Bifunctional small molecules to target the selective degradation of circulating proteins

Abstract

The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In certain embodiments, the (CPBM) is a moiety which binds to Immunoglobulin G. In certain embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte.

Description

Bifunctional Small Molecules to Target the Selective Degradation of Circulating ProteinsCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 498,852, filed April 28, 2023 and U.S. Provisional Patent Application No. 63 / 517,984, filed August 7, 2023, both of which applications are incorporated herein by reference in their entireties.BACKGROUNDVarious diseases are associated with elevated levels of certain proteins in circulation, which play a role in disease progression. For example, increased levels of multiple circulating pro-inflammatory cytokines (i.e., signaling proteins that promote inflammatory effect) contribute to a variety of systemic inflammatory conditions and autoimmune diseases, such as Rheumatoid Arthritis (RA), systemic lupus erythematosus (SLE) and atherosclerosis. Studies have also linked chronic inflammation to an increased risk of heart disease, stroke, cancer and Alzheimer’s disease. In particular, increased levels of cytokines such as TNFa or MIF are associated with Rheumatoid arthritis (RA), atherosclerosis and other diseases. Taken together, the diseases and / or conditions which are associated with circulating proteins impact the lives of millions of people. There is a strong need for novel treatments to address these diseases.Current strategies to target circulating proteins include the use of inhibiting antibodies, which possess excellent specificity and affinity for target proteins. Despite these advantages, antibody-based therapies have several drawbacks that relate primarily to their high molecular weights and / or peptidic structures the likelihood of invoking immunogenicity, their high cost, short shelflife and low oral bioavailability. The small molecule based strategy pursuant to the present invention has the potential to combine the beneficial attributes of antibody-based therapies while overcoming their most significant disadvantages.The high prevalence of inflammatory diseases in the population presents a considerable economic burden to the healthcare system. The high demand and high cost of current antibody-based treatments is reflected in the 34.4 billion USD global sales of TNF-a antibodies. In contrast, the bifunctional small molecule according to the present invention is readily prepared by organic synthesis, and has the potential to substantially lower the cost of manufacturing, storage and treatment. Similarly, these bifunctional chemical constructs areeasier to produce in large quantity to ultimately meet high demand of treatments.BRIEF SUMMARY OF THE INVENTIONConceptually, the present invention is directed to bifunctional small molecules which can be used to remove circulating proteins, which mediate disease states and / or conditions in subjects. The present invention aims to establish a general small molecule strategy to target the selective degradation of disease-related circulating proteins. The bifunctional molecule construct contains a protein targeting motif derived from known small molecule ligands of the proteins of interest. The inventors refer to this moiety generically as a circulating protein binding moiety (CPBM). The other end of the bifunctional molecule is a cellular receptor binding moiety (CRBM) that binds to a cell surface receptor and leads to internalization of the circulating protein and bifunctional molecule. The two motifs are covalently linked via a linker such as a polyethylene glycol (PEG) linker with adjustable length and optionally contains one or more connector molecule which connects the linker to the CPBM and / or theCRBM.The presently claimed bifunctional compounds selectively bind to the Immunoglobulin G (“IgG”) protein of interest (which can be a pathogenic form of IgG) in circulation and form an IgG protein complex that then binds a cellular receptor and is endocytosed and degraded. As a consequence of this mechanism, the IgG protein of interest is eliminated from circulation by hepatocytes, macrophages, or another cell type, thus resulting in lowered level of the IgG protein of interest with the potential of attenuating the corresponding disease symptoms. In certain instances, the IgG protein of interest may be eliminated, resulting in substantially reduced symptoms or even a cure or elimination of the disease state or condition.The approach pursuant to the present invention is inherently advantageous compared to the classical antibody-based strategy to target disease-related circulating proteins of the prior art. The small molecule based approach of the current invention overcomes limitations of traditional antibody-based strategies, including lack of oral bioavailability, low- temperature storage requirements, immunogenicity, and high-cost.Furthermore, the present invention is expected to have a more lasting effect compared to the conventional inhibitory approach because the disease relevant proteins are eliminated by degradation inside hepatocytes rather than simply inhibited by reversibly blocking the protein-receptor interaction. The bifunctional molecule construct pursuant to the present invention is also versatile in the sense that different disease related proteins can be targetedby simply switching the protein targeting motif in the construct. Thus, previously discovered non-inhibitory protein binders can be potentially therapeutically useful in these small molecules.In one embodiment, the present invention is directed to compounds which are useful for removing IgG circulating proteins which are associated with a disease state or condition in a patient or subject according to the general chemical structure:wherein [CPBM] is a Circulating Protein Binding Moiety which binds respectively to IgG circulating proteins as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the IgG circulating protein (the compounds preferably selectively binding to the IgG circulating protein in plasma of the subject or patient);[CRBM] is a Cellular Receptor binding moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k’ is an integer from 1 to 15; j’ is an integer from 1 to 15; h and h’ are each independently an integer from 0 to 15; iLis an integer from 0 to 15; with the proviso that at least one of h, h’ and iLis at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.In various embodiments, [LINKER] has a valency of 1 to 10. In various embodiments, [LINKER] has a valency of 1 to 5. In various embodiments, [LINKER] has a valency of 1, 2 or 3. A [MULTICON] group can connect one or more of a [CRBM] or [CPBM] to one or more of a [LINKER],In one embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In one embodiment, [CRBM] is an [ASGPRBM] is a group according to the chemicalstructure:where X is 1-4 atoms in length and is at each occurrence independently selected from the group consisting of O, S, N(RN1), and C(RN1)(RN1) such that: if X is 1 atom in length, X is O, S, N(RN1), or C(RN1)(RN1), if X is 2 atoms in length, no more than 1 atom of X is O, S, or N(RN1), if X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S or N(RN1); where RN1is H or a C1-C3alkyl group optionally substituted with from 1-3 halogen groups; R1and R3are each independently H, -(CH2)KOH, -(CH2)KOC1-C4alkyl, -C1-C4alkyl, -(CH2)Kvinyl, -O-(CH2)Kvinyl, -(CH2)Kalkynyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, - -O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in which each alkyl, vinyl, or alkynyl is optionally substituted with from 1-3 halogen groups. In various embodiments, each alkyl, vinyl, or alkynyl in R1and R3is optionally substituted with from 1-3 fluorines (F). K is independently at each occurrence an integer from 0-4.In one embodiment, R1and R3are each independently awhich is optionally substituted with 1-3 halogen groups, 1 to 3 C1-C4alkyl groups, or O -C1- C4alkyl groups, in which each of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently at each occurrence and integer from 0-4; or R1and R3are each independently a group according to the chemical structure:where R7is O-C1-C4alkyl, which is optionally substituted with from 1 to 3 halo groups or 1 to 2 hydroxy groups, and K1is independently at each occurrence an integer from 0-4; orR7is a -NRN3RN4group or and K is independently ateach occurrence an integer from 0-4; orR1and R3are each independently a group according to the structure:wherein CYC is a ring selected from the group consisting of:saturated carbocyclic, wherein each of LINKERX, Rc, and -(CH2)K- are attached to an open valence in CYC, including N-H;Rcis absent, H, C1-C4alkyl optionally substituted with from 1-3 halogen groups or 1- 2 hydroxyl groups; or a group according to the structure:where R4, R5and R6are each independently, H, halogen, CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C3alkyl, -O- C1-C3-alkyl, -(CH2)KCOOH, - (CH2)KC(O)O-C1-C4alkyl, O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in any of which the alkyl group is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; orRciswhere RN, RN1, and RN2are each independently H or a C1-C3alkyl group optionally substituted with 1-3 halogen groups, or 1-2 hydroxyl groups;K is independently at each occurrence an integer from 0-4;K' is independently at each occurrence an integer from 0-4;RN3is H or C1-C3alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; andRN4is H or C1-C3alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, orRN4iswhere K is 1;is a linker group which includes at least one [CPBM] group and connects the [CPBM] group to the [CRBM] through one or more optional [CON] groups, oris a linker group which includes at least one functional group that covalently bonds the linker group to at least one [CPBM] group or optional [CON] group;R2is where RN1and K are the same as above;RAMis H, C1-C4alkyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, -O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, -(CH2)K-NRN3RN4where RN3is H or C1-C3alkyl, in which any of the alkyl groups are optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; andRN4is H, C1-C3alkyl optionally substituted with 1-3 halo groups or 1 or 2 hydroxy groups, orRN4isR2is awhere RTAis H, CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C4alkyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in which each alkyl is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, orRTAis a C3-C10 aryl or a 3- to 10-membered heteroaryl group containing up to 5 hetero atoms, each of said aryl or heteroaryl groups being optionally substituted with 1-3 substituents selected from the group consisting of CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C3alkyl, -O-C1-C3-alkyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, O-C(O) -C1- C4alkyl, and -(CH2)KC(O)-C1-C4alkyl, in which each alkyl is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, orRTAisor;RTAis group which is optionally substituted with 1-3 C1-C3alkylgroups each of which are optionally substituted with 1-3 halogen groups, orRTAiswherein RN, RN1, and RN2are each independently H or a C1-C3alkyl group which is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups and wherein each -(CH2)Kgroup is optionally substituted with 1-4 C1-C3alkyl groups which are each optionally substituted with from 1-3 fluorines or 1-2 hydroxyl groups; and K is independently at each occurrence 0-4.In various embodiments, any of the alkyl groups described herein as being optionally substituted by 1-3 halogen groups, are substituted by 1, 2, or 3 fluorine (F) atoms.In various embodiments,where Rc,and K are the same as above.In some embodiments of the present invention X of the [CRBM] / [ ASGPRBM] group is OCH2or CH2O and RN1is preferably H.In various embodiments, the [CRBM] / [ ASGPRBM] group is a group according to the chemical structure:where R1, R2and R3are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.In some embodiment, the carbohydrate moiety of the [ASGPRBM] group has α- configuration at the anomeric center. In some embodiments, the carbohydrate moiety of the [ASGPRBM] group has β-configuration at the anomeric center.In some embodiments, [CRBM] is or includes an [ASGPRBM] group according to the chemical structure:In some embodiments, the [CRBM] / [ ASGPRBM] group is a group according to the chemical structure:where RAis C1-C3alkyl optionally substituted with 1-5 halogen groups;ZAis -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) residues, or -C(O)(CH2)IMNRM, where IM and RM are the same as above; andZBis absent, (CH2)IM, C(O)-(CH2)IM-, or C(O)-(CH2)IM-NRM, where IM and RM are the same as above.In various embodiments, R1and R3are each independently a group according to the chemical structure: and K are as definedherein.In an additional embodiment, the present invention is directed to a pharmaceutical composition comprising an effective amount of a compound according to the present invention in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional bioactive agent.In other embodiments, the present invention is directed to a method of treating a disease state or condition where a circulating protein is related to or contributes to a disease state and or condition or the symptomology associated with the disease state or condition. These disease states and / or conditions include autoimmune diseases and numerous inflammatory diseases for example, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer’s disease, atherosclerosis, heart disease, stroke and cancer (including leukemia), among numerous others as described herein. The method of treatment according to the present invention comprises administering to a patient or subject in need of therapy an effective amount of at least one compound according to the present invention, optionally in combination with an additional bioactive agent to reduce the likelihood of, inhibit and / or treatthe disease state or condition by removing Circulating Protein associated with the disease state and / or condition from the circulation of the patient or subject.In an additional embodiment, the present invention is directed to a pharmaceutical composition comprising an effective amount of a compound according to the present invention in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional bioactive agent.In other embodiments, the present invention is directed to a method of treating a disease state or condition where a circulating protein is related to the symptomology associated with the disease state or condition. These disease states and / or conditions include, for example, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer’s disease, atherosclerosis, heart disease, stroke and cancer (including leukemia), among numerous others as described herein. The method comprises administering to a patient or subject in need of therapy an effective amount of at least one compound according to the present invention, optionally in combination with an additional bioactive agent to reduce the likelihood of, inhibit and / or treat the disease state or condition by removing circulating proteins associated with the disease state and / or condition.DETAILED DESCRIPTION OF THE INVENTIONIn accordance with the present invention there may be employed conventional chemical synthetic and pharmaceutical formulation methods, as well as pharmacology, molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are well-known and are otherwise explained fully in the literature.Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the present invention, the preferred methods and materials are now described.It is to be noted that as used herein and in the appended claims, the singular forms "a," “an”, "and" and "the" include plural references unless the context clearly dictates otherwise.Furthermore, the following terms shall have the definitions set out below. It is understood that in the event a specific term is not defined hereinbelow, that term shall have a meaning within its typical use within context by those of ordinary skill in the art.The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, stereoisomers and where applicable, optical isomers (enantiomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. The term also refers, within context, to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents, linkers and connector molecules and variables associated with same, among others, are described. The use of a bond presented as - signifies that a single bond is present or absent, depending on the context of the chemistry described, including the attachment of the bond to another moiety. The use of a bond presented as - signifies that a single bond or a double bond is intended depending on the context of the chemistry described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder.The term “patient” or “subject” is used throughout the specification within context to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment (prophylaxis, including especially as that term is used with respect to reducing the likelihood of metastasis of an existing cancer), with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient or a patient of a particular gender, such as a human male or female patient, the term patient refers to that specific animal. Compounds according to the present invention are usefill for the treatment of numerous disease states including autoimmune disease states and / or conditions andinflammatory disease states and / or conditions as well as cancer, including especially for use in reducing the likelihood of metastasis or recurrence of a cancer.The term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition which, in context, is used to produce or effect an intended result, whether that result relates to the inhibition of the effects of a disease state (e.g. an autoimmune disease such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among others, atherosclerosis, heart disease or stroke, among numerous others or a cancer, including leukemia) on a subject or the treatment or prophylaxis of a subject for secondary conditions, disease states or manifestations of disease states as otherwise described herein. This term subsumes all other effective amount or effective concentration terms (including the term “therapeutically effective”) which are otherwise described in the present application.The terms “treat”, “treating”, and “treatment”, etc., as used herein, refer to any action providing a benefit to a patient at risk for a disease state or condition for which a MIF protein may be removed, such as an autoimmune disease including rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among others, atherosclerosis, heart disease, stroke and cancer (including leukemia) including recurrence and / or metastasis of cancer, improvement in the condition through lessening or suppression of at least one symptom of the disease state or condition, inhibition of one or more manifestations of the disease state (e.g., plaque formation, heart disease, cancer growth, reduction in cancer cells or tissue), prevention, reduction in the likelihood or delay in progression of a disease state or condition or manifestation of the disease state or condition, especially including plaque formation in atheroslerosis, deterioration of tissue and inflammation in rheumatoid arthritis, further damage to cardiovascular tissue in heart disease, further damage to central nervous tissue in stroke, cancer, its recurrence or metastasis of the cancer, prevention or delay in the onset of disease states or conditions which occur secondary to the disease state or condition including cancer recurrence or metastasis, among others. Treatment, as used herein, encompasses both prophylactic and therapeutic treatment, depending on the context of the treatment. The term “prophylactic” when used, means to reduce the likelihood of an occurrence or the severity of an occurrence within the context of treatment of disease state or condition, as otherwise described hereinabove.As used in this application, the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about / approximately are meant to cover any normal fluctuations in a value appreciated by one of ordinary skill in therelevant.The term “circulating protein binding moiety”, which term includes “immunoglobulin G binding moiety” or “IgGBM’ refers to a chemical moiety on one end of the bifunctional compounds according to the present invention which is capable of binding to a circulating protein which is associated with or contribute to a disease state or condition as otherwise described herein. In the present invention, the CPBM is capable of binding to the circulating protein, forming a complex with the present compounds, and delivering the bound protein to a hepatocyte or other cell whereupon the other end of the bifunctional molecule which contains a cellular receptor binding moiety (CRBM) such an asialoglycoprotein receptor binding moiety (ASGPRBM) or as otherwise described herein can bind to the surface of a hepatocyte or other cell, respectively. Once attached to the cell, the bifunctional molecule to which is bound circulating protein is internalized by the cell through a phagocytosis / endocytosis mechanism whereupon the cell will destroy the protein via a lysosomal degradation or other degradation pathway. The term “immunoglobulin G binding moiety” or “IgGBM” is used to describe a moiety which binds to circulating IgG immunoglobulin, forming a complex with bifunctional molecules according to the present invention to be ultimately destroyed in hepatocytes. In certain instances, in describing the present invention, the terms IgGBM and other cell binding moieties are used synonymously.CPBM groups, such as IgGBM bind to the respective circulating proteins, thus forming a complex with the bifunctional compounds according to the present invention and the bifunctional compounds complexed with the bound circulating proteins can be bound to cellular receptors on cells which can take up the complexed compounds using phagocytosis / endocytosis mechanisms of the cell and remove the proteins through a degradation process. It is noted that the CPBM which are peptides which bind to IgGBM are covalently linked to other portions of the bifunctional molecules according to the present invention through the terminal amine or carboxylic acid group of the peptide. In preferred embodiments, the carboxylic acid is amidated to form a non-reactive amide group, often with a free amine group (substituted with two H’s) or an amine group which alkylated with at least one Ci-Cio alkyl group, more often at least one C1-C3alkyl group so that the free amine on the other end of the peptide may be used to covalently link to other portions of the bifunctional molecule. In other embodiments, the amine terminus is rendered non-reactive by end-capping the amine group with a C2-C10 acyl group, preferably a C2-C4 acyl group, so that the carboxylic acid group may be reacted, often with an amine to form an amide.In one embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:In another embodiment, [CPBM] is or includes the moiety:The term “cellular receptor binding moiety” refers to a moiety of the bifunctional compounds according to the present invention which is capable of binding to a receptor on a cell capable of degrading circulating proteins pursuant to the present invention herein. These are moieties which bind to asialoglycoprotein receptor, LRPR, LDLR, RcγRI, FcRN, Transferrin Receptor or Macrophage Scavenger Receptor (e.g., membrane receptors of degradation cells) as otherwise described herein. Many of these binding moieties are peptides which are covalently linked to other portions of the bifunctional compounds according to the present invention through a terminal amine or carboxylic acid group. As for the CPBM group described above, in preferred embodiments, the carboxylic acid is amidated to form a non-reactive amide group, often with a free amine group (substituted with two H’s) or an amine group which alkylated with at least one C1-C10alkyl group, more often at least one C1-C3alkyl group so that the free amine on the other end of the peptide may be used to covalently link to other portions of the bifunctional molecule. In other embodiments, the amine terminus is rendered non-reactive by end-capping the amine group with a C2-C10acyl group, preferably a C2-C4acyl group, so that the carboxylic acid group may be reacted, often with an amine to form an amide.The term “asialoglycoprotein receptor binding moiety” (“ASGPRBM’) refers to a binding moiety which binds to hepatocyte asialoglycoprotein receptor. This binding moiety is also a component of the presently claimed bifunctional compounds as a CRBM group which is covalently bound to the CPBM group moiety through a CON group, a linker or directly. The ASGPRBM group selectively binds to hepatocyte asialoglycoprotein receptor on the surface of hepatocytes. It is through this moiety that bifunctional compounds complexed with circulating protein bind to hepatocytes. Once bound to the hepatocyte, the circulating protein is taken into the hepatocytes or other cells via a phagocytosis mechanism wherein the circulating protein is degraded through lysosomal degradation.Exemplary ASGPRBM groups for use in compounds according to the present invention, among others, include moieties according to the chemical structures:where X is 1-4 atoms in length and is at each occurrence independently selected from the group consisting of O, S, N(RN1), and C(RN1)(RN1) such that: if X is 1 atom in length, X is O, S, N(RN1), or C(RN1)(RN1),if X is 2 atoms in length, no more than 1 atom of X is O, S, or N(RN1), if X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S or N(RN1); where RN1is H or a C1-C3alkyl group optionally substituted with from 1-3 halogen groups; R1and R3are each independently H, -(CH2)KOH, -(CH2)KOC1-C4alkyl, -C1-C4alkyl, -(CH2)Kvinyl, -O-(CH2)Kvinyl, -(CH2)Kalkynyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, - -O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in which each alkyl, vinyl, or alkynyl is optionally substituted with from 1-3 halogen groups. In various embodiments, each alkyl, vinyl, or alkynyl in R1and R3is optionally substituted with from 1-3 fluorines (F). K is independently at each occurrence an integer from 0-4.In one embodiment, R1and R3are each independently awhich is optionally substituted with 1-3 halogen groups, 1 to 3 C1-C4alkyl groups, or O-C1- C4alkyl groups, in which each of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, and K is independently at each occurrence and integer from 0-4; or R1and R3are each independently a group according to the chemical structure:where R7is O-C1-C4alkyl, which is optionally substituted with from 1 to 3 halo groups or 1 to 2 hydroxy groups, and K' is independently at each occurrence an integer from 0-4; orR7is a -NRN3RN4group or and K is independently ateach occurrence an integer from 0-4; or R1and R3are each independently a group according to the structure: R1and R3are each independently a group according to the structure: wherein K is independently at eachoccurrence 0-4; or awherein CYC is a ring selected from the group consisting of:saturated carbocyclic, wherein each of LINKERX, Rc, and -(CH2)K- are attached to an open valence in CYC, including N-H;Rcis absent, H, C1-C4alkyl optionally substituted with from 1-3 halogen groups or 1- 2 hydroxyl groups; or a group according to the structure:where R4, R5and R6are each independently, H, halogen, CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C3alkyl, -O-C1-C3-alkyl, -(CH2)KCOOH, - (CH2)KC(O)O-C1-C4alkyl, O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in any of which the alkyl group is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; or Rciswhere RN, RN1, and RN2are each independently H or a C1-C3alkyl group optionally substituted with 1-3 halogen groups, or 1-2 hydroxyl groups;K is independently at each occurrence an integer from 0-4;K' is independently at each occurrence an integer from 0-4;RN3is H or C1-C3alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups; andRN4is H or C1-C3alkyl optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, orRN4is, where K is 1;is a linker group which includes at least one [CPBM] group and connects the [CPBM] group to the [CRBM] through one or more optional [CON] groups, oris a linker group which includes at least one functional group that covalently bonds the linker group to at least one [CPBM] group or optional [CON] group;R2iswhere RN1and K are the same as above;RAMis H, C1-C4alkyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, -O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, -(CH2)K-NRN3RN4where RN3is H or C1-C3alkyl, in which any of the alkyl groups are optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups; andRN4is H, C1-C3alkyl optionally substituted with 1-3 halo groups or 1 or 2 hydroxy groups, orRN4isR2is awhere RTAis H, CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C4alkyl, - (CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, O-C(O)-C1-C4alkyl, -C(O)-C1-C4alkyl, in which each alkyl is optionally substituted by 1-3 halogen groups or 1-2 hydroxyl groups, orRTAis a C3-C10 aryl or a 3- to 10-membered heteroaryl group containing up to 5 hetero atoms, each of said aryl or heteroaryl groups being optionally substituted with 1-3 substituents selected from the group consisting of CN, NRN1RN2, -(CH2)KOH, -(CH2)KOC1-C4alkyl, C1-C3alkyl, -O-C1-C3-alkyl, -(CH2)KCOOH, -(CH2)KC(O)O-C1-C4alkyl, O-C(O)-C1- C4alkyl, and -(CH2)KC(O)-C1-C4alkyl, in which each alkyl is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, orRTAisor;RTAisgroup which is optionally substituted with 1-3 C1-C3alkyl groups each of which are optionally substituted with 1-3 halogen groups, orRTAiswherein RN, RN1, and RN2are each independently H or a C1-C3alkyl group which is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups and wherein each -(CH2)Kgroup is optionally substituted with 1-4 C1-C3alkyl groups which are each optionally substituted with from 1-3 fluorines or 1-2 hydroxyl groups; and K is independently at each occurrence 0-4. In various embodiments, K is 0. In various embodiments, K is 1. In various embodiments, K is 2. In various embodiments, K is 3. In various embodiments, K is 4.In some embodiment, the carbohydrate moiety of the [ASGPRBM] group has a- configuration at the anomeric center. In some embodiments, the carbohydrate moiety of the [ASGPRBM] group has β-configuration at the anomeric center.In some embodiments, [CRBM] is or includes an [ASGPRBM] group according to the chemical structure:[CON] is a connector moiety (including a [MULTICON]) as otherwise described herein; and [LINKER] is a linking moiety as otherwise described herein which links [CPBM] to