM, covalently links Ab to a linking group, and / or covalently links a linking group to CRM;

[1154] The linking group is a group having a valence ranging from 1 to 15;

[1155] k' is an integer ranging from 1 to 15;

[1156] h is an integer ranging from 0 to 15;

[1157] i is an integer ranging from 0 to 15;

[1158] h' is an integer ranging from 0 to 15;

[1159] j is an integer ranging from 1 to 15.

[1160] Embodiment 2 provides a compound according to embodiment 1, wherein the valency of the linking group is 1, 2 or 3.

[1161] Embodiment 3 provides a compound according to any one of embodiments 1-2, wherein k′ is 1, 2 or 3.

[1162] Embodiment 4 provides a compound according to any one of embodiments 1-3, wherein j is 1, 2 or 3.

[1163] Embodiment 5 provides a compound according to any one of embodiments 1-4, wherein h is 1, 2 or 3.

[1164] Embodiment 6 provides a compound according to any one of embodiments 1-5, wherein h′ is 1, 2 or 3.

[1165] Embodiment 7 provides a compound according to any one of embodiments 1-6, wherein i is 1, 2 or 3.

[1166] Embodiment 8 provides a compound according to any one of embodiments 1-7, wherein at least one of h, h' and i is at least 1.

[1167] Embodiment 9 provides a compound according to any one of embodiments 1-8, wherein k', j', h, h' and i are each independently 1, 2 or 3.

[1168] Embodiment 10 provides a compound according to any one of embodiments 1-9, wherein k' is 1 and j' is 1, 2 or 3.

[1169] Embodiment 11 provides a compound according to any one of embodiments 1-10, which is:

[1170] [Ab]—[CON] 0-1 —[Linking group]—[CON] 0-1 —[CRBM](Ia).

[1171] Embodiment 12 provides a compound according to any one of embodiments 1-11, wherein the degrading cells include hepatocytes.

[1172] Embodiment 13 provides a compound according to 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.

[1173] Embodiment 14 provides a compound according to any one of embodiments 1-13, wherein the CRBM is:

[1174] (a) a folate receptor binding agent comprising at least one of folic acid, methotrexate, a pre-treatment or a biologically active fragment thereof;

[1175] (b) a mannose receptor binding agent comprising at least one of the following:

[1176]

[1177] Where: X is S or O, R is selected from:

[1178]

[1179] 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; and

[1180] Figure 1-7 The polymer molecules shown;

[1181] (c) the mannose-6-phosphate (M6P) receptor binding agent comprises at least one of the following:

[1182]

[1183] Where X is O or S, R 1 Selected from the following groups:

[1184]

[1185] R 2 Selected from the following groups:

[1186]

[1187] 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;

[1188] Figure 8 The polymer molecule shown; a compound selected from the following:

[1189]

[1190] A compound selected from the group consisting of:

[1191]

[1192]

[1193] (d) a low-density lipoprotein receptor-related protein 1 (LRP1) receptor binding agent comprising at least one amino acid sequence of SEQ ID NO: 1-9;

[1194] (e) a low-density lipoprotein receptor (LDLR) binding agent comprising at least one amino acid sequence of SEQ ID NO: 10-35;

[1195] (f) an FcγRI receptor binding agent comprising at least one amino acid sequence of SEQ ID NO: 36-52;

[1196] (g) a transferrin receptor binding agent comprising at least one amino acid sequence of SEQ ID NOs: 53-59 and 67;

[1197] (h) a macrophage scavenger receptor binding agent comprising at least one amino acid sequence of SEQ ID NO: 60-65;

[1198] (i) a G protein-coupled receptor binding agent comprising at least one of the following:

[1199]

[1200] wherein each occurrence of R is independently H or C1-C6 alkyl;

[1201] (j) an asialoglycoprotein receptor (ASGPR) binding agent comprising:

[1202]

[1203] in:

[1204] X is a linking group of 1 to 4 atoms in length, including O, S, N (R N1 ) or C(R N1 )(R N1 ) groups such that:

[1205] When X is a linking group of 1 atom in length, X is O, S, N (R N1 ) or C(R N1 )(R N1 ),

[1206] When X is a linking group of 2 atoms in length, no more than 1 atom in X is O, S or N (R N1 ),

[1207] When X is a linking group of 3 or 4 atoms in length, no more than 2 atoms in X are independently O, S or N (R N1 );

[1208] Where R N1 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydrocarbyl groups;

[1209] R 1 and R 3 Each independently represents H, -(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 independently selected halogens, -(CH2) K (vinyl), -O(CH2) K (vinyl), -(CH2) K (Alkynyl), -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(═O)O(C1-C4 alkyl), —OC(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or —C(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens; or

[1210] R 1 and R 3 Each independently is Ph(CH2) K-, which is optionally substituted by the following groups; 1-3 independently selected halogens; C1-C4 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxyls; or C1-C4 alkoxy optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxyls; or

[1211] R 1 and R 3 Each is independently a group of the following structure:

[1212] -O-(CH2) K' -CH(OH)-(CH2)K'-R 7 ,

[1213] in:

[1214] Where R 7 is: C1-C4 alkoxy optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxyl groups; -NR N3 R N4 ; or -(CH2) K' -O-(CH2) K -CH2-CH=CH2;

[1215] K is 0, 1, 2, 3 or 4;

[1216] K' is 1, 2, 3 or 4;

[1217] 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;

[1218] R N4 Each occurrence of is independently H, C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyls, or Ph-(CH2) K -;or

[1219] R 1 and R 3 Each independently selected from:

[1220] -(CH2) K OH, L 1 -≡-, L 1 -(CH2) K - and CYC-(CH2) K -,

[1221] Where CYC is selected from:

[1222]

[1223]

[1224] in:

[1225] Among them The key marked indicates CYC on and -(CH2) K The site of connection;

[1226] L 1 is a bond, a -linker, a -CON-linker, or a -CON-linker-CON;

[1227] R C is absent, H, C1-C4 alkyl optionally substituted by 1-3 optionally substituted halogens and / or 1-2 hydroxy groups, or a group having the following structure:

[1228]

[1229] in:

[1230] R 4 , R 5 and R 6 Each independently represents H, F, Cl, Br, I, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 independently selected halogens, C1-C3 alkoxy optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(═O)O-(C1-C4 alkyl), OC(═O)-(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -C(═O)-(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens;

[1231] 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;

[1232] R N2 Each occurrence of is independently H or C1-C3 alkyl optionally substituted with 1-3 independently selected halogens and / or 1-2 hydroxyls; or

[1233] R 1 and R 3Each is independently (C3-C8 saturated carbocyclic ring)-(CH2) K -, wherein the carbocyclic ring is further replaced by -L 1 and -R C replace;

[1234] R 2 Yes - (CH2) K -N(R N1 )-C(=O)R AM ,in:

[1235] R AM is H, C1-C4 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydroxy groups, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(=O)O(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, -C(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -(CH2) K -NR N3 R N4 ,or

[1236] R 2 yes in:

[1237] R TA It is H, CN, NR N1 R N2 、-(CH2) K OH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C4 alkyl optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(═O)O(C1-C4 alkyl), —OC(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or —C(═O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or

[1238] R TA It is C3-C 10 Aryl or 3-membered or 10-membered heteroaryl containing 1-5 non-carbon ring atoms, each aryl or heteroaryl is optionally substituted by 1-3 groups independently selected from the following groups: CN, NR N1 R N2 、-(CH2) KOH, -(CH2) optionally substituted by 1-3 independently selected halogens K O(C1-C4 alkyl), C1-C3 alkyl optionally substituted by 1-3 independently selected halogens and / or 1-2 hydrocarbon groups, -(C1-C3-alkoxy) optionally substituted by 1-3 independently selected halogens, -(CH2) K COOH, -(CH2) optionally substituted by 1-3 independently selected halogens K C(=O)O-(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl) optionally substituted by 1-3 independently selected halogens, or -(CH2) optionally substituted by 1-3 independently selected halogens K C(═O)-(C1-C4 alkyl), or

[1239] R TA is optionally substituted by 1-3 C1-C3 alkyl groups optionally substituted by 1-3 independently selected halogen groups

[1240] or

[1241] R TA yes Each -(CH2) K The group is optionally substituted with 1 to 4 C1-C3 alkyl groups which are optionally substituted with 1 to 3 fluoro groups or 1 to 2 hydrocarbon groups.

[1242] Embodiment 15 provides a compound according to any one of embodiments 1-14, wherein:

[1243] When the length of X is 2 atoms, X in ASGPRBM is -OC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-O-、-SC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-S-、-N(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-N(R N1 )-or-C(R N1 )(R N1 )-C(R N1 )(R N1 )-;

[1244] When the length of X is 3 atoms, X in ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-、-OC(R N1 )(R N1 )-O-、-OC(R N1 )(R N1 )-S-、-OC(R N1 )(R N1 )-N(R N1 )-、-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1 )(R N1 )-S、-SC(R N1 )(R N1 )-S-、-SC(R N1 )(R N1 )-O-、-SC(R N1 )(R N1 )-N(R N1 )-、-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 )-、-N(R N1 )-C(R N1 )(R N1 )-N(R N1 )-or-C(RN1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 );or

[1245] When the length of X is 4 atoms, X in ASGPRBM is -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-OC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-OC(R N1 )(R N1 )-OC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-、-C(R N1 )(R N1 )-C(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-、-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-or-C(R N1 )(R N1 )-N(R N1)-C(R N1 )(R N1 )-C(R N1 )(R N1 )-.

[1246] Embodiment 16 provides a compound according to any one of embodiments 1-15, wherein X is OCH2 and R N1 is H or where X is CH2O and R N1 It's H.