the [CRBM] group and optionally contains one or more connector moieties (which optionally connects) more than one chemical moiety to provide said linking moiety or whichconnects said linking moiety to said [CPBM] group or said [CRBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.In various embodiments, X is -O-C(RN1)(RN1),C(RN1)(RN1)-O-, -S-C(RN1XRN1), C(RN1)(RN1)-S-, N(RN1)-C(RN1)(RN1),C(RN1)(RN1)-N(RN1) or C(RN1)(RN1)-C(RN1XRN1) when X is 2 atoms in length, X is -O-C(RN1)(RN1)-C(RN1XRN1), C(RN1)(RN1)-O-C(RN1)(RN1)-, -O-C(RN1XRN1)-O-, -O-C(RN1)(RN1)-S-, -O-C(RN1XRN1)-N(RN1)-, -S-C(RN1XRN1)-C(RN1)(RN1), C(RN1XRN1)-S-C(RN1XRN1)-, C(RN1XRN1)-C(RN1)(RN1)-S, -S-C(RN1)(RN1)-S-, -S-C(RN1XRN1)-O-, -S-C(RN1)(RN1)-N(RN1)-, N(RN1)-C(RN1)(RN1)-C(RN1)(RN1), C(RN1XRN1)-N(RN1)-C(RN1XRN1), C(RN1XRN1)-C(RN1)(RN1)- N(RN1), N(RN>C(RN1)(RN1)-N(RN1) or C(RN1)(RN>C(RN1)(RN1)- C(RN1)(RN1) when X is 3 atoms in length, andX is -O-C(RN1)(RN1)-C(RN1XRN1)-C(RN1XRN1), C(RN1XRN1)-O-C(RN1)(RN1)- (RN1)(RN1)-, -O-C(RN1)(RN1>O-C(RN1XRN1)-, -S-C(RN1XRN1)-C(RN1)(RN1)- C(RN1)(RN>, C(RN1)(RN>S-C(RN1)(RN1)-C(RN1)(RN1)-, C(RN1)(RN1)-(RN1)(RN1>- S-C(RN1XRN1)-, -S-C(RN1XRN1)-S-C(RN1)(RN1)-, N(RN1)-C(RN1)(RN1)- C(RN1)(RN1>- C(RN1XRN1)-, C(RN1)(RN>N(RN1)-C(RN1)(RN1)-C(RN1)(RN1), C(RN1)(RN>C(RN1)(RN1>- N(RN1), N(RN>C(RN1)(RN1)-N(RN1) or C(RN1)(RN1)- C(RN1)(RN1)- C(RN1)(RN1) when X is 4 atoms in length where RN1is the same as above. Most often, RN1is H.In various embodiments, X is OCH2or CH2O and RN1is H.In various embodiments, the [CRBM] / [ASGPRBM] group is a group according to the chemical structure:where R1, R2and R3are as defined herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.In various embodiments, the [CRBM] / [ASGPRBM] group is a group according to the chemical structure:where RAis -C1-C3alkyl optionally substituted with 1-5 halogen groups;ZA is -(CH2)IM, -O-(CH2)IM, S-(CH2)IM, NRM-(CH2)IM, C(O)-(CH2)IM-, a PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) units, or -C(O)(CH2)IMNRM, where IM and RM are the same as above; andZB is absent, (CH2)IM, C(O)-(CH2)IM-, or C(O)-(CH2)IM-NRM, where IM and RM are the same as above.In various embodiments, ZA is a PEG group containing 1-4 ethylene glycol units. In various embodiments, ZA is a PEG group containing 2-4 ethylene glycol units. In various embodiments, RAis C1-C3alkyl optionally substituted with 1-5 fluorine atoms. In various embodiments, RAis -CH3optionally substituted with 1-3 fluorine atoms. In various embodiments, RAis -CH2CH3optionally substituted with 1-3 fluorine atoms;Note that the [CRBM][ASGPRBM] group set forth above may also be represented as follows:In the above structure, the anomeric center of the carbohydrate moieties has 0- configuration. In some embodiments, the anomeric center of the carbohydrate moieties may have a-configuration.The term "neoplasia" or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Neoplasms include, without limitation, morphological irregularities in cells in tissue of a subject or host, as well as pathologic proliferation of cells in tissue of a subject, as compared with normal proliferation in the same type of tissue. Additionally, neoplasms include benign tumors and malignant tumors (e.g., colon tumors) that are either invasive or noninvasive. Malignant neoplasms (cancer) are distinguished from benign neoplasms in that the former show a greater degree of anaplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis. Examples of neoplasms or neoplasias from which the target cell of the present invention may be derived include, without limitation, carcinomas (e.g., squamouscell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas),particularly those of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of neoplasias, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas (Beers and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms may be treated using compounds according to the present invention.Representative common cancers to be treated with compounds according to the present invention include, for example, prostate cancer, metastatic prostate cancer, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain / CNS, head and neck, throat, 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, mouth / pharynx, oesophagus, larynx, kidney cancer and lymphoma, among others, which may be treated by one or more compounds according to the present invention. Because of the activity of the present compounds, the present invention has general applicability treating virtually any cancer in any tissue, thus the compounds, compositions and methods of the present invention are generally applicable to the treatment of cancer and in reducing the likelihood of development of cancer and / or the metastasis of an existing cancer.In certain particular aspects of the present invention, the cancer which is treated is metastatic cancer, a recurrent cancer or a drug resistant cancer, especially including a multiple drug resistant cancer. Separately, metastatic cancer may be found in virtually alltissues of a cancer patient in late stages of the disease, typically metastatic cancer is found in lymph system / nodes (lymphoma), in bones, in lungs, in bladder tissue, in kidney tissue, liver tissue and in virtually any tissue, including brain (brain cancer / tumor). Thus, the present invention is generally applicable and may be used to treat any cancer in any tissue, regardless of etiology.The term “tumor” is used to describe a malignant or benign growth or tumefacent. The term “autoimmune disease” refers to a disease or illness that occurs when the body tissues are attacked by its own immune system. The immune system is a complex organization within the body that is designed normally to "seek and destroy" invaders of the body, including infectious agents. In diseases which are described as autoimmune diseases, MIF levels are often elevated. The present invention seeks to inhibit or lower elevated MIF levels in patients with autoimmune disease (as well as inflammatory diseases and conditions and cancer) and by decreasing MIF levels, ameliorate many of the symptoms and secondary effects of these disease states and conditions. Examples of autoimmune diseases which often exhibit high expressed levels of MIF including, for example, systemic lupus erythematosus, Sjogren syndrome, Hashimoto thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes, polymyositis, scleroderma, Addison's disease, vtiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis, among numerous others.A more complete list of autoimmune diseases which may be treated by compounds and pharmaceutical compositions according to the present invention includes Addison's Disease, Autoimmune polyendodrine syndrome (APS) types 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitus type 1, autoimmune thyroiditis, Ord's thyroiditis, Grave's disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren's syndrome, autoimmune enteropathy, coeliac disease, Grohns' disease, microscopic colitis, ulcerative colitis, autophospholipid syndrome (APIS), aplastic anemia, autoimmune hemolytica anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglulinemia, Evans sndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler 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 axonic neuropathy, anti-NMDA receptor encephalitis, Balo concentric sclerosis, Bickerstaffs encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating diseases, Lambert- Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oshtoran Syndrome, Pendiatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), progressive inflammatory neuropathy, restless leg syndrome, stiff person syndrome, Syndenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate uveitis, ligneous conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmia, Tol osa-Hunt syndrome, autoimmune inner ear disease (AIED), Meniere's disease, Behçet's disease, Eosiniphilic 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, primary immune deficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiency and pyoderma gangrenosum, among others.The term “inflammatory disease” is used to describe a disease or illness with acute, but more often chronic inflammation as a principal manifestation of the disease or illness. Inflammatory diseases include diseases of neurodegeneration (including, for example, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease; other ataxias), diseases of compromised immune response causing inflammation (e.g., dysregulation of T cell maturation, B cell and T cell homeostasis, counters damaging inflammation), chronic inflammatory diseases including, for example, inflammatory bowel disease, including Crohn’s disease, rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjogren’s disease; hyperglycemic disorders, diabetes (I and II), affecting lipid metabolism islet function and / or structure, pancreatic 0-cell death and related hyperglycemic disorders, including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g. Mendenhall's Syndrome, Werner Syndrome, leprechaunism, and lipoatrophic diabetes) and dyslipidemia (e.g.hyperlipidemia as expressed by obese subjects, elevated low-density lipoprotein (LDL), depressed high-density lipoprotein (HDL), elevated triglycerides and metabolic syndrome, liver disease, renal disease (apoptosis in plaques, glomerular disease), cardiovascular disease (especially including infarction, ischemia, stroke, pressure overload and complications during reperfusion), muscle degeneration and atrophy, low grade inflammation, gout, silicosis, atherosclerosis and associated conditions such as cardiac and neurological (both central and peripheral) manifestations including stroke, age-associated dementia and sporadic form of Alzheimer's disease, and psychiatric conditions including depression), stroke and spinal cord injury, arteriosclerosis, among others. In these diseases, elevated MIF is very often observed, making these disease states and / or conditions response to therapy using compounds and / or pharmaceutical compositions according to the present invention. It is noted that there is some overlap between certain autoimmune diseases and inflammatory diseases as described herein.The term “linker”, refers to a chemical entity including a complex linker connecting a circulating protein binding moiety (CPBM) to the cellular receptor binding moiety (CRBM) including an asialoglycoprotein receptor binding moiety (ASGPRBM), optionally through at least one (preferably one or two) connector moiety [CON] through covalent bonds in compounds according to the present invention. The linker between the two active portions of the molecule, that is the CPBM group and the CRBM / ASGPRBM group ranges from about 5Å to about 50A or more in length, about 6Å to about 45Å in length, about 7Å to about 40A in length, about 8Å to about 35A in length, about 9Å to about 30A in length, about 10A to about 25Å in length, about 7Å to about 20 A in length, about 5Å to about 16Å in length, about 5Å to about 15Å in length, about 6Å to about 14A in length, about 10A to about 20A in length, about 11Å to about 25Å in length, etc. Linkers which are based upon ethylene glycol units and are between 2 and 15 glycol units, 1 and 8 glycol units, 1, 2, 3, 4, 5, and 6 glycol units in length may be preferred, although the length of certain linkers may be far greater. By having a linker with a length as otherwise disclosed herein, the CPBM group and the CRBM / ASGPRBM group may be situated to advantageously take advantage of the biological activity of compounds according to the present invention which bind to receptors, including asialoglycoprotein receptors on hepatocytes and other cells resulting in the selective and targeted degradation of circulating proteins within the lysosomal degradation mechanism or other degradation mechanism of the hepatocytes. The selection of a linker component is based on its documented properties of biocompatibility, solubility in aqueous and organic media, and low immunogenicity / antigenicity. Although numerous linkers may be used asotherwise described herein, a linker based upon polyethyleneglycol (PEG) linkages, polypropylene glycol linkages, or polyethyleneglycol-co-polypropylene oligomers (up to about 100 units, about 1 to 100, about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 1 to 8, 1 to 3, 1 to 4, 2 to 6, 1 to 5, etc.) may be favored as a linker because of the chemical and biological characteristics of these molecules. The use of polyethylene (PEG) linkages of between 2 and 15 ethylene glycol units is preferred. When describing linkers according to the present invention, including polyethylene glycol linkers or other linkers, one or more additional groups (e.g., methylene groups, amide groups, keto groups, amine groups, etc., with methylene groups or amide groups being preferred) may be covalently attached at either end of the linker group to attach to a CRBM / ASGPRBM group, a [CON] group, another linker group or a CPBM group.Alternative linkers may include, for example, poly amino acid linkers of up to 100 amino acids (of any type, preferably D- or L- amino acids, preferably naturally occurring L- amino acids) in length (about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10, about 4 to 6, about 1 to 8, about 1 to 6 , about 1 to 5, about 1 to 4, about 1 to 3, etc. in length), optionally including one or more connecting groups (preferably 1 or 2 connecting groups at one or both ends of the poly amino acid linker).Preferred linkers include those according to the chemical structures:or a polypropylene glycol or polypropylene-co-polyethylene glycol linker having between 1 and 100 alkylene glycol units, preferably about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10, about 4 to 6, about 1 to 8, about 1 to 6 , about 1 to 5, about 1 to 4, about 1 to 3 ; where R, is H, C1-C3alkyl or alkanol or forms a cyclic ring with R3(proline) and R3is a side chain derived from a D- or L amino acid (preferably a naturally occurring L-amino acid) preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1 -methylpropane),leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline hydroxyproline (R3forms a cyclic ring with R, and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1 -hydroxy ethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl), where the R3group is indicated in parentheses; m (within the context of this use) is an integer from 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, l to 45, I to 40, 2 to 35, 3 to 30, I to 15, I to 12, I to 10, I to 8, I to 6, 1, 2, 3, 4 or 5.In another embodiment, a linker according to the present invention comprises a polyethylene glycol linker containing from 1 to 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5 ethylene glycol units, to which is bonded a lysine group or other amino acid moiety at one or both ends of the linker (which can consist of between 1 and 10 amino acids which can bind the CPBM and / or the CRBM / ASGPRBM group. Still other linkers comprise amino acid residues (D or L) which are bonded to CPBM and / or CRBM / ASGPRBM moieties as otherwise described herein. In another embodiment, as otherwise described herein, the amino acid has anywhere from 1-15 methylene groups separating the amino group from the acid (acyl) group in providing a linker to the MIFBM and / or the ASGPRBM group, wherein the linker contains from 1 to 100, 1 to 75, I to 60, I to 55, I to 50, I to 45, I to 40, 2 to 35, 3 to 30, I to 15, I to 10, I to 8, I to 6, 1, 2, 3, 4 or 5 amino acid groups linked together through peptide linkages to form the linker. This linker is represented by the chemical structure:where Ramis H or a C1-C3alkyl optionally substituted with one or two hydroxyl groups; na is 1-15, 1-12, 1-10, 1-8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; m is an integer from 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, I to 15, I to 12, I to 10, I to 8, I to 6, 1, 2, 3, 4 or 51 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.In various embodiments, the linker is according to the chemical formula:where Z and Z’ are each independently a bond, -(CH2)i-O, -(CH2)i-S, -(CH2)i-N-R,wherein said -(CH2)igroup, if present in Z or Z’, is bonded to a connector (CON), CPBM or CRBM / ASGPRBM; each R is H, or a C1-C3alkyl or alkanol group; each R2is independently H or a C1-C3alkyl group; each Y is independently a bond, O, S or N-R; each i is independently 0 to 100, 0 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 0, 1, 2, 3, 4 or 5;D isa bond, with the proviso that Z, Z’ and D are not each simultaneously bonds; j is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5; m’ is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5; n is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5 (n is preferably 2);X1is O, S orN-R; andR is H, or a C1-C3alkyl or alkanol group, or a pharmaceutical salt thereof.In one embodiment, other linkers which are included herein include linkers according to the chemical structure:where each n and n’ is independently 1 to 25, 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and each n” is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 2, 3, 4 or5).Linkers also can comprise two or more linker segments (based upon the linkers described above) which are attached directly to each other or through [CON] groups forming a complex linker. Certain linkers which include a [CON] group connecting a first and second (PEG) linker group include the following structures: orwhere each n and n’ is independently 1 to 25, 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and each n” is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 3).Each of these linkers can also contain alkylene groups containing from 1 to 4 methylene groups at the distal ends of each linker group in order to facilitate connection of the linker group.Other linkers which include a connector group [CON] include groups which are represented by the chemical formula:PEG-[CON]-PEG, wherein each PEG linker is independently a polyethylene glycol group containing from 1-12 ethylene glycol units and [CON] is a connector group as otherwise set forth herein. In various embodiments, [CON] is:The term “connector”, symbolized in the generic formulas by “CON” or [CON], isused to describe a chemical moiety which is optionally included in bifunctional compounds according to the present invention which forms from the reaction product of an activated linker with a CPBM moiety (which also is preferably activated for covalently bonding the linker with the moiety) or a CRBM / ASGPRBM group with an activated linker. The connector group is often the resulting moiety which forms from the facile condensation of two or more separate chemical fragments which contain reactive groups which can provide connector groups as otherwise described to produce bifunctional or multifunctional compounds according to the present invention. It is noted that a connector may be distinguishable from a linker in that the connector is the result of a specific chemistry which is used to provide bifunctional compounds according to the present invention wherein the reaction product of these groups results in an identifiable connector group or part of a connector group which is distinguishable from the linker group, although in certain instances, the connector group is incorporated into and integral with the linker group as otherwise described herein.It is noted also that a connector group may be linked to a number of linkers to provide multifunctionality (i.e., more than one CPBM moiety and / or more than one CRBM / ASGPRBM moiety) within the same molecule. It is noted that there may be some overlap between the description of the connector group and the linker group such that the connector group is actually incorporated or forms part of the linker, especially with respect to more common connector groups such as amide groups, oxygen (ether), sulfur (thioether) or amine linkages, urea or carbonate -OC(O)O- groups or as otherwise described herein. It is further noted that a connector (or linker) may be connected to CPBM, CRBM / ASGPRBM or a linker at positions which are represented as being linked to another group using the symbol:Where two or more such groups (symbols) are present in a linker or connector, any of an CRBM / ASGPRBM, a linker or a CPBM group may be bonded to such a group. Where that symbol is not used, the linker may be at one or more positions of a moiety where an open valence is present.In various embodiments, suitable [CON] connector groups which are used in the present invention include the following chemical groups:where RCON1and RCON2are each independently H, methyl or a bond (for attachment to another moiety); or a diamide group according to the structure:where X2is CH2, O, S, NR4, C(O), S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O;X3is O, S, NR4;R4is H, a C1-C3alkyl or alkanol group, or a -C(O)( C1-C3) group;R1is H or a C1-C3alkyl group (preferably H); and n" is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 3); or the connector group [CON] is a group according to the chemical structure:where R1CON, R2CON, and R3CONare each independently H, -(CH2)MC1, - (CH2)MC1aC(O)XA(NR4)XA-(CH2)MC1a, -(CH2)MC1a(NR4)XAC(O)XA-(CH2)MC1a, Or -(CH2)MC1aO- (CH2)MC1-C(O)NR4-, with the proviso that R1CON, R2CON, and R3CONare not simultaneously H; each MCI is independently an integer from 1-4; each MCI a is independently an integer from 0-4; andR4is H, a C1-C3alkyl or alkanol group, or a -C(O)(C1-C3) group.In various embodiments, MCI is 1 or 2. In various embodiments, MCla is 0, 1, or 2. The triazole group, indicated above, may be a preferred connector group. An additional preferred connector group is:which is linked to at least one CPBM and / or at least one CRBM / ASPRGBM (preferably 3 CRBM / ASPRGBM moieties). This connector group may be used to form GN3 as otherwise described herein.It is noted that each connector may be extended with one or more methylene groups to facilitate connection to a linker group, another CON group, a CPBM group or a CRBM / ASGPRBM group. It is noted that in certain instances, within context the diamide group may also function independently as a linker group.In some embodiments, at least one of [CON] and [LINKER] is or includes In some embodiments, at least one of [CON] includes In someembodiments, [LINKER] is or includesAdditional Galactose- and Talose-based ASGPR Binding MoietiesIn one embodiment, the present invention is directed to compounds which are usefill for removing circulating proteins which are associated with a disease state or condition in a patient or subject according to the general chemical structure of Formula II:Formula IIThe term "Extracellular Protein Targeting Ligand" as used herein is interchangeably used with the term CPBM (cellular protein binding moiety). The term "ASGPR Ligand" as used herein is interchangeably used with an asialoglycoprotein receptor (ASGPR) binding moiety as defined herein.In the compound of Formula II, each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER- 2] to [CPBM] or to [CRBM],In the compound of Formula II:[LINKER-2] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER-2] optionally itself contains one or more [CON] or [MULTICON] group(s); k’ is an integer from 1 to 15; j’ is an integer from 1 to 15; h and h’ are each independently an integer from 0 to 15; iLis an integer from 0 to 15; with the proviso that at least one of h, h’ and iLis at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.A [MULTICON] group can connect one or more of a [CRBM] or [CPBM] to one or more of a [LINKER-2]. In various embodiments, [LINKER-2] has a valency of 1 to 10. In various embodiments, [LINKER-2] has a valency of 1 to 5. In various embodiments, [LINKER-2] has a valency of 1, 2 or 3. In various embodiments, in the compound of Formula II, the [LINKER-2] includes one or more of LinkerALinkerB, LinkerCLinkerD, and / or combinations thereof as defined herein.In the compound 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.In the compound 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.In the compound 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.In the compound of Formula II, X1is 1 to 5 contiguous atoms independently selected from O, S, N(Rb), and C(R4)(R4), wherein if X1is 1 atom then X1is O, S, N(R6), or C(R4)(R4), if X1is 2 atoms then no more than 1 atom of X1is O, S, or N(R6), if X1is 3, 4, or 5 atoms then no more than 2 atoms of X1are O, S, or N(R6);R3at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and, heteroaryl, heterocycle, -OR8, and -NR8R9;R4is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR6, - NR6R7,R6and R7are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroaryl alkyl, alkenyl, alkynyl, and, haloalkyl, heteroaryl, heterocycle, - alkyl-OR8, -alkyl-NR’R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3;R8and R9are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.In chemical structures, throughout this application, “Extracellular Protein Targeting Ligand” corresponds to [CPBM] as described above.A. Galactose-Based ASGPR-Binding Cellular Receptor Binding Moieties of Formula II In certain embodiments, the compound of Formula II is selected from:In one embodiment, the compound of Formula II has one of the following structures:In various embodiments, the ASGPR ligand is linked at either the C1or C5(R1or R5) position to form a degrading compound. In various embodiments, the ASGPR ligand is linked at C6position to form a degrading compound. For example, when the ASGPR ligand isthen non- limiting examples of ASGPR binding compounds of Formula II include: andor the bi- or tri- substituted versions thereof or pharmaceutically acceptable salts thereof, where the bi- or tri- substitutionrefers to the number additional galactose derivatives attached to a linker moiety.In any of the embodiments herein where an ASGPR ligand is drawn for use in a degrader the ASGPR ligand is typically linked through to the Extracellular Protein Targeting Ligand in the C5position (e.g., which can refer to the adjacent C6carbon hydroxyl or other functional moiety that can be used for linking purposes). When the linker and Extracellular Protein Targeting Ligand is connected through the C1position, then that carbon is appropriately functionalized for linking, for example with a hydroxyl, amino, allyl, alkyne or hydroxyl-allyl group.In various embodiments, the ASGPR ligand is not linked in the C3or C4position, because these positions chelate with the calcium for ASGPR binding in the liver. In certain embodiments, an ASGPR ligand usefill for incorporation into a compound of Formula II is selected from:In certain embodiments, the compound of Formula II is selected from:B. Talose-Based ASGPR-Binding Cellular Receptor Binding Moieties of Formula IIIn certain embodiments, the compound of Formula II is selected from:5In one embodiment, the compound of Formula II is an Extracellular Protein degrading compound in which the ASGPR ligand is a ligand as described hereinIn one embodiment, in the compound of Formula II, the ASGPR ligand is linked at either the Cl or C5 (R1or R5) position to form a degrading compound. In one embodiment, in the compound of Formula II, the ASGPR ligand is linked at C6. In various embodiments, when the ASGPR ligand isthen non- limiting examples of ASGPR binding compounds of Formula II include:or the bi- or tri- substituted versions thereof or pharmaceutically acceptable salts thereof, where the bi- or tri- substitution refers to the number additional galactose derivatives attached to a linker moiety. In certain embodiments the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR3, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NRbCOR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:wherein in certain embodiments R2is selected from -NR6COR10, -NR6-(5-membered heteroaryl), and-NR6-(6-membered heteroaryl), each of which R2groups is optionally substituted with 1, 2, 3, or 4 independent, substituents as described herein, for example 1, 2,3, or 4 substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.In certain embodiments, the compound of Formula II is selected from:In certain embodiments, an ASGPR ligand useful for incorporation into a compound of Formula II is selected from:C. The ASGPR Ligand / Binding Moiety in Compounds of Formula II In certain embodiments, in the compound of Formula II, R1is hydrogen.In certain embodiments, in the compound of Formula II, R1isIn certain embodiments, in the compound of Formula II, R1In certain embodiments, in the compound of Formula II, R1isIn certain embodiments, in the compound of Formula II, R1isIn certain embodiments, in the compound of Formula II, R1isIn certain embodiments, in the compound of Formula II, R1isIn certain embodiments, in the compound of Formula II, R1is C0-C6alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is alkyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R1is alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R1is haloalkyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of Formula II, R1is F.In certain embodiments, in the compound of Formula II, R1is Cl.In certain embodiments, in the compound of Formula II, R1is Br.In certain embodiments, in the compound of Formula II, R1is aryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is arylalkyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is heteroaryl alkyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is heterocycle optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is haloalkoxy optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R1is -O-alkenyl, -O-alkynyl, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)- S(O)R3, C0-C6alkyl-N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0- C6alkyl-O-S(O)R3, C0-C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, or C0-C6alkyl-O- S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is aryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is heterocycle optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is heterocycle optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8-S(O)-R3optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8-C(S)-R3optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8-S(O)(NR6)-R3optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -N=S(O)(R3)2optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8C(O)NR9S(O)2R3optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8-S(O)2-R10optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR8-C(NR6)-R3optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is hydrogen.In certain embodiments, in the compound of Formula II, R2is R10,In certain embodiments, in the compound of Formula II, R2is alkyl-C(O)-R3.In certain embodiments, in the compound of Formula II, R2is -C(O)-R3.In certain embodiments, in the compound of Formula II, R2is alkyl.In certain embodiments, in the compound of Formula II, R2is haloalkyl.In certain