[1247] Embodiment 17 provides a compound according to any one of embodiments 14-16, wherein the ASGPRBM comprises the following structure:

[1248]

[1249] Embodiment 18 provides a compound according to any one of embodiments 14-17, wherein the ASGPRBM group comprises:

[1250]

[1251]

[1252] in:

[1253] R A is C1-C3 alkyl optionally substituted by 1-5 independently selected halogens;

[1254] Z A Yes - (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 -;

[1255] Z B Does not exist, -(CH2) IM -、-C(=O)-(CH2) IM - or -C(=O)(CH2) IM -NR M -;

[1256] R M is H or C1-C3 alkyl optionally substituted by 1-2 hydrocarbon groups; and

[1257] Each occurrence of IM is independently 0, 1, 2, 3, 4, 5, or 6;

[1258]

[1259]

[1260] R=CH3, CF3 or CH2CF3;

[1261]

[1262]

[1263] Embodiment 19 provides a compound according to any one of embodiments 1-18, wherein the linking group is a polyethylene glycol-containing linking group having 1-12 ethylene glycol residues.

[1264] Embodiment 20 provides a compound according to any one of embodiments 1-19, wherein the linking group comprises the following structure:

[1265] -CH2CH2(OCH2CH2) m OCH2-、-(CH2) m CH2-、-[N(R a )-CH(R b (C=O)] m -, or a polypropylene glycol or polypropylene-co-polyethylene glycol group containing 1 to 100 alkylene glycol units;

[1266] Each R a independently H, C1-C3 alkyl or C1-C6 alkanol, or with R b combine to form a pyrrolidine or hydroxypyrroline group;

[1267] Each R b independently selected from hydrogen, methyl, isopropyl, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)3-guanidine, -CH2C(=O)NH2, -CH2C(=O)OH, -CH2SH, -(CH2)2C(=O)NH2, -(CH2)2C(=O)OH, -(CH2)imidazole, -(CH2)4NH2, -CH2CH2SCH3, benzyl, -CH2OH, -CH(OH)CH3, -(CH2)imidazole or -(CH2)phenol; and

[1268] wherein m is an integer ranging from 1 to 15; or

[1269] The linking group comprises the following structure:

[1270] -[N(R'-(CH2) 1-15 -C(=O)]-,

[1271] wherein R' is H or C1-C3 alkyl optionally substituted by 1-2 hydroxyl groups, and

[1272] m is an integer from 1 to 100; or

[1273] The linking group comprises the following structure:

[1274] -ZD-Z'-,

[1275] in:

[1276] Z and Z' are each independently a bond, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, -(CH2) i -C(R 2 )=C(R 2 )-(cis or trans), -(CH2) i -≡- or -YC(=O)-Y-;

[1277] Each R is independently H, C1-C3 alkyl or C1-C6 alkanol;

[1278] Each R 2 are independently H or C1-C3 alkyl;

[1279] Each Y is independently a bond, O, S or N(R);

[1280] Each i is independently 0 to 100;

[1281] D is a bond, -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m’ -or-[(CH2) n -X1)] j -, provided that Z, Z' and D are not each simultaneously a bond;

[1282] X 1 is O, S or N(R);

[1283] j is an integer ranging from 1 to 100;

[1284] m' is an integer ranging from 1 to 100;

[1285] n is an integer ranging from 1 to 100; or

[1286] The linking group comprises the following structure:

[1287] -CH2-(OCH2CH2) n -CH2-, -(CH2CH2O) n’ CH2CH2-or-(CH2CH2CH2O) n -,

[1288] wherein each n and n' is independently an integer ranging from 1 to 25; or wherein the linking group comprises the following structure:

[1289] -PEG-CON-PEG-

[1290] wherein each PEG is independently a polyethylene glycol group containing 1-12 ethylene glycol residues and CON is a triazole group

[1291] Embodiment 21 provides a compound according to any one of embodiments 1-20, wherein CON comprises the structure:

[1292] wherein R' and R" are each independently H, methyl or a bond; or

[1293] Wherein the CON comprises the following structure:

[1294] -C(=O)-N(R 1 )-(CH2) n” -N(R 1 )C(=O)-,

[1295] -N(R 1 )-C(=O)(CH2) n” -C(=O)N(R 1 )-,or

[1296] -N(R 1 )-C(=O)(CH2) n” -N(R 1 )C(=O)-;

[1297] 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, in certain embodiments 1, 2, 3, 4, 5 or 6; or

[1298] Wherein the CON comprises the following structure:

[1299]

[1300] in:

[1301] R 1a , R 2a and R 3a Each independently represents H, -(CH2) M1 -、-(CH2) M2 C(=O) M3 (NR 4 ) M3 -(CH2) M2 -、-(CH2) M2 (NR 4 ) M3 C(O) M3 -(CH2) M2 -or-(CH2) M2 O-(CH2) M1 -C(O)NR 4 -, the condition is R 1a , R 2a and R 3a Not at the same time H;

[1302] Each M1 is independently 1, 2, 3 or 4;

[1303] Each M2 is independently 0, 1, 2, 3 or 4;

[1304] Each M3 is independently 0 or 1; and

[1305] 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 Both M2 and M3 in cannot be 0 at the same time; or

[1306] Wherein the CON comprises the following structure:

[1307]

[1308] Embodiment 22 provides a compound according to any one of embodiments 1-21, wherein the extracellular protein comprises: 1-40-β-amyloid protein, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid protein, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), anthrax, BAFF, β-amyloid protein, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, canine IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, aggregation factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli Shiga toxin type 1, Escherichia coli Shiga toxin type 2, EGFL7, endotoxin, epithelial sialoprotein, FGF 23, fibrin II, beta chain, fibronectin extracellular domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid protein, 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, hepatitis A virus hemagglutinin HA, interferon gamma, interferon gamma-induced 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), neural apoptosis regulating proteinase 1, NGF, NOGO-A, Notch 1. NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, root plate-specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A, 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.

[1309] Embodiment 23 provides a compound according to any one of embodiments 1-22, wherein the Ab is a monoclonal antibody.

[1310] Embodiment 24 provides a compound according to any one of embodiments 1-23, wherein the antibody comprises abavotumab, azetuzumab, adalimumab, aducanumab, afacilumab, afelimomab, amorobumab, atumomab, atumomab, atumomab pentetate, andreximab, anrulumab, acitumomab, afacitumomab, atezolizumab, adulumab, atenumab, avelumab, bavirucumab, bavirucumab, belimumab, bemakinumab, besotumab, bevacizumab, bicizumab, bimegizumab, potitumomab, busutuzumab, brecuzumab, bricupuzumab, brian ... Antibody, cabilizumab, canakinumab, cantuzumab, recantuzumab, capazumab, calcineurin, certuzumab, almudexyl interleukin-2-certuzumab, certolizumab, becelizumab, cerbituzumab, clazazumab, clituzumab, titan-clituzumab, concelizumab, crezumab, decubitus, denosumab, di Zanamizumab, delevomab, domarozumab, dolimumab, atoduzumab, durvalumab, durvalumab, eculizumab, ebumab, ifengucumab, edirumab, elenuzumab, ecitumomab, imibutumab, epazomab, emivacumab, enoxaparin, ipilimumab, sipilimumab, iprevacumab , erenumab, evezumab, eloumab, farcitumab, fasenosumab, fizanulumab, felatuzumab, felivomab, furilkumab, fontuzumab, remanezumab, fesumumab, flocumab, fulvelumab, forlanumab, ganezumab, gantuzumab, gantuzumab, gatuzumab, givuzumab, givuzumab, jinsi Lulumab, gemtuximab, golimumab, gonelumab, guselkumab, idarucizumab, igovolumab, imatinib, indaclizumab, ranutuximab, infliximab, estuximab, ixekizumab, labetuzumab, latuzumab, lambazumab, lanacuzumab, lanlozumab, lerezumab, lemassozumab, lendeluzumab Monoclonal antibody, renzlumab, lerdetumumab, lesovolumab, ligralizumab, lodicuzumab, logivirumab, rugizumab, matasizumab, mepolizumab, metilimab, migizumab, nacolizumab, tanalizumab, namerucizumab, nannetuzumab, navirocumab, nasitumumab, nebacumab, nemolizumab, NEOD, ne Remoluzumab, Nevacuzumab, Nitrazumab, Nofitumomab, Thiorozumab, Otosacizumab, Olelumab, Orendalizumab, Olozumab, Omalizumab, OMS, Onatuzumab, Ogovotumab, Otizumab, Otilizumab, Ozanezumab, Olizumab, Pasatuzumab, Pacolizumab, Pertuximab,Patinizumab, panitumumab, pelakezumab, pexelizumab, pralulumab, ponetuzumab, putinizumab, retosacizumab, quilizumab, ratrastuzumab, rapavir, ranevizumab, ranibizumab, ranibizumab, ravulizumab, rexilumab, REGN-EB, nontolumab, reslizumab, rituximab, risankizumab, rokizumab, romumab, longizumab, lomantuzumab, sacituzumab, gosatutumab, samatumomab, vetin-samatumomab, sarrelumab, secukinumab, setosacizumab, certosacizumab, sifalimumab, silotuzumab, sintuzumab, sirukumab, sofitumab tuzumab, sofituzumab, vetin-sofituzumab, solanizumab, sontuzumab, setumab, thiosomab, sutitumomab, suvituzumab, sutosumab, tabemucumab, tacatuzumab, tacilizumab, talizumab, tanizumab, tefezumab, tetumomab, atemucumab, terdotumumab, tezerumab, tibulizumab, tirazumab, temozolomide, tisotuzumab, vetin-tesotuzumab, trorocitumumab, trefotaxime, ouzolizumab, ustekinumab, vanucezumab, valiximab, varisucomab, velpatumomab, vesenkumab, wolbalizumab, vonagizumab, or centuzumab.

[1311] Embodiment 25 provides a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound according to any one of embodiments 1-24.

[1312] Embodiment 26 provides a pharmaceutical composition according to embodiment 25, further comprising another therapeutically active compound.

[1313] Embodiment 27 provides a compound selected from the group consisting of:

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322] or a salt, stereoisomer or solvate thereof.