embodiments, in the compound of Formula II, R2is -OC(O)R3.In certain embodiments, in the compound of Formula II, R2is -NR8-C(O)R10.In certain embodiments, in the compound of Formula II, R2is alkenyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is allyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is alkynyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR6-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -O-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR6-alkynyl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR6-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -NR6-aryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -O-aryl optionally substituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is -O-alkynyl optionallysubstituted with 1, 2, 3, or 4 substituents.In certain embodiments, in the compound of Formula II, R2is selected from andIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromwhereinR is an optional substituent as defined herein.In certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2Ais selected fromis an optional substituent as defined herein.In certain embodiments, in the compound of Formula II, R2Ais selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2or R2Ais selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is selected fromIn certain embodiments, in the compound of Formula II, R2is a spirocyclic heterocycle, for example, and without limitation,In certain embodiments, in the compound of Formula II, R2is a silicon containing heterocycle, for example, and without limitation,In certain embodiments, in the compound of Formula II, R2is substituted with SF5,In certain embodiments, in the compound of Formula II, R2is substituted with a sulfoxime, for example, and without limitation,In certain embodiments, in the compound of Formula II, R10is selected from bicyclic heterocycle.In certain embodiments, in the compound of Formula II, R10is selected from spirocyclic heterocycle.In certain embodiments, in the compound of Formula II, R10is selected from -NR6- heterocycle.In certain embodiments, in the compound of Formula II, R10is selected fromIn certain embodiments, in the compound of Formula II, R10is selected fromIn certain embodiments, in the compound of Formula II, R10is selected fromIn certain embodiments, in the compound of Formula II, R10is selected fromIn certain embodiments, in the compound of Formula II, Cycle is selected fromIn certain embodiments, in the compound of Formula II, R30is selected from:In certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isIn certain embodiments, in the compound of Formula II, R200isLinkersIn non-limiting embodiments, in the compound of Formula II, LinkerAand LinkerBare independently selected from:wherein:R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, adivalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, and, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, CH2CH2-[O-(CH2)2]n-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 mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, - NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, heteroalkyl, and, heteroaryl, and heterocycle; and the remaining variables are as defined herein.In one embodiment, in the compound of Formula II, LinkerAis bond and LinkerBisIn one embodiment, in the compound of Formula II, LinkerBis bond and LinkerAisIn one embodiment, in the compound of Formula II, a divalent residue of an amino acid is selected fromwherein the amino acid can be oriented in either direction and wherein the amino acid can be in the L- or D-form or a mixture thereof.In one embodiment, in the compound of Formula II, a divalent residue of a dicarboxylic acid is generated from a nucleophilic addition reaction:Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a nucleophilic addition reaction include:In one embodiment, in the compound of Formula II, a divalent residue of a dicarboxylic acid is generated from a condensation reaction:Non-limiting embodiments of a divalent residue of a dicarboxylic acid generated from a condensation include:Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include:Non-limiting embodiments of a divalent residue of a saturated dicarboxylic acid include:Non-limiting embodiments of a divalent residue of a saturated monocarboxylic acid is selected from butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), lauric acid (- OC(O)(CH2)10CH2-), myristic acid (-OC(O)(CH2)12CH2-), pentadecanoic acid (- OC(O)(CH2)13CH2-), palmitic acid (-OC(O)(CH2)14CH2-), stearic acid (-OC(O)(CH2)16CH2-), behenic acid (-OC(O)(CH2)2oCH2-), and lignoceric acid (-OC(O)(CH2)22CH2-);Non-limiting embodiments of a divalent residue of a fatty acid 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:Non-limiting embodiments of a divalent residue of a fatty acid is 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-), alpha-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-) stearidonic 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-), paullinic acid(-C(O)(CH2)11CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid(-C(O)(CH2)7CHCH(CH2)7CH2-), gondoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadoleic acid (- C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (- C(O)(CH2)13CHCH(CH2)3CH2-), mead acid (- C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (- C(O)(CH2)11CHCH(CH2)7CH2-).In certain embodiments, in the compound of Formula II, LinkerCis selected from:wherein:R22is independently at each occurrence selected from the group consisting of alkyl, - C(O)N-, -NC(O)-, -N-, -C(R21)-, -P(O)O-, -P(O)-, -P(O)(NR6R7)N-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and the remaining variables are as defined herein.In certain embodiments, in the compound of Formula II, LinkerDis selected from:wherein:R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21;X- is an anionic group, for example Br- or Cl";and all other variables are as defined herein.In certain embodiments, in the compound of Formula II, LinkerAis selected from:wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence.In certain embodiments, in the compound of Formula II, LinkerAis selected from:wherein each heteroaryl, heterocycle, cycloalkyl, and and can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence. In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerB, Linker^ or LinkerDis selected from:wherein tt is independently selected from 1, 2, or 3 and ss is 3 minus tt (3-tt).In certain embodiments, in the compound of Formula II, LinkerB, Linker^ or Linker3is selected from:wherein tt and ss are as defined herein.In certain embodiments, in the compound of Formula II, LinkerB, Linker^ or LinkerDis selected from:wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein.In certain embodiments, in the compound of Formula II, LinkerB, LinkerCor LinkerDis selected from:wherein each heteroaryl, heterocycle, cycloalkyl, and aryl can optionally be substituted with 1, 23, or 4 of any combination of halogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence: and tt and ss are as defined herein.In certain embodiments, in the compound of Formula II, LinkerB, LinkerC, or LinkerDis selected from:wherein each heteroaryl and aryl can optionally be substituted with 1, 2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and tt and ss are as defined herein.In certain embodiments, in the compound of Formula II, LinkerAis selected from:In certain embodiments, in the compound of Formula II, LinkerAis selected from:In certain embodiments, in the compound of Formula II, LinkerAis selected from:In certain embodiments, in the compound of Formula II, LinkerAis selected from:In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerD is selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments in the compound of Formula II the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, the LinkerAis selected fromwherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21.In certain embodiments, in the compound of Formula II, LinkerAis selected from:In certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromto >— *In certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerAis selected fromIn certain embodiments, in the compound of Formula II, the LinkerBis selected fromIn certain embodiments, in the compound of Formula II, the LinkerBis selected fromIn certain embodiments, in the compound of Formula II, the LinkerBis selected fromIn certain embodiments, in the compound of Formula II, the LinkerBis selected from wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21.In certain embodiments, in the compound of Formula II LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, the LinkerBis selected from:In certain embodiments, in the compound of Formula II, LinkerB-LinkerAis selected from:In certain embodiments, in the compound of Formula II, LinkerB-LinkerAis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from: wherein each is optionally substituted with 1, 2, 3, or 4 substituents substituent selected from R21.In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, the LinkerCis selected from:In certain embodiments, in the compound of Formula II, LinkerC-(LinkerA)2is selected from:In certain embodiments, in the compound of Formula II, LinkerC-(LinkerA)2is selected from:In certain embodiments, in the compound of Formula II, LinkerC-(LinkerA)2is selected from:In certain embodiments, in the compound of Formula II, LinkerC-(LinkerA)2is selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:In certain embodiments, in the compound of Formula II, LinkerDis selected from:wherein each is optionally substituted with 1, 2, 3, or 4 substituents are selected fromR21.In certain embodiments, in the compound of Formula II, LinkerB-(LinkerA) is selected fromIn certain embodiments, in the compound of Formula II, LinkerC-(LinkerA) is selected fromIn certain embodiments, in the compound of Formula II, LinkerD-(LinkerA) is selected fromIn various embodiments, R4is independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR6, -NR6R7, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3.In various embodiments, in the compound of Formula II, R5is independently selectedfrom hydrogen, heteroalkyl,C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6alkyl- OR6, C0-C6alkyl-SR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl- C(S)R3, C0-C6alkyl- S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl- N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-O-C(O)R3, C0-C6alkyl-O-S(O)R3, C0- C6alkyl-O- C(S)R3, -N=S(O)(R3)2, C0-C6alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents.In various embodiments, in the compound of Formula II, R6and R7are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroaryl alkyl, alkenyl, alkynyl, and, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3.In various embodiments, in the compound of Formula II, R8and R9are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle.In various embodiments, the compound of Formula II has the structure of Formula II-A.A compound of Formula II-A, having the structure: wherein:[CPBM] is a Circulating Protein Binding Moiety which binds to a circulating protein in a subject, wherein the circulating protein mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject;[ASGPBM] is an asialoglycoprotein receptor binding moiety having the structure selected fromeach [CON] is an optional connector chemical moiety which, when present, connects the [LIN] to [CPBM] or to [ASGPBM];[LIN] is [LINKER] or [LINKER-2], each of which is a chemical moiety having a valency from 1 to 15, which covalently attaches to one or more [ASGPBM] or [CPBM] groups, optionally through a [CON], wherein the [LIN] optionally itself contains one or more [CON] groups;ZBis absent, (CH2)IM, C(O)-(CH2)IM-, or C(O)-(CH2)IM-NRM;RMis H or a C1-C3alkyl group optionally substituted with one or two hydroxyl groups;R2iswherein R^ is H, C1-C4alkyl optionally substituted with up to 3 halo groups and one or two hydroxyl groups, -(CH2)KCOOH, -(CH2)KC(O)O-(C1-C4alkyl) optionally substituted with 1-3 halo groups, -O-C(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, - C(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, or -(CH2)K-NRN3RN4,orwhereinRTAis H, CN, NRN1RN2, -(CH2)KOH, -(CH2)KO(C1-C4alkyl) optionally substituted with 1-3 halo groups, C1-C4alkyl optionally substituted with 1-3 halo groups, - (CH2)KCOOH, -(CH2)KC(O)O-(C1-C4alkyl) optionally substituted with 1-3 halo groups, -O- C(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, or -C(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, orRTAis a C3-C10 aryl or a three- to ten-membered heteroaryl group containing up to 5 heteroaryl atoms, each of the aryl or heteroaryl groups being optionally substituted with up to three CN, NRN1RN2, -(CH2)KOH, -(CH2)KO(C1-C4alkyl) optionally substituted with 1-3 halo groups, C1-C3alkyl optionally substituted with 1-3 halo groups or 1-2 hydroxy groups, -O-(C1-C3-alkyl) optionally substituted from 1-3 halo groups, -(CH2)KCOOH, - (CH2)KC(O)O-(C1-C4alkyl) optionally substituted with 1-3 halo groups, O-C(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, or -(CH2)KC(O)-(C1-C4alkyl) optionally substituted with 1-3 halo groups, oroptionally substituted with up to three C1-C3alkylgroups which are optionally substituted with up to three halo groups; orRTAisRN, RN1, RN2, RN3, RN4are each independently H or C1-C3alkyl optionally substituted with one to three halo groups or one or two hydroxyl groups and each -(CH2)Kgroup is optionally substituted with 1-4 C1-C3alkyl groups which are optionally substituted with 1-3 fluoro groups or 1-2 hydroxyl groups;IM is independently at each occurrence an integer from 0 to 6;K is independently at each occurrence an integer from 0 to 4; k’ is an integer ranging from 1 to 15; j’ is an integer ranging from 1 to 15; h and h’ are each independently an integer ranging from 0 to 15; iLis O to 15; with the proviso that at least one of h, h’, and iLis at least 1, or a salt, stereoisomer, or solvate thereof.In various embodiments, in the compound of Formula II-A, R2is -NC(=O)CH3.The term "organic group" as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid,carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (Ci-Cioo)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted.The term "substituted" as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The substitution can be direct substitution, whereby the hydrogen atom is replaced by a functional group or substituent, or an indirect substitution, whereby an intervening linker group replaces the hydrogen atom, and the substituent or functional group is bonded to the intervening linker group. A non-limiting example of direct substitution is: RR-H -> RR-C1, wherein RR is an organic moiety / fragment / molecule. A non-limiting example of indirect substitution is: RR-H -> RR- (LL)zz-Cl, wherein RR is an organic moiety / fragment / molecule, LL is an intervening linker group, and 'zz' is an integer from 0 to 100 inclusive. When zz is 0, LL is absent, and direct substitution results. The intervening linker group LL is at each occurrence independently selected from the group consisting of -H, -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, - NR2, -CR=, -C=, -CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, -C(=NR)-, and combinations thereof. (LL)zz can be linear, branched, cyclic, acyclic, and combinations thereof.The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides,and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (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 (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (Ci-Cioo)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl.The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2,-C (CH3)=CH(CH3), -C(CH2CH3)=CH2cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.The term "acyl" as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3 -carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.The term "heterocycloalkyl" as used herein refers to a cycloalkyl group as defined herein in which one or more carbon atoms in the ring are replaced by a heteroatom such as O, N, S, P, and the like, each of which may be substituted as described herein if an open valence is present, and each may be in any suitable stable oxidation state.The term "aryl" as used herein refers to cyclic aromatic hydrocarbon groups that donot contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.The term "aralkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings where a CH2group in the ring is replaced by one or more C=O groups, such as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing a C=O group include, but are not limited to, β- propiolactam, γ-butyrolactam, 5-valerolactam, and e-caprolactam, as well as the corresponding lactones. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as,but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group 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 so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring designated Cx.ycan be any ring containing 'x' members up to *y* members, including all intermediate integers between 'x' and *y* and that contains one or more heteroatoms, as defined herein. In a ring designated Cx.y, all non-heteroatom members are carbon. Heterocyclyl rings designated Cx.ycan also be polycyclic ring systems, such as bicyclic or tricyclic ring systems. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.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-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3 -thienyl), furyl (2-furyl, 3 -furyl) , 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-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1 -benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7 -benzimidazolyl, 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-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,1 l-dihydro-5H-dibenz[b,f]azepine (10,1 l-dihydro-5H-dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.The term "heterocyclylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bondto a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, fur an- 3 -yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.The term "arylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.The term "heteroarylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.The term "amine" as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3"1", wherein each R is independently selected, and protonated forms of each, except for -NR3"1", which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" groupincludes a monoalkylamino, dialkylamino, and trialkylamino group.The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1 -dichloroethyl, 1,2-dichloroethyl, l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.The terms "epoxy-functional" or "epoxy-substituted" as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- epoxyhexyl.The term "monovalent" as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.The term "hydrocarbon" or "hydrocarbyl" as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (Ci), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group.As used herein, the term "C6-10-5-6 membered heterobiaryl" means a C6-10aryl moiety covalently bonded through a single bond to a 5- or 6-membered heteroaryl moiety. The C6-10aryl moiety and the 5-6-membered heteroaryl moiety can be any of the suitable aryl and heteroaryl groups described herein. Non-limiting examples of a C6-10-5-6 membered heterobiaryl includeWhen the C6-10-5-6 membered heterobiaryl is listed as a substituent (e.g., as an "R" group), the C6-10-5-6 membered heterobiaryl is bonded to the rest of the molecule through the C6-10moiety.As used herein, the term "5-6 membered- C6-10heterobiaryl " is the same as a C6-10-5- 6 membered heterobiaryl, except that when the 5-6 membered- C6-10heterobiaryl is listed as a substituent (e.g., as an "R" group), the 5-6 membered- C6-10heterobiaryl is bonded to the rest of the molecule through the 5-6-membered heteroaryl moiety.As used herein, the term "C6-10- C6-10biaryl" means a C6-10aryl moiety covalently bonded through a single bond to another C6-10aryl moiety. The C6-10aryl moiety can be any of the suitable aryl groups described herein. Non-limiting example of a C6-10- C6-10biaryl include biphenyl and binaphthyl.The term “pharmaceutically acceptable salt” or “salf ’ is used throughout the specification to describe a salt form of one or more of the compositions herein which are presented to increase the solubility of the compound in saline for parenteral delivery or in the gastric juices of the patient’s gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. Sodium and potassium salts may be preferred as neutralization salts of carboxylic acids and free acid phosphate containing compositions according to the present invention. The term “salt” shall mean any salt consistent with the use of the compounds according to the present invention. In the case where the compounds are used in pharmaceutical indications, including the treatment of prostate cancer, including metastatic prostate cancer, the term “salf’ shall mean a pharmaceutically acceptable salt, consistent withthe use of the compounds as pharmaceutical agents.The term “coadministration” shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided that effective concentrations of all coadministered compounds or compositions are found in the subject at a given time. Chimeric antibodyrecruiting compounds according to the present invention may be administered with one or more additional anti-cancer agents or other agents which are used to treat or ameliorate the symptoms of cancer, especially prostate cancer, including metastatic prostate cancer.The term “anticancer agent” or “additional anticancer agent” refers to a compound other than the chimeric compounds according to the present invention which may be used in combination with a compound according to the present invention for the treatment of cancer. Exemplary anticancer agents which may be coadministered in combination with one or more chimeric compounds according to the present invention include, for example, antimetabolites, inhibitors of topoisomerase I and n, alkylating agents and microtubule inhibitors (e.g., taxol), among others. Exemplary anticancer compounds for use in the present invention may include everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT -9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK / STAT inhibitor, a checkpoint- 1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS- 100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N -[4-[2-(2-amino-4,7- dihydro-4-oxo-l H - pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-1 abeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethy I stilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)- indolylj -quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D- Ser(Bu t ) 6,Azgly 10 ] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t )-Leu-Arg-Pro- Azgly-NH 2 acetate [C59H84N18Oi4-(C2H4O2)Xwhere x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafamib, BMS-214662, tipifamib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette- Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethyl stilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox,gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS- 247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA- 923, arzoxifene, fiilvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR- 3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP- 23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684,LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, 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, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all- transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib among others, including immunotherapy agents such as IDO inhibitors (an inhibitor of indoleamine 2,3 -dioxygenase (IDO) pathway) such as Indoximod (NLG-8187), Navoximod (GDC-0919) and NLG802, PDL1 inhibitors (an inhibitor of programmed death-ligand 1) including, for example, nivolumab, durvalumab and atezolizumab, PD1 inhibitors such as pembrolizumab (Merck) and CTLA-4 inhibitors (an inhibitor of cytotoxic T-lymphocyte associated protein 4 / cluster of differentiation 152), including ipilimumab and tremelimumab, among others.In addition to anticancer agents, a number of other agents may be co-administered with chimeric compounds according to the present invention in the treatment of cancer. These include active agents, minerals, vitamins and nutritional supplements which have shown some efficacy in inhibiting cancer tissue or its growth or are otherwise useful in the treatment of cancer. For example, one or more of dietary selenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids and phytoestrogens, including beta-sitosterol, may be utilized in combination with the present compounds to treat cancer.Without not being limited by way of theory, compounds according to the present invention which contain a CPBM binding moiety (CPBM) and CRBM / ASGPR binding moiety selectively bind to circulating proteins and through that binding, facilitate the introduction of the cellular protein into hepatocytes or other cells (degrading cells) which bind the CRBM / ASGPRBM selectively, where, the circulating protein, inside the hepatocyte or other degrading cell is degraded and removed from circulation. Thus, compoundsaccording to the present invention both bind to MIF proteins and remove the MIF proteins from circulation resulting in a dual action which is particularly effective for treating disease states and conditions.Pharmaceutical compositions comprising combinations of an effective amount of at least one compound disclosed herein, often a bi-functional chimeric compound (containing at least one MIFBM group or antibody binding moiety and at least one ASGPRBM) according to the present invention, and one or more of the compounds as otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present invention. These may be used in combination with at least one additional, optional anticancer agent as otherwise disclosed herein.The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, among others. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally (including via intubation through the mouth or nose into the stomach), intraperitoneally or intravenously.Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3 -butanediol. Amongthe acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, usefill diluents include lactose and dried com starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.The pharmaceutical compositions of this invention may also be administered topically, especially to treat skin cancers, psoriasis or other diseases which occur in or on the skin. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-acceptable transdermal patches may also be used.For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.The amount of compound in a pharmaceutical composition of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration. Preferably, the compositions should be formulated to contain between about 0.05 mg to about 1.5 g, from 0.1 mg to 1 g, 0.5 mg to 750 mg, more often about 1 mg to about 600 mg, and even more often about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one additional compound which may be used to treat cancer, prostate cancer or metastatic prostate cancer or a secondary effect or condition thereof.Methods of treating patients or subjects in need for a particular disease state or condition as otherwise described herein, especially cancer, comprise administration of an effective amount of a pharmaceutical composition comprising therapeutic amounts of one or more of the novel compounds described herein and optionally at least one additional bioactive (e.g. anti-cancer, anti-inflammatory) agent according to the present invention. The amount of active ingredients) used in the methods of treatment of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. For example, the compositions could be formulated so that a therapeutically effective dose of between about 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 100 mg / kg of patient / day or in some embodiments, greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg / kg of the novel compounds can be administered to a patient receiving these compositions.It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.A patient or subject (e.g. a human) suffering from an autoimmune disease, an inflammatory disease or cancer can be treated by administering to the patient (subject) an effective amount of a chimeric / bi-functional compound according to the present invention including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known pharmaceutical agents, preferably agents which can assist in treating autoimmune and / or inflammatory diseases or cancer, including metastatic cancer or recurrent cancer or ameliorating the secondary effects and / or symptoms associated with these disease states and / or conditions. This treatment can also be administered in conjunction with other conventional therapies, such as radiation treatment or surgery for cancer.The present compounds, alone or in combination with other agents as described herein, can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel, or solid form, or by aerosol form.The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient / patient per day. A typical topical dosage will range from about 0.01-3% wt / wt in a suitable carrier.The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than Img, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25-500 mg is often convenient.The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 pM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the activeingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition.The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.The active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, symp, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.The active compound or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, anti-inflammatory agents,immunosuppressants, antibiotics, antifimgals, or antiviral compounds. In certain preferred aspects of the invention, one or more chimeric / bi-functional CPBM binding compound according to the present invention is co-administered with another anticancer agent and / or another bioactive agent, as otherwise described herein.Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled and / or sustained release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.Liposomal suspensions or cholestosomes may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.The compound according to embodiments of the present invention may be a compound listed in Table 1 below:260•*_»The invention is further illustrated by the following non-limiting examples.EXAMPLE 1. Procedure for Preparation of Target A011A