[1323] Embodiment 28 provides a compound according to any one of embodiments 1-27, which has one of the following formulae:

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339] or a pharmaceutically acceptable salt thereof

[1340] in:

[1341] The extracellular protein targeting ligand is a circulating protein binding moiety [CPBM] that binds to a circulating protein in a subject, wherein the circulating protein mediates a disease state or condition and is cleared by the action of hepatocytes or other cells of the subject;

[1342] X 1 are independently selected from O, S, N(R b ) and C(R 4 )(R 4 ) of 1 to 5 groups, wherein if X 1 is 1 group, then X1 O, S, N (R 6 ) or C(R 4 )(R 4 ); if X 1 is 2 groups, then X 1 No more than one of the groups is O, S or N (R 6 ), if X 1 is 3, 4 or 5 groups, then X 1 No more than 2 groups are O, S or N (R 6 );

[1343] R 2 Selected from

[1344] (i) aryl, heterocycle and heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein each of the aryl, heterocycle and heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents;

[1345] (ii)

[1346] (iii)-NR 8 -S(O)-R 3 、-NR 8 -C(S)-R 3 、-NR 8 -S(O)(NR 6 )-R 3 、-N=S(O)(R 3 )2.-NR 8 C(O)NR 9 S(O)2R 3 、-NR 8 -S(O)2-R 10 and-NR 8 -C(NR 6 )-R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents; and

[1347] (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 ;

[1348] R 10 Selected from aryl, alkyl-NR 8 -C(O)-R 3, alkyl-aryl, alkyl-heteroaryl having 1, 2 or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 , alkyl-NR 6 R 8 NR 8 -NR 6 -C(O)R 3 NR 8 -S(O)2-R 3 , alkenyl, allyl, alkynyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -Alkynyl, -NR 6 -heteroaryl, -NR 6 -aryl, -O-heteroaryl, -O-aryl and -O-alkynyl, wherein each R 10 is optionally substituted with 1, 2, 3 or 4 substituents;

[1349] R 1 and R 5 independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 、C0-C6 alkyl-C(S)R 3 、C0-C6 alkyl-S(O)2R 3 、C0-C6 alkyl-N(R 8 )-C(O)R 3 、C0-C6 alkyl-N(R 8 )-S(O)R 3 、C0-C6 alkyl-N(R 8 )-C(S)R 3 、C0-C6 alkyl-N(R 8 )-S(O)2R 3 、C0-C6 alkyl-OC(O)R 3 、C0-C6 alkyl-OS(O)R 3 、C0-C6 alkyl-OC(S)R 3 、-N=S(O)(R 3 )2, C0-C6 alkyl N3 and C0-C6 alkyl-OS(O)2R 3, wherein each is optionally substituted with 1, 2, 3 or 4 substituents;

[1350] R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 and-NR 8 R 9 ;

[1351] R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 ;

[1352] R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 ;

[1353] R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;

[1354] Ring is a 3-8 membered fused ring group optionally substituted by 1, 2, 3 or 4 substituents;

[1355] Each linking group A is to covalently link the ASGPR ligand to a linker group B a key or part of;

[1356] Linking group B The linking group A a bond or moiety that is covalently attached to an extracellular protein targeting ligand;

[1357] Linking group C Each linking group A a chemical group attached to an extracellular protein targeting ligand; and

[1358] Linking group D Each linking group A a chemical group attached to an extracellular protein targeting ligand; and

[1359] Among them, when R 2 YesNR 6 -Alkenyl, -NR 6 -Alkynyl, -NR 8 -C(O)R 10 、-NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl or -NR 6 -aryl, the extracellular protein targeting ligand does not include an oligonucleotide; and

[1360] The optional substituents are selected from alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 、F、Cl、Br、I、-NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , This results in stable compounds as valency permits.

[1361] Embodiment 29 provides a method for treating, ameliorating and / or preventing a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound according to any one of Embodiments 1-24 and 27-29 and / or at least one pharmaceutical composition according to any one of Embodiments 25-26.

[1362] Embodiment 30 provides a method according to embodiment 29, wherein the disease or disorder comprises an autoimmune disease, cancer, or inflammation.

[1363] Embodiment 31 provides a method according to embodiment 30, wherein the autoimmune disease comprises Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed cold agglutininemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful lipomatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, Enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry-Romberg syndrome, Parsner-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD ), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton muscular dystrophy syndrome, multiple sclerosis, patternII, Oshtolan Mountain syndrome, Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sindenham's chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Blepharoconjunctivitis, Moren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, Eosinophilia EGPA, giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum.

[1364] Embodiment 32 provides a method according to 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 corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, laryngeal cancer, Hodgkin's disease, non-Hodgkin's 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, esophageal, laryngeal, kidney cancer or lymphoma.

[1365] Embodiment 33 provides a method according to embodiment 30, wherein the inflammation includes neurodegenerative inflammatory diseases, diseases of impaired immune response causing inflammation, chronic inflammatory diseases, hyperglycemia, diabetes (type I and type II), pancreatic beta cell death and its related hyperglycemia, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury or arteriosclerosis.

[1366] Embodiment 34 provides the method of any of embodiments 29-33, wherein the subject is further administered at least one additional therapeutic agent for treating or preventing the disease or disorder.

[1367] Embodiment 35 provides a method according to any one of embodiments 29-34, wherein the subject is a mammal.

[1368] Embodiment 36 provides a method according to any one of embodiments 29-35, wherein the subject is a human.

[1369] Embodiment 37 provides a method of treating, preventing or prophylaxis of autoimmune diseases, cancer or inflammation, the method comprising administering a composition comprising a therapeutically effective amount of at least one compound according to claim 27 or 28 and at least one pharmaceutically acceptable carrier or excipient,

[1370] The autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed cold agglutininemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful lipomatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, Eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry-Romberg syndrome, Parsner-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis , fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton muscular dystrophy syndrome, multiple sclerosis, patternII, Oshtolan Mountain syndrome, Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sindenham's chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Blepharoconjunctivitis, Moren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, Eosinophilia EGPA, giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum;

[1371] wherein the cancer comprises prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, laryngeal cancer, Hodgkin's disease, non-Hodgkin's 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, esophageal, laryngeal, kidney cancer, or lymphoma; and

[1372] The inflammation includes neurodegenerative inflammatory diseases, diseases of impaired immune response causing inflammation, chronic inflammatory diseases, hyperglycemia, diabetes (type I and II), pancreatic beta cell death and its related hyperglycemia, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury or arteriosclerosis.

[1373] The disclosure of each patent, patent application, and publication cited herein is incorporated herein by reference in its entirety. Although the present disclosure is disclosed with reference to specific embodiments, it is apparent that other persons skilled in the art can design other embodiments and variations of the present disclosure without departing from the true spirit and scope of the present disclosure. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

Claims

1. A compound of the following chemical formula or its salt, geometric isomer, stereoisomer or solvate: [Ab] k’ —[CON] h —[Linking group] i —[CON] h’ —[CRBM] j’ (I) in: The 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 the extracellular protein, Each CON is independently a bond or group that covalently links Ab to CRBM, covalently links Ab to a linking group, and / or covalently links a linking group to CRM, The linking group is a group having a valence ranging from 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; Wherein the compound is selected from: or a pharmaceutically acceptable salt thereof, in: Extracellular protein targeting ligands are antibodies (Abs) that bind to extracellular proteins; X 1 is 1 to 5 independently selected from O, S, N(R b ) and C(R 4 )(R 4 ) group, where if X 1 is 1 group, then X 1 O, S, N (R 6 ) or C(R 4 )(R 4 ); if X 1 is 2 groups, then X 1 No more than one of the groups is O, S or N (R 6 ); if X 1 is 3, 4 or 5 groups, then X 1 No more than 2 groups are O, S or N (R 6 ); R 2 Selected from (i) aryl, heterocycle and heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein each of the aryl, heterocycle and heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents; (ii) (iii)-NR 8 -S(O)-R 3 、-NR 8 -C(S)-R 3 、-NR 8 -S(O)(NR 6 )-R 3 、-N=S(O)(R 3 )2、 -NR 8 C(O)NR 9 S(O)2R 3 、-NR 8 -S(O)2-R 10 and-NR 8 -C(NR 6 )-R 3 , each of which is optionally substituted with 1, 2, 3 or 4 substituents; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 、-C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 and-NR 8 -C(O)R 10 ; R 10 Selected from aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl having 1, 2 or 4 heteroatoms, alkyl-cyano, alkyl-OR 6 、Alkyl-NR 6 R 8 NR 8 -NR 6 -C(O)R 3 NR 8 -S(O)2-R 3 , alkenyl, allyl, alkynyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -Alkynyl, -NR 6 -heteroaryl, -NR 6 -aryl, -O-heteroaryl, -O-aryl and -O-alkynyl, wherein each R 10 is optionally substituted with 1, 2, 3 or 4 substituents; R 1 and R 5 independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 、C0-C6 alkyl-SR 6 、C0-C6 alkyl-NR 6 R 7 、C0-C6 alkyl-C(O)R 3 、C0-C6 alkyl-S(O)R 3 、C0-C6 alkyl-C(S)R 3 、C0-C6 alkyl-S(O)2R 3 、C0-C6 alkyl-N(R 8 )-C(O)R 3 、C0-C6 alkyl-N(R 8 )-S(O)R 3 、C0-C6 alkyl-N(R 8 )-C(S)R 3 、C0-C6 alkyl-N(R 8 )-S(O)2R 3 、C0-C6 alkyl-OC(O)R 3 、C0-C6 alkyl-OS(O)R 3 、C0-C6 alkyl-OC(S)R 3 、-N=S(O)(R 3 )2, C0-C6 alkyl N3 and C0-C6 alkyl-OS(O)2R 3 , wherein each is optionally substituted with 1, 2, 3 or 4 substituents; R 3 is independently selected at each occurrence from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF3), aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 and-NR 8 R 9 ; R 4 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 、-NR 6 R 7 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 ; R 6 and R 7 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 、C(O)R 3 、S(O)R 3 、C(S)R 3 and S(O)2R 3 ; R 8 and R 9 is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; Ring is a 3-8 membered fused ring group optionally substituted by 1, 2, 3 or 4 substituents; Each linking group A is to covalently link the ASGPR ligand to a linker group B a key or part of; Linking group B The linking group A a bond or moiety that is covalently attached to an extracellular protein targeting ligand; Linking group C Each linking group A a chemical group attached to an extracellular protein targeting ligand; and Linking group D Each linking group A a chemical group attached to an extracellular protein targeting ligand; and Among them, when R 2 YesNR 6 -Alkenyl, -NR 6 -Alkynyl, -NR 8 -C(O)R 10 、-NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl or -NR 6 -aryl, the extracellular protein targeting ligand does not include an oligonucleotide; and The optional substituents are selected from alkyl, alkenyl, alkynyl, haloalkyl, -OR 6 、F、Cl、Br、I、-NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , This results in stable compounds as valency permits.