[0002] To a solution of Int. 9 (5.00 g, 26.15 mmol, 1.00 equiv.) in Py (100 ml) was added propanoyl propanoate (27.23 g, 209.23 mmol, 8.00 equiv.). The mixture was stirred at 20 °C for 12 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was concentrated under reduced pressure to afford Intermediate 1 (10.86 g, crude) as yellow oil, which was used in the next step without further purification. LCMS: RT = 0.715 min, MS cal.: 415.2, found: [M + H]+= 416.2.

[0003] Preparation of Intermediate 2:

[0004] To a solution of Intermediate 1 (5.40 g, 13.00 mmol, 1.00 equiv.) in MeOH (50 ml) was added NaOMe (2.81 g, 51.99 mmol, 4.00 equiv.). The mixture was stirred at 20 °C for 2 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was neutralized by addition ofIM HCI. The resulting solution was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=10 / l to 5 / 1) to give Intermediate 2 (4.20 g,16.99 mmol, 65.3% yield) as a yellow solid. LCMS: RT = 0.174 min, MS cal.: 247.1, found: [M + H]+= 248.3.1H NMR (400 MHz, CD3OD) δ = 5.23 (d, J = 1.4 Hz, 1H), 4.01 - 3.69 (m, 5H), 2.42 - 2.20 (m, 2H), 1.27 - 1.04(m, 3H).