2. The compound according to claim 1, which is selected from:

3. The compound according to claim 1, which is selected from:

4. A compound according to any one of claims 1 to 3, wherein R 1 It's H.

5. The compound according to any one of claims 1 to 4, wherein R 2 YesR 10 .

6. A compound according to any one of claims 1 to 5, wherein R 10 Yes - NR 6 -heteroaryl.

7. A compound according to any one of claims 1 to 6, wherein R 6 It's H.

8. A compound according to any one of claims 1 to 7, wherein -NR 6 - Heteroaryl is selected from:

9. The compound according to any one of claims 1 to 8, wherein the linking group A Selected from:

10. The compound of any one of claims 1 to 9, wherein the extracellular protein is 1-40-β-amyloid, 5'-nucleotidase, activated F9, F10, activin receptor-like kinase 1, alpha-fetoprotein, amyloid, angiopoietin 2, angiopoietin 3, anthrax toxin, AOC3, AOC3 (VAP-1), Bacillus anthracis, BAFF, β-amyloid, c-Met, C1s, C242 antigen, C5, CA-125, calcitonin, calcitonin gene-related peptide, calcitonin gene-related peptide alpha, canine IL31, carbonic anhydrase 9 (CA-IX), CEA, CEA-related antigen, CEACAM5, CFD, CGRP, aggregation factor A, coagulation factor III, complement C5a, CSF1, MCSF, CSF2, dabigatran, Escherichia coli Shiga toxin type 1, Escherichia coli Shiga toxin type 2, EGFL7, endotoxin, epithelial sialoprotein, FGF 23, fibrin II, beta chain, fibronectin extracellular domain B, folate hydrolase, GDF-8, gelatinase B, GMCSF, growth differentiation factor 8, hemagglutinin, hemagglutinin HA, HGF, HIV-1, HNGF, Hsp90, human beta-amyloid protein, 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, hepatitis A virus hemagglutinin HA, interferon gamma, interferon gamma-induced 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), neural apoptosis regulating proteinase 1, NGF, NOGO-A, Notch 1. NRP1, oxLDL, PCSK9, PD-L1, phosphatidylserine, RANKL, RGMA, root plate-specific spondin 3, RTN4, sclerostin, SDC1, serum amyloid A, 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.

11. The compound according to any one of claims 1-10, wherein the Ab is a monoclonal antibody.

12. The compound of any one of claims 1-11, wherein the antibody is abavotumab, azekizumab, adalimumab, aducanumab, afacilumab, afelimomab, amorobumab, atumomab, atumomab pentetate, andreximab, anrulumab, acitumomab, afacitumomab, atezolizumab, adulumab, atenumab, avelumab, bavirumizumab, bavitumomab, belimumab, bemakinumab, besotumomab, bevacizumab, bicizumab, bimegizumab, potitumomab, busutuzumab, brecuzumab, bricupuzumab, brianuzumab, brakinumab, brakinumab, brodalumab, brolucizumab, brontuzumab, brosutumomab, cabiluzumab Antibody, canakinumab, cantuzumab, recantuzumab, capazumab, karuzumab, certuzumab, almudex-2-certuzumab, certolizumab, becelizumab, cerbituzumab, clazakizumab, clituzumab, titan-clituzumab, concelizumab, crezumab, detucumab, denosumab, dizumab, di Rivolumab, domaloizumab, dolimumab, atoduzumab, durvalumab, durvalumab, eculizumab, ebumab, ifengucumab, edirumab, elenuzumab, ecitumomab, emituzumab, epavacumab, emicizumab, enokizumab, ipilimumab, sipilimumab, iprenazumab, erezumab, Evizumab, Elouizumab, Faresimab, Fasenoside, Fizakumab, Filatumumab, Filivolumab, Fulcumulumab, Fontuzumab, Remanezumab, Fisotumumab, Flocumab, Fuluvumab, Fulanuzumab, Ganezumab, Gantuzumab, Gatuzumab, Gedivotumab, Gevotumab, Jinsilumab, Gemtuzumab Infliximab, golimumab, gonelumab, guselkumab, idarucizumab, igovomab, imatinib, indaclizumab, ranutuximab, infliximab, estuximab, ixekizumab, labetuzumab, latuzumab, lambazumab, lanacuzumab, lanlozumab, lerezumab, lemzosumab, lendlizumab, lenzlumab Monoclonal antibody, ledetumumab, lesovotumab, ligralizumab, lodicuzumab, logivirumab, rugizumab, matasizumab, mepolizumab, metilimab, migizumab, nacolizumab, tanacizumab, namerucizumab, nannetumab, navivotumab, nacitumomab, nebacumab, nemolizumab, NEOD, nerimumab, ne Vasotumab, nitrazumab, nofitumomab, thionotumomab, octosacizumab, olerulumab, orendalizumab, olozumab, omalizumab, OMS, onatumumab, ogavuzumab, otizumab, otizumab, ozanezumab, orizumab, pasatuzumab, pacolizumab, pertuximab, patuximab,Panitumumab, pelakezumab, pramezolizumab, pralulumab, ponetuzumab, putinizumab, retosacizumab, quilizumab, ratrastuzumab, rapavir, ranevizumab, ranibizumab, ranibizumab, ravulizumab, raxicumab, REGN-EB, nontolumab, reslizumab, rituximab, risakizumab, rokizumab, romumab, longizumab, lomantuzumab, sacizumab, gosatotuzumab, samatumomab, vetin-samatumomab, sarrelumab, secukinumab, setosacizumab, cetusumab, sifalimumab, silotuzumab, sintuzumab, sirukumab, sofetozumab , sofituzumab, vetin-sofituzumab, solanizumab, sontuzumab, setumab, thiosomab, sutitumomab, suvituzumab, sutosutumab, tabemucumab, tacatuzumab, tacilizumab, talizumab, tanizumab, tefizumab, tetumomab, atemucumab, terdolumab, tezerumab, tibulizumab, tirazumab, temozolomide, tesotumab, vetin-tesotumab, trorocitumab, trefotaxime, ouzolizumab, ustekinumab, vanucezumab, valiximab, varisucomab, velpatumomab, vesenkumab, wolbalizumab, vonagizumab, or centuzumab. , 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 an additional therapeutically active compound.