[0005]

[0006] To a solution of Intermediate 2 (2.10 g, 8.49 mmol, 1.00 equiv.) in DMF (15 ml) was added[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-l-yl]methanesulfonic acid (1.06 g, 4.25 mmol, 0.5 equiv.) and 2A(4.42 g, 42.47 mmol, 5.00 equiv.). The mixture was stirred at 70 °C for 12 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (30 ml * 3). The combined organic layer was washed with brine (30 ml * 3), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1 to 0 / 1) to give Intermediate 3 (4.25 g, 14.79 mmol, 87.0% yield) as a white solid. LCMS: RT = 0.426 min, MS cal.: 287.1, found: [M + H]+= 288.2.1HNMR (400 MHz, CD3OD) δ = 5.23 (s, 1H), 4.59 (s, 1H), 4.30 (d, J = 5.7 Hz, 1H), 4.18 (t, J = 6.4 Hz, 1H), 3.97 -3.68 (m, 6H), 2.30 - 2.17 (m, 2H), 1.49 (s, 3H), 1.34 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H).

[0007] Preparation of Intermediate 4:

[0008] To a solution of Intermediate 3 (2.20 g, 7.66 mmol, 1.00 equiv.) in THF (20 ml) was addedNaH (3.06 g, 76.57 mmol, 60% purity, 10.00 equiv.) at 0 °C. The mixture was stirred at 0°C for 0.5 h, then was added 3A (4.54 g, 13.78 mmol, 1.80 equiv.) at 0°C, the mixture was stirred at 20 °C for 1 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was diluted with water(20 ml) and extracted with DCM (20 ml * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 to 0 / 1) to giveIntermediate 4 (3.70 g, 7.57 mmol, 49.4% yield) as a white solid. LCMS: RT = 1.475 min, MS cal.: 488.2, found: [M + H]+= 489.3.1H NMR (400 MHz, CDCl3) δ = 5.60 (br d, J = 8.8 Hz, 1H), 5.33 (d, J = 2.0 Hz, 1H),4.21 (d, J = 5.9 Hz, 1H), 4.27 - 4.19 (m, 1H), 4.19 - 4.10 (m, 1H), 4.04 - 3.92 (m, 2H), 3.86 - 3.74 (m, 3H), 3.76 - 3.58 (m, 15H), 3.43 - 3.34 (m, 2H), 2.31 - 2.21(m, 2H), 1.55 (s, 3H), 1.38 - 1.32 (m, 3H), 1.20 - 1.12(m, 3H).

[0009] Preparation of Intermediate 6:

[0010] To a solution of Intermediate 5 (2.50 g, 7.45 mmol, 1.00 equiv.) in DCM (25 ml) was addedTFA (10 ml) at 0 °C. The mixture was stirred at 20 °C for 2 h. TLC (DCM: MEOH = 5:1, Rf= 0.43) showed anew spot and the reactant was consumed. The reaction mixture was concentrated under reduced pressure to give Intermediate 6 (1.75 g, crude) as colorless oil, which was used in the next step directly.

[0011] Preparation of Intermediate 7:

[0012] To a solution of 6A (1.56 g, 7.44 mmol, 1.00 equiv.) in DMF (10 mL) was added HATU (2.83 g, 7.44 mmol, 1.00 equiv.) and DIEA (4.81 g, 37.19 mmol, 6.48 mL, 5.00 equiv.) at 0 °C, and the mixture was stirred at 0°C for 0.5 h. Intermediate 6 (1.75 g, 7.44 mmol, 1.00 equiv.) was added to the mixture.The mixture was stirred at 20 °C for 2 h. LCMS showed 6A was consumed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layer was washed with brine (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1) to afford Intermediate 7 (1.02 g, 2.39 mmol, 32.1% yield) as a white solid. LCMS: RT = 2.188 min, MS cal.:426.2, found: [M + H]+= 427.3.1H NMR (400 MHz, CDCI3) δ = 7.40 - 7.29 (m, 5H), 6.08 (s, 1H), 5.40 (br s,1H), 5.13 (s, 2H), 4.13 (d, J = 1.7 Hz, 6H), 3.84 (s, 6H), 2.44 (t, J = 2.3 Hz, 3H).

[0013] Preparation of Intermediate 8:

[0014] To a solution of Intermediate 7 (552.0 mg, 1.28 mmol, 99.0% purity, 1.00 equiv.),Intermediate 4 (1.88 g, 3.84 mmol, 3.00 equiv.) in DMSO (8 mL) was added sodium ascorbate (634.6 mg,3.20 mmol, 2.50 equiv.) and CuSO4.5H2O (320.0 mg, 1.28 mmol, 1.00 equiv.). The mixture was stirred at25 °C for 2 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was diluted with water (20 ml) and extracted with DCM (10 ml * 3). The combined organic layer was washedwith brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give Intermediate 8 (1.25 g, 660.66 μmol, 51.6% yield) as yellow oil. LCMS: RT = 2.065 min, MS cal.: 1891.9, found: [M + 2H]2+= 947.2.1H NMR(400MHz, DMSO-d6) p δpm = 8.06 - 7.99 (m, 6H), 7.40 - 7.27 (m, 6H), 5.15 (d, J = 1.9 Hz, 3H), 5.03 (s, 2H),4.55 - 4.43 (m, 12H), 4.24 (d, J = 5.9 Hz, 3H), 4.17 - 4.11 (m, 3H), 3.84 - 3.78 (m, 12H), 3.76 - 3.69 (m, 6H),3.67 - 3.62 (m, 9H), 3.62 - 3.55 (m, 7H), 3.54 - 3.43 (m, 32H), 2.13 (q, J = 7.6 Hz, 6H), 1.39 (s, 9H), 1.30 - 1.22 (m, 9H), 0.99 (t, J = 7.6 Hz, 9H).

[0015] Preparation of Target A011A_Cpd.l7:

[0016] To a solution of Intermediate 8 (400.0 mg, 211.41 μmol, 1.00 equiv.) in THF (1.0 mL) was added Pd / C (5.00 mg, 21.14 μmol, 10% purity). The mixture was stirred at 20 °C for 2 h under H2(15 Psi).LCMS showed the desired mass and the reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to afford Target A011A_Cpd,17 (330.3 mg, 187.89 μmol, 88.8% yield) as yellow oil. LCMS: RT = 1.810 min, MS cal.: 1757.9, found: [M+ 2H]2+= 880.1.1H NMR (400 MHz, DMSOd6) 5= 8.05 - 7.99 (m, 6H), 5.16 (d, J = 2.0 Hz, 3H), 4.55 - 4.45 (m, 13H), 4.25 (d, J = 5.9 Hz, 3H), 4.15- 4.10 (m, 3H), 3.84 - 3.56 (m, 35H), 3.53 - 3.46 (m, 32H), 2.13 (q, J = 7.5 Hz, 6H), 1.40 (s, 9H), 1.27 (s, 9H),0.99 (t, J = 7.6 Hz, 9H).

[0017] Preparation of Target A011A:

[0018] A mixture of Target A011A_Cpd.l7 (90.0 mg, 51.20 μmol, 1.00 equiv.) in HCI / H2O (2.0 M,1.0 ml) and MeCN (0.5 ml) was stirred at 20 ºC for 1 h. The mixture was lyophilized to afford Target A011A (85.0 mg, 45.69 μmol, 90.0% purity, 89.3% yield, HCI salt) as a colorless solid. LCMS: RT = 0.705 min, MS cal.: 1637.73, found: [M + 2H]2+= 819.600.EXAMPLE 2. Procedure for Preparation of Target A093.

[0020] Intermediate 4 (500.0 mg, 1.02 mmol, 1.00 equiv.) was dissolved in HCI (1 M, 5 ml, 10.05 equiv.). The mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed and the desired mass of product was detected. The residue was purified by prep-HPLC (column: WatersXbridge Prep OBD C18 150 * 40 mm * 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-35%, 8 min) to give Target A093 (305.0 mg, 680.09 umol, 66.4% yield) as colorless oil. LCMS: RT = 1.810 min, MS cal.:448.5, mass observed: [M + H]+= 449.3.1H NMR (400 MHz, METHANOL-d<) 6 = 5.21 (d, J = 1.4 Hz, 1H),3.98 (d, J = 9.5 Hz, 1H), 3.95 (dd, J = 1.4, 10.0 Hz, 1H), 3.91 - 3.87 (m, 1H), 3.78 (d, J = 8.0 Hz, 1H), 3.75 -3.57 (m, 17H), 3.41 - 3.35 (m, 2H), 2.27 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H).EXAMPLE 3. Procedure for Preparation of Target A092.

[0022] To a solution of 6A (4.00 g, 22.83 mmol, 1.05 equiv.) in DMF (50 ml) was added HATU(9.12 g, 23.98 mmol, 1.05 equiv.) and DIEA (8.85 g, 68.50 mmol, 11.93 mL, 3.00 equiv.) at 0 "C and the mixture was stirred at 0 °C for 0.5 h. Then Intermediate 6 (9.17 g, 22.83 mmol, 87.0% purity, 1.00 equiv.,TFA) was added and the mixture was stirred at 20 "C for 1 h. LCMS showed 6A was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water 50 ml and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to giveIntermediate 9 (6.50 g, 16.56 mmol, 72.5% yield) as colorless oil. LCMS: RT = 2.143 min, MS cal.: 392.2,[M + H]+= 393.3.

[0024] A solution of Intermediate 9 (5.00 g, 12.74 mmol, 1.00 equiv.) in HCI / EtOAc (4 M, 50 ml) was stirred at 20 °C for 3 h. LCMS showed Intermediate 9 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered. The filtrate was purified by prep-HPLC(column: Agela DuraShell C18 250 * 70 mm * 10 ;μm mobile phase: [water (NH4HCO3)-ACNJ; 8%: 15%-45%, 8 min) to afford Target A092 (2.10 g, 7.18 mmol, 56.4% yield, 100.0% purity) as yellow oil. LCMS: RT= 1.519 min, MS cal.: 292.3, [M + H]+= 293.2.1H NMR (400 MHz, METHANO L-d4) δ = 4.15 (d, J =2.38 Hz, 6H), 3.82 (s, 6 H), 3.23 (s, 2 H), 2.84 (t, J =2.44 Hz, 3 H).EXAMPLE 4. Procedure for Preparation of Target A096.

[0025] Preparation of Intermediate 11:

[0026] To a solution of 10 (40.0 mg, 171.51 μmol, 1.00 equiv.) in DCM (1 ml) was added oxalyl chloride (25.2 mg, 205.8 μmol, 18.9 μL, 1.20 equiv.) and DMF (1.25 mg, 17.15 μmol, 1.32 μL, 0.10 equiv.).The mixture was stirred at 0 ºC for 0.5 h. TLC (DCM: MeOH =10:1, Rf= 0.6) showed the reactant was consumed and one main spot was formed. Intermediate 11 (43.0 mg, 170.86 μmol, crude) was used to next step directly.

[0027] Preparation of Intermediate 12:

[0028] To a solution of Target A011A_cpd 17 (210.0 mg, 119.46 μmol, 1.00 equiv.) in DCM (1 mL) was added DIEA (46.3 mg, 358.38 μmol, 62.42 μL, 3.00 equiv.), then Intermediate 11 (30.0 mg, 119.46 μmol, 1.00 equiv.) was added to the mixture. The mixture was stirred at 20 ºC for 1 h. LCMS showed the desired mass and the reactant was consumed. Intermediate 12 (230.0 mg, crude) was obtained as yellow oil and used into the next step without further purification. LCMS: RT=1.990 min, MS cal.: 1971.9, [M + 2H]2+= 987.6.

[0029] Preparation of Target AO96:

[0030] A solution of Intermediate 12 (230.0 mg, 116.57 μmol, 1.00 equiv.) in HCI (3 M, 1 ml) was stirred at 40 °C for 1 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 ; μ mmobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to afford Target A096 (72.0 mg, 38.86 μmol, 33.3% yield) as a white solid. LCMS: RT = 1.521 min, MS cal.: 1851.8, [M + 2H]2+= 927.7.1H NMR (400 MHz, DMSO-d6) δ =8.01 (s, 3H), 7.80 - 7.75 (m, 3H), 7.35 (br s, 1H), 6.11 - 5.97 (m, 1H), 6.04 (br s, 1H), 5.08 (s, 3H), 4.55 - 4.43(m, 13H), 3.92 (s, 2H), 3.85 - 3.77 (m, 9H), 3.72 (br d, J = 6.4 Hz, 5H), 3.66 - 3.62 (m, 9H), 3.60 - 3.54 (m,17H), 3.66 - 3.45 (m, 1H), 3.41 - 3.36 (m, 5H), 2.12 (q, J = 7.6 Hz, 6H), 1.02 - 0.92 (m, 9H).EXAMPLE 5. Procedure for Preparation of Target A098.

[0031] Preparation of Intermediate 11:

[0032] To a solution of Intermediate 10 (400.0 mg, 1.72 mmol, 1.00 equiv.) in DCM (5 ml) was added oxalyl chloride (252.1 mg, 2.06 mmol, 189.58 μL, 1.20 equiv.) and DMF (12.5 mg, 171.51 μmol,13.20 μL, 0.10 equiv.). The mixture was stirred at 0 ºC for 0.5 h. TLC (DCM: MeOH =10:1, Rf=0.43) showed the reactant was consumed and one main spot was formed. Intermediate 11 (420.0 mg, 1.67 mmol, crude) was used to next step directly.

[0033] Preparation of Intermediate 14:

[0034] To a solution of Intermediate 13 (950.0 mg, 1.47 mmol, 1.00 equiv.) in DCM (20 ml) was added DIEA (952.1 mg, 7.37 mmol, 1.28 ml, 5.00 equiv.), followed by the addition of Intermediate 11(370.8 mg, 1.47 mmol, 1.00 equiv.). The mixture was stirred at 20 ºC for 1 h. LCMS showed the desired mass and the reactant was consumed. Intermediate 14 (1.20 g, crude) was obtained as yellow oil and used into the next step without further purification. LCMS: RT=1.645 min, MS cal.: 859.4, [M + H]+= 860.4.[00351 Preparation of Target A098:[00361 To a solution of Intermediate 14 (1.20 g, 1.40 mmol, 1.00 equiv.) in HCI (3 M, 1 ml). The mixture was stirred at 40 ºC for 0.5 h. LCMS showed the desired mass and the reactant was consumed.The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 ; mobileμm phase:[water (NH4HCO3)-ACN]; B%: 5%-35%, 8 min) to afford Target A098 (350.0 mg, 426.90 μmol, 30.6% yield) as a white solid. LCMS: RT = 1.283 min, MS cal.: 819.4, [M + H]+= 820.3.1H NMR (400MHz, DMSO-d6) = δ8.05 (s, 1H), 7.96 (br d, J = 5.1 Hz, 1H), 7.88 - 7.72 (m, 2H), 5.07 (s, 1H), 4.51 (br s, 4H), 3.92 (s, 2H), 3.86 -3.77 (m, 3H), 3.71 (br d, J = 6.0 Hz, 3H), 3.66 - 3.35 (m, 31H), 3.30 - 3.20 (m, 4H), 2.11 (q, J = 7.5 Hz, 2H),1.07 - 0.88 (m, 3H).EXAMPLE 6. Procedure for Preparation of Target A097.[00371 Preparation of Intermediate 16:[00381 To a solution of Intermediate 10 (40.0 mg, 171.51 μmol, 1.00 equiv.) in DCM (1 ml) was added oxalyl dichloride (26.12 mg, 205.81 μmol, 18.02 μL, 1.20 equiv.) and DMF (12.5 mg, 171.51 μmol,13.20 μL, 1.00 equiv.) at 0 °C. The mixture was stirred at 25 ºC for 0.5 h. Then Intermediate 15 (140.0 mg,116.54 μmol, 1.00 equiv.), DIEA (45.1 mg, 349.62 μmol, 60.90 μL, 3.00 equiv.) were dissolved in the mixture. The mixture was stirred at 25 °C for 0.5 h. LCMS showed Intermediate 15 was consumed completely and one main peak with desired mass was detected. After filtration, Intermediate 16 was afforded as colorless liquid and used into the next step directly. LCMS: RT = 1.818 min, MS cal.:1415.7, [M + 2H]2+=709.3.

[0039] Preparation of Target AO97:

[0040] HCI (3 M, 376.51 uL, 10.00 equiv.) was added to the solution of Intermediate 16. The mixture was stirred at 40 °C for 1 h. LC-MS showed Intermediate 16 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 ; mμombile phase: [water (NH4HCO3)-ACN]; B%: 25%-45%, 8 min) to afford Target A097 (64.0 mg, 47.89 μmol, 42.4% yield, 100.0% purity) as colorless oil. LCMS: RT = 1.459 min, MS cal.: 1335.6, [M + 2H]2+= 669.3.1H NMR (400 MHz, DMSO-d6) = δ8.05 (s, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 5.08 (d, J = 1.1 Hz, 2H), 4.83 (d, J = 5.4 Hz, 2H),4.56 - 4.49 (m, 10H), 4.07 - 3.99 (m, 1H), 3.92 (s, 2H), 3.85 - 3.79 (m, 6H), 3.77 - 3.71 (m, 4H), 3.67 - 3.44(m, 49H), 3.41 - 3.37 (m, 2H), 2.12 (q, J = 7.6 Hz, 4H), 0.99 (t, J = 7.6 Hz, 6H).EXAMPLE 7. Procedure for Preparation of Target A090.

[0041] Preparation of intermediate 18:

[0042] To a solution of Intermediate 17 (420.0 mg, 773.75 μmol, 90.0% purity, 1.00 equiv.) andIntermediate 4 (269.5 mg, 928.50 μmol, 1.20 equiv.) in DMSO (4 ml) was added sodium ascorbate (168.6 mg, 851.12 μmol, 1.10 equiv.) and CuSO4.5H2O (193.1 mg, 773.75 μmol, 1.00 equiv.) at 25 ºC. Then the reaction was stirred for 1 h at 25 °C. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure to give crude product. The crude product was purified by prep- HPLC (column: Phenomenex C18 80 * 40 mm * 3 ; μ mmobile phase: [water (NH4HCO3)-ACN]; 8%: 20%-50%, 8 min) to afford Intermediate 18 (300.0 mg, 385.19 μmol, 49.8% yield) as yellow oil. LCMS: RT = 1.793 min, MS cal.: 778.4, [M+H]4= 779.6.1H NMR (400 MHz, CDCI3) = 7.74 (s, 1H δ), 7.41 - 7.29 (m, 5H), 6.58 (br s, 1H), 5.76 (br d, J = 8.1 Hz, 1H), 5.63 (br s, 1H), 5.33 (d, J = 1.9 Hz, 1H), 5.13 (s, 2H), 4.64 (s, 2H), 4.53 (t, J = 4.9 Hz, 2H), 4.19 (d, J = 5.9 Hz, 1H), 4.13 (ddd, J = 2.0, 6.8, 8.8 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.94(d, J = 10.1 Hz, 1H), 3.90 - 3.84 (m, 4H), 3.83 - 3.72 (m, 2H), 3.66 (br s, 3H), 3.65 - 3.55 (m, 12H), 2.25 (dq,J = 2.8, 7.6 Hz, 2H), 1.63 (s, 2H), 1.56 (s, 3H), 1.35 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H).[00431 Preparation of Intermediate 13:

[0044] To a solution of Intermediate 18 (400.0 mg, 513.58 μmol, 1.00 equiv.) in THF (1 ml) was added Pd / C (100 mg, 10 % purity) at 25 °C. Then the reaction was stirred for 1 h at 25 °C. LCMS showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford Intermediate 13 (200.0 mg, 310.22 μmol, 60.4% yield) as yellow oil. LCMS: RT = 1.218 min, MS cal.: 644.3, [M+H]+= 645.4.1H NMR (400 MHz, CDCI3) 5 = 7.92 (br s, 1H), 7.80 (s, 1H), 6.02 (br d,J = 8.6 Hz, 1H), 5.33 (d, J = 1.5 Hz, 1H), 4.69 - 4.59 (m, 3H), 4.55 (br t, J = 4.9 Hz, 2H), 4.17 (br d, J = 5.8 Hz,2H), 4.14 - 4.01 (m, 3H), 3.96 - 3.54 (m, 30H), 3.50 - 3.39 (m, 3H), 2.25 (dq, J = 2.3, 7.6 Hz, 2H), 1.55 (s, 3H),1.34 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H).

[0045] Preparation of Target A090:

[0046] A mixture of Intermediate 13 (70.0 mg, 108.58 μmol, 1.00 equiv.) in MCI (1 M, 2 ml) was degassed and purged with N2for 3 times, and then the mixture was stirred at 40 °C for 1 h under N2atmosphere. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure to afford Target A090 (60.0 mg, 99.23 μmol, 91.3% yield) as colorless oil. LCMS: RT = 1.471 min,MS cal.: 604.3, [M+H]+= 605.2.1H NMR (400 MHz, MeOH-d<) 6 = 8.51 (s, 1H), 5.20 (s, 1H), 4.82 -4.75 (m,4H), 4.00 - 3.95 (m, 2H), 3.94 - 3.86 (m, 3H), 3.79 - 3.74 (m, 3H), 3.73 - 3.69 (m, 3H), 3.68 - 3.57 (m, 14H),3.52 - 3.47 (m, 2H), 2.29 (q, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H).EXAMPLE 8. Procedure for preparation of BH0003610, BH0003665, BH0003611, BH0003782 andBH0003795.

[0048] Peptide was synthesized using standard Fmoc chemistry (Rink AM resin).1) Resin preparation: To the vessel containing Rink Amide AM resin (15.62 g, 5.00 mmol, 0.32 mmol / g) and DMF (100 ml) was bubbled with N2for 2 h at 25 °C. Then 20% piperidine in DMF (200 ml) was added and the mixture was bubbled with N2for 30 min at 25 °C. The mixture was filtered and washed with DMF (100 ml) * 5 before proceeding to next step.2) Coupling: A solution of Fmoc-Thr(tBu)-OH (5.95 g, 15.00 mmol, 3.00 equiv.), HBTU (5.48 g, 14.25 mmol, 2.85 equiv.), DIEA (3.87 g, 30.00 mmol, 6.00 equiv.) in DMF (100 ml) was added to the resin withN2bubbling for 30 min at 25 °C. The coupling reaction was monitored by ninhydrin test. The resin was then washed with DMF (200 ml) * 5.3) Deprotection: 20% piperidine in DMF (200 ml) was added to the resin and the mixture was bubbled with N2for 30 min at 25 °C. The deprotection reaction was monitored by ninhydrin test. The resin was then washed with DMF (200 ml) * 5.4) Steps 2 and 3 were repeated for the following amino acids elongation: Number # 2-14, Table 1.5) After all the steps were completed, the resin was washed with DMF (100 ml) * 5, MeOH (100 ml)* 5 i , then dried under reduced pressure to afford resin-bound peptide Intermediate 19 (Rink AM resin, 12.3 g, 5.00 mmol).Table 1: The list of amino acids and the corresponding reagents used on SPPS.[00491 Peptide cleavage and cyclization.1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 250 ml) was added to the flask containing the side-chain protected resin-bound peptide Intermediate 19 (Rink AM resin, 12.3 g, 5.00 mmol) at 25 °C and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (3.0 L). After filtration, the solid was washed with isopropyl ether (1.5 L) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 20 (10.1 g, crude) as a white solid.4) To a mixture of Intermediate 20 (10.1 g, crude) in HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 3.0 L) was added 0.1 M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 °C for 5min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 21 (2.00 g, 92.1% purity, 24.6% yield) as a white solid. LCMS: RT = 1.764 min, MS calcd.: Mav, = 1623.85, mass observed: [M + H]+= 1625.0, [M + 2H]2+= 813.1.

[0050] Preparation of BH0003610 (dick reaction):

[0051] To a solution of Intermediate 21 (65.7 mg, 40.5 μmol, 1.00 equiv.) and Target A096 (75.0 mg, 40.5 μmol, 1.00 equiv.) in DMF (5 ml) was added CuSO4(0.4 M, 101.25 μL, 40.5 μmol, 1.00 equiv.), sodium ascorbate (0.4 M, 405.0 μL, 162.0 μmol, 4.00 equiv.) and THPTA (trishydroxypropyltriazolylmethylamine, 17.6 mg, 40.5 μmol, 1.00 equiv.) under nitrogen atmosphere at 0°C, and the resulting mixture was stirred for 3 h at 0 °C. After completion monitored by LC-MS, the reaction was filtered off and purified by prep-HPLC (A: 0.075% TFA / H2O; B: MeCN), followed by lyophilization to afford BH0003610 (30.5 mg, 91.8% purity, 21.7% yield) as a white solid. LCMS: RT = 9.0 min, MS calcd.: Mav, = 3476.79, mass observed: [M + 2H]2+= 1738.80, [M + 3H]3+= 1159.53, [M + 4H]4+= 869.90, [M + 5H]*= 696.12.

[0052] BH0003665, BH0003611, BH0003782, BH0003781, BH0003795 were synthesized using the same procedure as BH0003610, which was performed by following the procedure mentioned in

[0050] -

[0051] ,

[0053] 58.0 mg of Target A097 afforded BH0003665 (17.9 mg, 95.6% purity, 13.9% yield) as a white solid. LCMS: RT = 9.1 min, MS calcd.: Mav= 2960.25, mass observed: [2M + 3H]3+= 1974.23, [M + 2H]2+= 1480.67, [M + 3H]3+= 987.79, [M + 4H]4+= 740.84.

[0054] 57.9 mg of Target A098 afforded BH0003611 (29.2 mg, 95.7% purity, 16.9% yield) as a white solid. LCMS: RT = 9.0 min, MS calcd.: Mav= 2443.71, mass observed: [2M + 3H]3+= 1629.74, [M + 2H]2+= 1223.06, [M + 3H]3+= 815.04, [M + 4H]4+= 611.53.

[0055] 130 mg of Target A100 afforded BH0003795 (98 mg, 94.5% purity, 22.3% yield) as a white solid. LCMS: RT = 1.34 min, MS calcd.: Mav= 2363.62, mass observed: [2M + 3H]3+= 1576.5, [M + Na]2+= 1193.8, [M + 2H]2+= 1182.8, [M-Sugar + 2H]2+= 1080.8 [M + 3H]3+= 788.8.

[0056] 110 mg of Target A099 afforded BH0003782 (149 mg, 96.0% purity, 54.6% yield) as a white solid. LCMS: RT = 1.34 min, MS calcd.: Mav= 2800.07, mass observed: [2M + 3H]3+= 1867.3, [M + Na]2+= 1411.5, [M + 2H]2+= 1400.9, [M-Sugar + 2H]2+= 1299.4 [M + 3H]3+= 934.4.[00571 26 mg of Target A094 afforded BH0003781 (19 mg, 95.5% purity, 35.9% yield) as a white solid. LCMS: RT = 1.32 min, MS calcd.: Mav= 3311.69, mass observed: [M + 2H]2+= 1656.3, [M-203 + 2H]2+= 1554.7, [M + 3H]3+= 1104.7.EXAMPLE 9. Procedure for preparation of BH0003080, BH0003081, BH0003083 and BH0003050.

[0059] Peptide was synthesized using standard Fmoc chemistry (CTC resin).1) Resin preparation: To the vessel containing CTC resin (0.50 g, 0.50 mmol, 1.00 mmol / g) and Fmoc-Thr(tBU)-OH (198.5 mg, 0.5 mmol, 1.00 equiv.) in DCM (10 ml) was added DIEA (4.00 equiv.) dropwise and mixed for 2 h with N2bubbling at 25 ºC. Then MeOH (2.0 ml) was added and bubbled with N2for another 30 min. The resin was washed with DMF (10 ml) * 5, followed by the addition of 20% piperidine in DMF (10 ml) and bubbled with N2for 30 min at 25 ºC for Fmoc deprotection. The mixture was filtered and the resin was washed with DMF (10 ml) * 5 before proceeding to next step.2) Coupling: A solution of Fmoc-Leu-OH (0.53 g, 1.5 mmol, 3.00 equiv.), HBTU (0.41 g, 1.43 mmol,2.85 equiv.) in DMF (10 ml) was added to the resin with N2bubbling. Then DIEA (6.00 equiv.) was added to the mixture dropwise and bubbled with N2for 30 min at 25 ºC. The coupling reaction was monitored by ninhydrin test, if it showed colorless, the coupling was completed. The resin was then washed withDMF (10 ml) * 5.3) Deprotection: 20% piperidine in DMF (10 ml) was added to the resin and the mixture was bubbled with N2for 30 min at 25 "C. The resin was then washed with DMF (10 ml) * 5.4) Steps 2 and 3 were repeated for the following amino acids elongation: Number # 2-14, Table 2.5) After all the steps were completed, the resin was washed with DMF (100 ml) * 5, MeOH (100 ml)* 5, then dried under reduced pressure to afford resin-bound peptide Intermediate 22 (CTC resin, 1.10 g,0.50 mmol).Table 2: The list of amino acids and the corresponding reagents used on SPPS.[00601 Peptide cleavage and cyclization.1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 20 ml) was added to the flask containing the side-chain protected resin-bound peptide Intermediate 22, 1.23 g, 0.50 mmol at 25 ºC and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (100 ml). After filtration, the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure for2 h to afford Intermediate 23 (768 mg, crude) as a white solid.4) To a mixture of Intermediate 23 (768 mg, crude) in MeCN / H2O (4 / 6, v / v, 500 ml) was added 0.1M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 °C for 5 min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 24 (56.2 mg, 90.0% purity) as a white solid.

[0061] Preparation of BH0003080

[0062] Click reaction: BH0003080 was synthesized using the same procedure as BH0003610, which was performed by following the procedure mentioned in

[0050] -

[0051] .

[0063] 50.0 mgof Target A043 afforded BH0003080 (28 mg, 95.4% purity, 50.1% yield) as a white solid. LCMS: RT = 1.44 min, MS calcd.: Mav= 3237.51, mass observed: [M + 2H]2+= 1620.10, [M - 203 + 2H]2+= 1519.10, [M - 2 x 203 + 2H]2+= 1417.10, [M + 3H]3+= 1080.50.

[0064] BH0003081, BH0003083, BH0003050 were synthesized using the same procedure asBH0003080, which were performed by following the procedure mentioned in

[0059] -

[0063] .

[0065] 50.0 mg of Target A044 afforded BH0003081 (53.0 mg, 95.8% purity, 49.2% yield) as a white solid. LCMS: RT = 1.44 min, MS calcd.: Mav= 3253.51, mass observed: [M + 2H]2+= 1628.70, [M - 203 + 2H]2+= 1526.50, [M - 2 x 203 + 2H]2+= 1424.50, [M + 3H]3+= 1085.80.

[0066] 50.0 mg of Target A042 afforded BH0003083 (45.0 mg, 95.8% purity, 43.7% yield) as a white solid. LCMS: RT = 1.45 min, MS calcd.: Mav= 3295.59, mass observed: [M + 2H]2+= 1649.10, [M - 203 + 2H]2+= 1547.50, [M - 2 x 203 + 2H]2+=1446.00, [M + 3H]3+= 1099.80.

[0067] 20 mg of Target A041 afforded BH0003050 (19.8 mg, 97.2% purity, 37.7% yield) as a white solid. LCMS: RT = 0.84 min, MS calcd.: Mav= 3383.70, mass observed: [M + 2H]2+= 1692.40, [M - sugar + 2H]2+= 1590.90, [M + 3H]3+= 1128.50.EXAMPLE 10. Procedure for Preparation of BH0003746 and BH-0003602.

[0068] Preparation of Compound 1562:

[0069] Peptide was synthesized using standard Fmoc chemistry (CTC resin).1) Resin preparation: To the vessel containing CTC resin (0.50 g, 0.50 mmol, 1.00 mmol / g) and Fmoc-Gly-OH (148.8 mg, 0.5 mmol, 1.00 equiv.) in DCM (10 ml) was added DIEA (4.00 equiv.) dropwise and mixed for 2 h with N2 bubbling at 25 °C. Then MeOH (2.0 ml) was added and bubbled with N2 for another30 min. The resin was washed with DMF (10 ml) * 5, followed by the addition of 20% piperidine in DMF(10 ml) and bubbled with N2 for 30 min at 25 "C for Fmoc deprotection. The mixture was filtered and the resin was washed with DMF (10 ml) * 5 before proceeding to next step.2) Coupling: A solution of Fmoc-Leu-OH (0.53 g, 1.5 mmol, 3.00 equiv.), HBTU (0.41 g, 1.43 mmol,2.85 equiv.) in DMF (10 ml) was added to the resin with N2bubbling. Then DIEA (6.00 equiv.) was added to the mixture dropwise and bubbled with N2for 30 min at 25 ºC. The coupling reaction was monitored by ninhydrin test, if it showed colorless, the coupling was completed. The resin was then washed withDMF (10 ml) * 5.3) Deprotection: 20% piperidine in DMF (10 ml) was added to the resin and the mixture was bubbled with N2for 30 min at 25 ºC. The resin was then washed with DMF (10 ml) * 5.4) Steps 2 and 3 were repeated for the following amino acids elongation: Number # 3-15, Table 3.5) After all the steps were completed, the resin was washed with DMF (100 ml) * 5, MeOH (100 ml)* 5, then dried under reduced pressure to afford resin-bound peptide Intermediate 25 (CTC resin, 1.10 g, 0.5 mmol).Table 3: The list of amino adds and the corresponding reagents used on SPPS.

[0070] Peptide cleavage and cyclization, TFA de-protection and disulfide formation:1) Cleavage: A solution of 1% TFA / DCM (20 ml) was added to the resin above at room temperature and stirred for 2 h. After filtration, the filtrate was collected (which contained Intermediate 26).2) Head to tail cyclization: The filtrate was diluted with DCM to 500 ml (1 mM), then HATU (380.2 mg, 1.0 mmol, 2.00 equiv.) was added, followed by the addition of DIEA (348.6 μL, 2.0 mmol, 4.00 equiv.), and the resulting mixture was stirred for 30 min at 25 "G After completion monitored by LC-MS, the reaction was washed with 1 M HCI (300 ml), then washed with H2O (300 ml). The organic layer was collected and concentrated under reduced pressure to give a residue.3) Deprotection: To the residue from step 2 was added a solution of TFA / TIS / H2O / 3- mercaptopropanoic acid (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 50 ml), and the resulting mixture was stirred for 1 h at 25 °C. The mixture was precipitated with cold isopropyl ether (cold, 300 ml). After filtration, the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure.4) Disulfide formation: To the crude peptide from step 3 in MeCN / H2O (1 / 1, v / v, 500 ml) was added 0.1 M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 ºC for 5 min. Themixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Compound 1562 (164.8 mg, 96.6% purity, 19.4% yield) as a white solid. LCMS: RT = 7.9 min, MS calcd.: Mav= 1696.95, mass observed: [M + H]+= 1696.76, [2M + 3H]3+= 1132.18, [M + 2H]2+= 848.88, [M + 3H]3+= 566.26.