15. A method of treating, ameliorating and / or preventing a disease or disorder in a subject, the method comprising administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 12.

16. The method of claim 15, wherein the disease or disorder comprises an autoimmune disease, cancer, or inflammation.

17. The method of claim 16, wherein the autoimmune disease comprises Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed cold agglutininemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful lipomatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesin Inflammatory arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry-Romberg syndrome, Parsner-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD) , dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton muscular dystrophy syndrome, multiple sclerosis, patternII, Oshtolan Mountain syndrome, Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS), Progressive inflammatory neuropathy, Restless legs syndrome, Stiff person syndrome, Sindenham's chorea, Transverse myelitis, Autoimmune retinopathy, Autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, Intermediate uveitis, Blepharoconjunctivitis, Moren's ulcer, Neuromyelitis optica, Opsoclonus-myoclonus syndrome, Optic neuritis, Scleritis, Susac syndrome, Sympathetic ophthalmia, Tolosa-Hunt syndrome, Autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, Eosinophilia EGPA, giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum.

18. The method of claim 16, 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 corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, laryngeal cancer, Hodgkin's disease, non-Hodgkin's 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, esophageal, laryngeal, kidney cancer, or lymphoma.

19. The method of claim 16, wherein the inflammation comprises neurodegenerative inflammatory diseases, diseases of impaired immune response causing inflammation, chronic inflammatory diseases, hyperglycemia, diabetes (type I and II), pancreatic beta cell death and its associated hyperglycemia, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury or arteriosclerosis.

20. The method of any one of claims 15-19, wherein the subject is further administered at least one additional therapeutic agent that treats, ameliorates or prevents the disease or disorder.

21. The method of any one of claims 15-20, wherein the subject is a mammal.

22. The method of any one of claims 15-21, wherein the subject is a human.

23. A method for treating, ameliorating or preventing autoimmune diseases, cancer or inflammation, the method comprising administering a composition 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, The autoimmune diseases include Addison's disease, autoimmune polyendocrine syndrome (APS) type 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, basic mixed cold agglutininemia, Evans' syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful lipomatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesinosis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatic disease, Parry-Romberg syndrome, Parsner-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, severe Muscle weakness, nerve myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow's concentric sclerosis, Bickerstaff encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton muscular dystrophy syndrome, multiple sclerosis, pattern II, Oshtolan-Mountain syndrome, streptococcal pediatric autoimmune neuropsychiatric disorder (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sindenham's chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, blepharoconjunctivitis, Moren's ulcer, neuromyelitis optica, strabismus opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Susac syndrome, sympathetic ophthalmia, Torosa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behcet's disease, eosinophilia EGPA, giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), IgA nephropathy, Kawasaki disease, leukocytic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency, or pyoderma gangrenosum; wherein the cancer comprises prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, laryngeal cancer, Hodgkin's disease, non-Hodgkin's 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, esophageal, laryngeal, kidney cancer, or lymphoma; and The inflammation includes neurodegenerative inflammatory diseases, diseases of impaired immune response causing inflammation, chronic inflammatory diseases, hyperglycemia, diabetes (type I and II), pancreatic beta cell death and its related hyperglycemia, liver disease, kidney disease, cardiovascular disease, muscle degeneration and atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, stroke and spinal cord injury or arteriosclerosis.

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