[0071] BH-0003602 was synthesized using the same procedure as Compound 1562 which was performed by following the procedure mentioned in

[0069] -

[0070] . 0.50 mmol resin afforded BH- 0003602 (110.4mg, 95.0% purity, 12.9% yield) as a white solid. LCMS: RT = 1.78 min, MS calcd.: Mav= 1706.94, mass observed: [M + H]+= 1707.1, [M + 2H]2+= 854.1.

[0072] Preparation of Intermediate 27:

[0073] To a mixture of 27A (151.1 mg, 329.7 μmol, 3.00 equiv.) in DMF (0.5 ml) was added a mixture of Target A011A (180.0 mg, 109.9 μmol, 1.00 equiv.) and DIEA (76.6 uL, 439.63 μmol, 4.00 equiv.) in DMF (0.5 ml) at 0 ºC, and the resulting reaction was stirred for 5 min at 0 °C. After completion monitored by LC-MS. The mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O,B: MeCN) directly, followed by lyophilization to afford Intermediate 27 (160.0 mg, 75.4% yield) as colorless oil. LCMS: RT = 0.828 min, MS calcd.: Mav= 1929.92, mass observed: [M + 2H]2+= 965.7.

[0074] Preparation of BH0003746:

[0075] To a mixture of Intermediate 27 (24.9 mg, 12.9 μmol, 1.00 equiv.) and Compound 1562(21.9 mg, 12.9 μmol, 1.00 equiv.) in DMF (0.2 mL) was added DIEA (22.0 μL, 129 μmol, 10.0 equiv.) at 25°C. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford BH0003746 (8.1 mg, 92.5% purity, 18.1% yield) as a white solid. LCMS: RT = 9.3 min, MS calcd.: Mav= 3460.79, mass observed: [M + 2H]2+= 1730.80, [M + 3H]3+= 1154.54, [M + 4H]4+=865.90.EXAMPLE 11. Procedure for Preparation of BH0003716, BH0003789 and BH0003082.

[0076] Preparation of BH0003716:

[0077] SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 4 by following the procedure mentioned in section

[0048] .

[0078] Acetylation: A solution of Ac2O / NMM / DMF (2 / 1 / 17, v / v / v, 40 ml) was added to the resin, the mixture was bubbled with N2for 20 min. The acetylation reaction was monitored by ninhydrin test.The resin was then washed with DMF (20 ml) * 5, MeOH (20 ml) * 3, then dried under reduced pressure to afford Intermediate 28 (peptide resin, 0.50 mmol).Table 4: The list of amino acids and the corresponding reagents used on SPPS.

[0079] Peptide cleavage and disulfide formation:5) Cleavage solution (TFA / TlS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 ml) was added to the flask containing the side-chain protected resin-bound peptide (Rink AM resin, 1.84 g, 0.50 mmol) at 25 °C and stirred for 2 h.6) After filtration, the filtrate was collected.7) The filtrate was precipitated with cold isopropyl ether (150 ml). After filtration, the solid was washed with isopropyl ether (150 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 28 (785 mg, crude) as a white solid.5) Disulfide formation: To the Intermediate 28 in MeCN / H2O (1 / 1, v / v, 500 ml) was added 0.1 M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 ºC for 5 min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilizationto afford BH0003716 (59.7 mg, 95.2% purity, 7.2% yield) as a white solid. LCMS: RT = 1.23 min, MS calcd.: Mav= 1586.79, mass observed: [M + H]+= 1586.79, [M + 2H]2+= 794.1.

[0080] Preparation of BH0003789:081] BH0003789, BH-0003082 were synthesized using the same procedure as BH0003746, hich was performed by following the procedure mentioned in

[0072] -

[0075] .[00821 Preparation of BH0003789:[00831 Intermediate 30 were synthesized using the same procedure which was performed by following the procedure mentioned in

[0048] -

[0049] .

[0084] 50.0 mg of Intermediate 29 afforded BH0003789 (20.3 mg, 93.2% purity, 22.8% yield) as a white solid. LCMS: RT = 1.31 min, MS calcd.: Mav= 3570.90, mass observed: [M + 2H]2+= 1786.7, [M +3H]3+= 1191.1, [M + 4H]4+= 893.7, [M + 5H]5+= 715.3.

[0085] Preparation of BH0003082:

[0086] Intermediate 31 were synthesized using the same procedure which was performed by following the procedure mentioned in

[0059] -

[0060] .

[0087] Intermediate 32 were synthesized using the same procedure as Intermediate 27, which was performed by following the procedure mentioned in

[0072] .

[0088] 8 mg of Target A001A afforded BH-0003082 (5 mg, 94.6% purity, 32.2% yield) as a white solid. LCMS: RT = 0.83 min, MS calcd.: = 3227.52, mass observed: [M + 2H]2+= 1614.17, [M - sugar + 4H]4+= 1076.40, [M + 3H]3+= 1076.40.EXAMPLE12. Procedure for Preparation of BH-0003714, BH-0003715 and BH-0003786

[0089] Preparation of BH-0003714:

[0090] BH-0003714 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 5.Table 5: The list of amino acids and the corresponding reagents used on SPPS.

[0091] Peptide cleavage and disulfide formation:1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 ml) was added to the flask containing the side-chain protected resin-bound peptide Rink AM resin, 1.84 g, 0.50 mmolat 25 ºC and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (150 ml). After filtration, the solid was washed with isopropyl ether (150 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 33 (785 mg, crude) as a white solid.4) Disulfide formation: To the Intermediate 30 in MeCN / H2O (1 / 1, v / v, 500 ml) was added 0.1 M12 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 ºC for 5 min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford BH-0003714 (156 mg, 96.5% purity, 19.3% yield) as a white solid. LCMS: RT = 1.26 min, MS calcd.: Mav =1561.78, mass observed: [M + H]+ = 1561.9, [M + 2H]2+= 781.6.0092] BH-0003715 was synthesized using the same procedure as BH-0003714 which was performed by following the procedure mentioned in

[0089] -

[0091] . 1.00 mmol resin to afford BH-0003715 (495.2 mg, 95.8% purity, 31.2% yield) as a white solid. LCMS: RT = 1.25, MS calcd.: Mav= 1519.75, mass observed: [M + H]+= 1519.75, [M + 2H]2+= 760.5.[00931 Preparation of BH0003786[00941 BH0003786 were synthesized using the same procedure as BH0003746 which was performed by following the procedure mentioned in

[0072] -

[0075] .

[0095] 54.0 mg of Intermediate 34 afforded BH-0003786 (28.3 mg, 96.7% purity, 28.7% yield) as a white solid. LCMS: RT = 1.31 min, MS calcd.: Mav= 3217.52, mass observed: [M + 2H]2+= 1609.5, [M- sugar + 2H]2+= 1508.0, [M- 2 x sugar +2H]2+= 1406.4, [M- 3 x sugar + 2H]2+= 1304.6, [M + 3H]3+= 1073.EXAMPLE13. Procedure for Preparation of BH-0003787[00961 Preparation of Intermediate 36:

[0097] Intermediate 35 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 6.Table 6: The list of amino acids and the corresponding reagents used on SPPS.

[0098] Intermediate 36 was synthesized using the same procedure as BH-0003714 which was performed by following the procedure mentioned in

[0086] -

[0088] . After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 36 (156 mg, 90% purity, 15.7% yield) as a white solid.

[0099] Preparation of Intermediate 37:

[0100] Intermediate 37 was synthesized using the same procedure as BH0003746 which was performed by following the procedure mentioned in

[0074] -

[0075] . 92.0 mg of Intermediate 34 afforded Intermediate 37 (80 mg, 51.27% yield) as a white solid.

[0101] Preparation of BH-0003787:[0102J To a mixture of Intermediate 37 (80 mg, 23.55 μmol, 1.00 equiv.) in 2%DBU / DMF (1.0 ml). The mixture was stirred at 25 ºC for 15 min. After completion monitored by LC-MS, the mixture was then purified by prep-HPLC (A: 0.075% TFA / H2O, 8: MeCN) directly, followed by lyophilization to affordedBH-0003787 (35.7 mg, 97.1% purity, 35.5% yield) as a white solid. LCMS: RT = 1.24 min, MS calcd.: Mav= 3175.48, mass observed: [M + 2H]2+= 1588.6, [M- sugar + 2H]2+=1487.1, [M- 2 x sugar +2H]2+= 1385.4, [M + 3H]3+= 1059.1.EXAMPLE 14. Procedure for Preparation of BH0003710 and BH0003711.

[0103] Preparation of Intermediate 38:

[0104] To a mixture of Intermediate 38A (2.35 g, 5.13 mmol, 3.0 equiv.) in DMF (5 ml) was added a mixture of Target A092 (0.50 g, 1.71 mmol, 1.0 equiv.) and DIEA (582.3 uL, 3.42 mmol, 2.0 equiv.) in DMF (2 ml), and the resulting reaction was stirred for 5 min at 0 ºC. After completion monitored by LC-MS. The mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A:0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 38 (750.0 mg,75.1% yield) as a white solid. LCMS: RT = 1.11 min, MS calcd.: Mav= 584.51, mass observed: [M + H]+=585.28.

[0105] Preparation of Intermediate 41:

[0106] Intermediate 39 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0069] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 7.Table 7: The list of amino acids and the corresponding reagents used on SPPS.

[0107] Intermediate 41 (peptide cleavage, cyclization, TFA deprotection, disulfide formation) was synthesized by following the procedure mentioned in section

[0070] . 0.50 mmol resin afforded Intermediate 41 (200.0 mg, 95.4% purity, 23.8% yield) was obtained as a white solid after lyophilization. LCMS: RT = 0.863 min, MS calcd.: Mav= 1677.94, mass observed: [M + H]+= 1678.7, [M + 2H]2+= 839.6.

[0108] preparation of Intermediate 42:

[0109] To a mixture of Intermediate 41 (103.2 mg, 61.5 μmol, 1.00 equiv.) in DMSO (0.5 ml) was added a mixture of Intermediate 38 (35.9 g, 61.5 μmol, 1.00 equiv.) and DIEA (20.9 ul, 123.0 μmol, 2.00 equiv.) in DMSO (0.2 ml), and the resulting reaction was stirred for 30 min at 0 °C. After completionmonitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 42 (44.7 mg, 34.7% yield) as a white solid. LCMS: RT = 1.76 min, MS calcd.: Mav= 2096.39, mass observed: [M + 2H]2+= 1048.96.

[0110] Preparation ofBH0003710:

[0111] To a solution of Intermediate 42 (45.0 mg, 21.5 μmol, 1.00 equiv.) and Target A093 (30.8 mg, 68.7 μmol, 3.20 equiv.) in DMF (0.5 mL) was added CuSO4(10.2 mg, 64.5 μmol, 3.00 equiv.), Na ascorbate (51.0 mg, 258.0 μmol, 12.00 equiv.) and THPTA (27.9 mg, 64.5 μmol, 3.00 equiv.) under nitrogen atmosphere at 0 °C, and the resulting mixture was stirred for 1 h at 0 ºC. After completion monitored by LC-MS, the reaction was filtered off and purified by prep-HPLC (A: 0.075% TFA / H2O; B: MeCN), followed by lyophilization to afford BH0003710 (22.1 mg, 96.7% purity, 28.9% yield) as a white solid. LCMS: RT = 1.437 min, MS calcd.: Mav= 3441.79, mass observed: [M + 2H]2+= 1721.80, [M + 3H]3+= 1148.20, [M + 4H]4+= 861.40.

[0112] Preparation of BH0003711:

[0113] BH-0003711 was synthesized using the same procedure as BH0003710 which was performed by following the procedure mentioned in

[0103] -

[0111] .

[0114] 16.8 mg of Target A093 with Intermediate 46 afforded BH-0003711 (23.7 mg, 93.7% purity, 59.3% yield) as a white solid. LCMS: RT = 1.37 min, MS calcd.: Mav, = 3485.80, mass observed: [M + 2H]2+= 1743.6, [M + 3H]3+= 1162.8, [M + 4H]4+=872.5.EXAMPLE15. Procedure for Preparation of BH-0003788 and BH-0003787.

[0115] Preparation of Intermediate 49:

[0116] Intermediate 48 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 8.Table 8: The list of amino acids and the corresponding reagents used on SPPS.

[0117] Intermediate 49 was synthesized using the same procedure as Intermediate 21 which was performed by following the procedure mentioned in

[0049] . After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 49 (162 mg, 90% purity, 16.5% yield) as a white solid.

[0118] Preparation of Intermediate 50:

[0119] Intermediate 50 was synthesized using the same procedure as Intermediate 38 which was performed by following the procedure mentioned in

[0104] , The mixture was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 50 (380 mg, 75.1% yield) as colorless oil.

[0120] Preparation of Intermediate 52:

[0121] Intermediate 52 was synthesized using the same procedure as BH0003710 which was performed by following the procedure mentioned in

[0108] -

[0111] . The reaction was filtered off and purified by prep-HPLC (A: 0.075% TFA / H2O; B: MeCN), followed by lyophilization to afford Intermediate52 (36 mg, 38.89% yield).

[0122] Preparation ofBH0003788:

[0123] BH0003788 was synthesized using the same procedure as BH-0003787 which was performed by following the procedure mentioned in

[0101] -

[0102] .

[0124] 38.89 mg of Intermediate 52 afforded BH0003788 (11.8 mg, 92.9% purity, 30.0% yield) as a white solid. LCMS: RT = 1.88 min, MS calcd.: Mav= 3528.86, mass observed: [M + 2H]2+= 1765.2, [M + 3H]3+= 1177.5, [M + 4H]4+= 883.1, [M + 5H]5+= 706.8.EXAMPLE 16. Procedure for Preparation of BH0003780.

[0125] Preparation of Compound 1569:

[0126] Intermediate 53 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0059] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 9.

[0127] Acetylation: A solution of Ac2O / NMM / DMF (2 / 1 / 17, v / v / v, 40 ml) was added to the resin, the mixture was bubbled with N2for 20 min. The acetylation reaction was monitored by ninhydrin test.The resin was then washed with DMF (20 ml) * 5, MeOH (20 ml) * 3, then dried under reduced pressure to afford Intermediate 53 (peptide resin, 0.50 mmol).Table 9: The list of amino acids and the corresponding reagents used on SPPS.

[0128] Peptide cleavage and double disulfide formation:1) Cleavage: A solution of TFA / TIS / H2O (95 / 2.5 / 2.5, v / v / v, 40 ml) was added to the flask containing the side-chain protected resin-bound peptide (Intermediate 53), and the resulting mixture was stirred for2 h at 25 °C. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 ml), then filtered off, and the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 54 (0.50 mmol, crude) as a white solid.2) First disulfide formation: To a mixture of Intermediate 54 (0.50 mmol, crude) in MeCN / H2O (4 / 6, v / v, 500 ml) was added NaHCO3to pH = 8 at 25 ºC. Then the mixture was open to the air and stirred at 25 "C for 24 h. After filtration, the mixture was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) to afford Intermediate 55 (355.4 mg, 20.1% yield) as a white solid.3) Second disulfide formation: To a mixture of Intermediate 55 (355.4 mg, 0.20 mmol) in MeCN / H2O(4 / 6, v / v, 200 mL) was added 1 M aq. HCI (1.5 mL), AcOH (3.0 mL) to pH = 1. The mixture was added 0.1 M I2 / AcOH dropwise until the yellow color persisted, then the mixture was stirred at 25 "C for 5 h. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified directly by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Compound 1569 (245.4 mg, 91.7% purity, 69.0% yield) as a white solid. LCMS: RT = 1.294 min, MS calcd.: Mav= 1767.04, mass observed: [M + H]+= 1767.7, [M + 2H]2+= 884.6.

[0129] Preparation of BH0003780

[0130] To a mixture of Compound 1569 (98.4 mg, 51.0 μmol, 1.00 equiv.) and Intermediate 27(90.1 mg, 51.0 μmol, 1.00 equiv.) in DMSO (0.5 ml) was added DIEA (87.0 μL, 510 μmol , 10.0 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford BH0003780 (36.2 mg, 96.9% purity, 20.1% yield) as a white solid. LCMS: RT = 1.346 min, MS calcd.: Mav, = 3530.88, mass observed: [M + 2H]2+= 1766.1, [M + 3H]3+= 1177.7, [M + 4H]4+= 883.7.EXAMPLE 17. Procedure for Preparation of BH0003794 and BH-0003793.[01311 Preparation of Intermediate 59:

[0132] Intermediate 56 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0059] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 10, Number# 1-15.Table 10: The list of amino acids and the corresponding reagents used on SPPS.

[0133] Intermediate 59 were synthesized using the same procedure as Compound 1569 which was performed by following the procedure mentioned in

[0128] .

[0134] Preparation of Intermediate 60:

[0135] Intermediate 60 was synthesized using the same procedure as BH0003780 which was performed by following the procedure mentioned in

[0129] -

[0130] .

[0136] Preparation o / BH-0003794;

[0137] To a mixture of Intermediate 60 (29 mg, 7.76 μmol, 1.00 equiv.) in 2%DBU / DMF (0.5 ml). The mixture was stirred at 25 ºC for 15 min. After completion monitored by LC-MS, the mixture was then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford BH0003794 (16.2 mg, 97.0% purity, 58.0% yield) as a white solid. LCMS: RT = 1.32 min, MS calcd.: Mav= 3488.84, mass observed: [M + 2H]2+= 1745.1, [M + 3H]3+= 1164.1, [M + 4H]4+= 873.2, [M + 5H]5+= 698.7.

[0138] Preparation of BH-0003793:

[0139] BH-0003793 was synthesized using the same procedure as BH0003794 which was performed by following the procedure mentioned in

[0131] -

[0137] .

[0140] Intermediate 64 afforded BH-0003793 (13.4 mg, 97.3% purity, 47.8% yield) as a white solid. LCMS: RT = 1.32 min, MS calcd.: Mav= 3513.85, mass observed: [M + 2H]2+= 1757.7, [M + 3H]3+=1172.3, [M + 4H]4+= 879.4, [M + 5H]5+= 703.6.EXAMPLE 18. Procedure for Preparation of BH-0003921, BH-0001685, BH-0003783 and BH-0003785.

[0141] Preparation of Intermediate 68:

[0142] Intermediate 65 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.30 mmol loading resin) was performed with amino acids elongation shown in Table 11, Number# 1-15.Table 11: The list of amino acids and the corresponding reagents used on SPPS.

[0143] Peptide cleavage and cyclization:1) Cleavage: A solution of TFA / TIS / H2O (95 / 2.5 / 2.5, v / v / v, 40 ml) was added to the flask containing the side-chain protected resin-bound peptide (Intermediate 50), and the resulting mixture was stirred for 2 h at 25 oC. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 ml), then filtered off, and the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 51 (0.30 mmol, crude) as a white solid.2) Thioether ring formation: To a mixture of Intermediate 66 (0.30 mmol, crude) in MeCN / H2O (4 / 6, v / v, 300 ml) was added NaHCO3to pH = 8 at 25 ºC. Then the mixture was stirred at 25 ºC for 24 h under N2atmosphere. After filtration, the mixture was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) to afford Intermediate 67 (240 mg, 90 purity, 38.6% yield) as a white solid.3) Disulfide formation: To a mixture of Intermediate 67 (240 mg, 0.13 mmol) in MeCN / H2O (4 / 6, v / v, 130 ml) was added 1 M aq. HCI (1.5 ml), AcOH (3.0 ml) to pH = 1. The mixture was added 0.1 M I2 / AcOH dropwise until the yellow color persisted, then the mixture was stirred at 25 ºC for 5 h. After filtration, the filtrate was purified directly by prep-HPLC (A: 0.075% TFA / H2O, 8: MeCN), followed by lyophilization to afford Intermediate 68 (173 mg, 95% purity, 76.5% yield) as a white solid. LCMS: RT = 0.82 min, MS calcd.: Mav= 1719.91, mass observed: [M + 2H]2+= 860.

[0144] BH-0001685 was synthesized using the same procedure as Intermediate 68 which was performed by following the procedure mentioned in

[0141] -

[0143] . 0.3 mmol resin afforded BH-0001685 (8.6 mg, 91.1% purity, 1.51% yield) as a white solid. LCMS: RT = 1.41 min, MS calcd.: Mav= 1729.96, mass observed: [M + H]+= 1729.9, [M + 2H]2+= 865.6.

[0145] Preparation of Intermediate 69:

[0146] To a mixture of Intermediate 68 (173 mg, 100.0 μmol, 1.00 equiv.) and Intermediate 38(59 mg, 100.0 μmol, 1.00 equiv.) in DMF (0.5 ml) was added DIEA (70.0 μL, 402 μmol, 4.00 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 0.5 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 69 (95 mg, 95% purity, 44.1% yield) as a white solid. LCMS: RT = 0.96 min, MS calcd.: = 2138.42, mass observed: [M + 2H]2+= 1069.7, [M + 3H]3+= 713.9.

[0147] Preparation of BH-0003921:

[0148] To a mixture of Intermediate 69 (30.0 mg, 14.3 μmol, 1.00 equiv.) and Target A093(25.2 mg, 56.1 μmol, 4.00 equiv.) in DMF (0.5 ml) was added CuSO*.5H2O (0.4 M, 105.2 μL, 3.00 equiv.) and sodium ascorbate (0.5 M, 252.5 μL, 9.00 equiv.) and THPTA (18.6 mg, 42.1 μmol, 3.00 equiv.). The resulting reaction was degassed and purged with N2for three times. Then the mixture was stirred at 25 ºC for 2 h under Ni atmosphere. LC-MS showed Intermediate 69 was consumed completely, one main peak was shown on LC-MS and desired compound was detected. The resulting reaction mixture was purified by prep-HPLC (A: 0.075% HOAc in H2O, B: MeCN) to afford BH-0003921 (20.1 mg, 92.4% purity, 38.0% as a white solid. LCMS: RT = 1.305 min, MS calcd.: Mav= 3483.84, mass observed: [M + 2H]2+= 1742.6, [M + 3H]3+= 1162.2, [M + 4HJ* = 872.0.

[0149] Preparation of BH-0003783:

[0150] BH-0003783 was synthesized using the same procedure as BH0003921 which was performed by following the procedure mentioned in

[0141] -

[0148] .

[0151] 33.1 mg of Target A093 with Intermediate 73 afforded BH-0003783 (18.1 mg, 93.7% purity, 26.1% yield) as a white solid. LCMS: RT = 1.30 min, MS calcd.: Mav= 3508.81, mass observed: [M + 2H]2+= 1755.2, [M + 3H]3+= 1170.5, [M + 4H]4+= 878.0.

[0152] Preparation of BH-0003785:

[0153] BH-0003785 was synthesized using the same procedure as BH0003921 which was performed by following the procedure mentioned in

[0141] -

[0148] .

[0154] 34.6 mg of Target A093 with Intermediate 74 afforded BH-0003785 (39.5 mg, 97.3% purity, 53.3% yield) as a white solid. LCMS: RT = 1.31 min, MS calcd.: Mav, = 3279.08, mass observed: [M + 2H]2+= 1864.9, [M + 3H]3+= 1244.0, [M + 4H]4+= 933.2, [M + 5H]5+= 746.9.EXAMPLE 19. Procedure for Preparation of BH003779 and BH-0003713.

[0155] Preparation of Compound 1512:[01561 Intermediate 75 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0059] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 12, Number# 1-15.Table 12: The list of amino acids and the corresponding reagents used on SPPS.

[0157] Peptide cleavage and double disulfide formation:1) Cleavage: A solution of TFA / TIS / H2O (95 / 2.5 / 2.5, v / v / v, 40 ml) was added to the flask containing the side-chain protected resin-bound peptide (Intermediate 75), and the resulting mixture was stirred for 2 h at 25 °C. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 ml), then filtered off, and the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 76 (0.50 mmol, crude) as a white solid.2) First disulfide formation: To a mixture of Intermediate 76 (0.50 mmol, crude) in MeCN / H2O (4 / 6, v / v, 500 ml) was added NaHCO3to pH = 8 at 25 ºC. Then the mixture was open to the air and stirred at 25 ºC for 24 h. After filtration, the mixture was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) to afford Intermediate 77 (439.5 mg, 25.3% yield) as a white solid.3) Second disulfide formation: To a mixture of Intermediate 77 (439.5 mg, 25.3% yield) in MeCN / H2O (4 / 6, v / v, 300 ml) was added 1 M aq. HCI (1.5 ml), AcOH (3.0 ml) to pH = 1. The mixture was added 0.1 M I2 / AcOH dropwise until the yellow color persisted, then the mixture was stirred at 25 "C for 5 h. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified directly by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Compound 1512 (160.5 mg, 95.8% purity, 36.5% yield) as a white solid. LCMS: RT = 1.355 min, MS calcd.: Mav= 1735.00, mass observed: [M + H]+= 1735.8, [M + 2H]2+= 868.6.[01581 Preparation ofBH0003779:

[0159] To a mixture of Compound 1512 (49.2 mg, 25.5 μmol, 1.00 equiv.) and Intermediate 27(44.2 mg, 25.5 μmol, 1.00 equiv.) in DMSO (0.5 ml) was added DIEA (43.5 μ l, 255 μmol, 10.0 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford BH0003779 (9.0 mg, 95.0% purity, 10.1% yield) as a white solid. LCMS: RT = 1.407 min, MS calcd.: Mav= 3498.84, mass observed: [M + 2H]2+= 1750.6, [M + 3H]3+= 1167.1, [M + 4H]4+= 876.1.

[0160] Preparation ofBH0003713:

[0161] BH-0003713 was synthesized using the same procedure as BH0003779 which was performed by following the procedure mentioned in

[0156] -

[0159] .

[0162] 30 mg of Intermediate 27 with Intermediate 80 afforded BH-0003713 (27.7 mg, 88.4% purity, 44.3% yield) as a white solid. LCMS: RT = 1.32 min, MS calcd.: Mav, = 3555.89, mass observed: [M + 2H]2+= 1778.7, [M + 3H]3+= 1186.1, [M + 4H]4+=889.7.EXAMPLE 20. Procedure for Preparation of BH0003712.

[0164] Intermediate 81 was synthesized by following the procedure mentioned in section

[0059] .SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 13, Number #1-15.

[0165] Acetylation: A solution of Ac2O / NMM / DMF (2 / 1 / 17, v / v / v, 40 ml) was added to the resin, the mixture was bubbled with N2for 20 min. The acetylation reaction was monitored by ninhydrin test.The resin was then washed with DMF (20 ml) * 5, MeOH (20 ml) * 3, then dried under reduced pressure to afford peptide resin (0.50 mmol).Table 13: The list of amino acids and the corresponding reagents used on SPPS.y[01661 Peptide cleavage and fragments coupling, TFA deprotection and double disulfide formation:1) Cleavage from resin: A solution of 20% HFIP / DCM (50 ml) was added to the resin above at room temperature and stirred for 1 h. After filtration, the filtrate was collected and concentrated under reduced pressure to afford fully protected peptide Intermediate 81 (1.40 g, crude) as a white solid.2) Fragments coupling: To the mixture of Intermediate 81 (1.40 g, crude, 496.72 μmol, 1.00 equiv.), 59A (238.7 mg, 1.49 mmol, 3.00 equiv.), HOBt (201.2 mg, 1.49 mmol, 3.00 equiv.) in DMF (2.0 ml) was added EDCI (285.6 mg, 1.49 mmol, 3.00 equiv.) at 0 ºC. The resulting reaction was stirred for 2 h at 0 "C. After completion monitored by LC-MS, the reaction was added into flask with cold 0.1 M HCI (30 ml), and the precipitate was filtered off to afford the crude as Intermediate 82.3) Deprotection: A solution of TFA / TIS / H2O / 3-mercaptopropanoic acid (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 20 ml) was added to the flask containing Intermediate 82 (crude) in step 2, and the resulting mixture was stirred for 1 h at 25 °C. The mixture was precipitated with cold isopropyl ether (100 ml), then filtered off, and the solid was washed with isopropyl ether (50 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 83 (858.3 mg, crude) as a white solid.4) First disulfide formation: A solution of Intermediate 83 (858.3 mg, crude) in MeCN / H2O (4 / 6, v / v,500 ml) based by NaHCO3to pH = 8. The mixture was open to the air and stirred at 25 ºC for 24 h. After filtration, the mixture was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) to afford Intermediate 84 (260.9 mg, 30.4% yield) as a white solid.5) Second disulfide formation: To a mixture of Intermediate 84 (260.9 mg, 133.0 μmol) in MeCN / H2O(4 / 6, v / v, 130 ml) was added 1 M aq. HCI (1.5 ml), AcOH (3.0 ml) to pH = 1. The mixture was added 0.1 M I2 / AcOH dropwise until the yellow color persisted, then the mixture was stirred at 25 "C for 5 h. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. Afterfiltration, the filtrate was purified directly by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 85 (86.1 mg, 33.0% yield) as a white solid. UPLC: RT = 0.845 min, MS calcd.: Mav= 1819.11, mass observed: [M + H]+= 1819.69, [M + 2H]2+= 910.04.

[0167] Preparation of BH0003712:

[0168] To a mixture of Intermediate 85 (36.7 mg, 20.21 umol, 1.30 equiv.) and Intermediate 27(30.0 mg, 15.54 μmol, 1.00 equiv.) in DMSO (0.5 ml) was added DIEA (6.03 mg, 46.63 μmol, 8.12 μL, 3.00 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was acidified by 1 M MCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford BH0003712 (13.5 mg, 92.2% purity, 22.3% yield) as a white solid. LCMS: RT = 1.401 min, MS calcd.: Mav= 3582.96, mass observed: [M + 2H]2+= 1792.7, [M + 3H]3+= 1195.1, [M + 4H]4+= 896.7.EXAMPLE 21. Procedure for Preparation of BH0003844.

[0169] Preparation of Intermediate 87:

[0170] To a mixture of Target A092 (200 mg, 684.1 umol, 1.00 equiv.) and dlhydrofuran-2,5- dlone (68.47 mg, 684.1 μmol, 1.00 equiv.) in DMF (2 ml) was added DIEA (176.8 mg, 1.37 mmol, 238.3 μL.2.00 equiv.) at 25 ºC. The mixture was stirred at 15 ºC for 1 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 86 (250 mg, 93. 12% yield) as a colorless oil. Toa mixture of Intermediate 86 (250 mg, 637.1 umol, 1.00 equiv.) and 2,3,5,6-tetrafluorophenol (423.2 mg, 2.55 mmol, 4.00 equiv.) in DMF (3 ml) was added EDCI (244.2 mg, 1.27 mmol, 2.00 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 87 (160 mg, 46.4% yield) as a colorless oil.

[0171] Preparation of Intermediate 92:

[0172] Intermediate 88 was synthesized by following the procedure mentioned in section

[0059] .SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 14, Number #1-15.Table 14: The list of amino acids and the corresponding reagents used on SPPS.

[0173] Intermediate 92 was synthesized using the same procedure as Intermediate 85 which was performed by following the procedure mentioned in

[0166] to afford Intermediate 92 (86.1 mg, 33.0% yield).

[0174] Preparation of Intermediate 93:

[0175] To a mixture of Intermediate 92 (73.9 mg, 37.0 umol, 1.00 equiv.) and Intermediate 87(20.0 mg, 37.0 μmol, 1.00 equiv.) in DMSO (1.0 ml) was added DIEA (19.1 mg, 148.0 μmol, 25.8 μL, 4.00 equiv.) at 25 ºC. The mixture was stirred at 25 ºC for 2 h. After completion monitored by LC-MS, the mixture was acidified by 1 M HCI to pH = 5, then purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to afford Intermediate 93 (26 mg, 90% purity, 26.6% yield) as a white solid.

[0176] Preparation of Intermediate 94:

[0177] To a mixture of Intermediate 93 (26 mg, 10.9 μmol, 1.00 equiv.) in 2%DBU / DMF (1.0 ml).The mixture was stirred at 25 "C for 15 min. After completion monitored by LC-MS, the mixture was thenpurified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN) directly, followed by lyophilization to affordedIntermediate 94 (15 mg, 90% purity, 57.3% yield) as a white solid.

[0178] Preparation of BH-0003844:

[0179] To a solution of Intermediate 94 (15 mg, 6.97 μmol, 1.00 equiv.) and Target A093 (11.8 mg, 27.9 μmol, 4.00 equiv.) in DMF (1 ml) was added CuSO4(0.4 M, 52.3 μL, 20.9 μmol, 3.00 equiv.), sodium ascorbate (0.4 M, 156.8 μL, 62.7 μmol, 9.0 equiv.) and THPTA (trishydroxypropyltriazolylmethylamine (9.09 mg, 20.9 μmol, 3.00 equiv.) under nitrogen atmosphere at 0°C, and the resulting mixture was stirred for 3 h at 0 °C. After completion monitored by LC-MS, the reaction was filtered off and purified by prep-HPLC (A: 0.075% TFA / H2O; B: MeCN), followed by lyophilization to afford BH0003844 (7.1 mg, 93.2% purity, 27.1% yield) as a white solid. LCMS: RT = 0.82 min, MS calcd.: Mav, = 3496.87, mass observed: [M + 2H]2+= 1748.40, [M + 3H]3+= 1166.17, [M + 4H]4+= 874.88.EXAMPLE 22. Procedure for Preparation of BH2640 (Fdll-GN3).[01801 Preparation of Intermediate 96:

[0181] To a solution of 95a (60.0 g, 400 mmol, 2.00 equiv.) in 2-Methyltetrahydrofuran (450 ml) was added 95 (34.2 g, 200 mmol, 1.00 equiv.) in 2-Methyltetrahydrofuran (160 ml) at 0 °C. The mixture was stirred at 25 ºC for 2 h. TLC (DCM: MeOH = 20: 1, Rf= 0.70) showed the reaction was completed, one major new spot with lower polarity was detected. The reaction mixture was added HCI / EA (1 N, 27.0 ml) and stirred for 30 min, and the white precipitate was removed by filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 96 (crude, 105.0 g, 370.6 mmol) as yellow oil. LCMS: RT = 0.797 min, MS cal.: 283.14, mass observed: [M + Na]+= 306.1.1H NMR (400 MHz, DMSO-d6) δ ppm 7.23 - 7.41 (m, 5 H), 5.01 (s, 2 H), 4.60 (br s, 1 H), 3.45 - 3.52 (m, 6 H), 3.38 - 3.43 (m, 5 H), 3.14 (q, J = 5.94 Hz, 2H), 2.53 - 2.55 (m, 1 H).

[0182] Preparation of Intermediate 97:

[0183] To a solution of 96a (100.0 g, 257 mmol, 1.00 equiv.) in DCE (500 ml) was added TMSOTf(85.6 g, 385 mmol, 1.50 equiv.) and stirred at 60 ºC for 2 h. The reaction was then cooled to room temperature (25 °C) and stirred for another 1 h. A mixture of Intermediate 96 (80.0 g, 282 mmol, 1.10 equiv.) and 4 A powder molecular sieves (50.0 g) in DCE (500 ml) was added to the reaction. The resulting mixture was stirred for 30 min under N2atmosphere. Then a solution of Intermediate 96a (100.0 g, 257 mmol, 1.00 equiv.) in DCE was added dropwise to the mixture at 0 °C. The mixture was stirred for 16 h at25 ºC under N2atmosphere. TLC (DCM: MeOH = 10: 1, Rf= 0.42) indicated Intermediate 96a was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was filtered and washed with sat. NaHCO3(500 ml), water (500 ml) and brine (500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 3: 1 to 1: 6, then DCM: MeOH = 20: 1) to affordIntermediate 97 (90.0 g, 146.9 mmol, 91.6% purity, 57.2% yield) as yellow oil. LCMS: RT = 0.860 min, MScal.: 612.25, mass observed: [M + H]+= 613.2.1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J = 9.03 Hz, 1H), 7.24 - 7.39 (m, 6 H), 5.22 (d, J = 3.51 Hz, 1 H), 4.95 - 5.05 (m, 3 H), 4.53 - 4.59 (m, 1 H), 3.99 - 4.06 (m,3 H), 3.84 - 3.92 (m, 1 H), 3.73 - 3.82 (m, 1 H), 3.55 - 3.61 (m, 1 H), 3.45 - 3.53 (m, 7 H), 3.41 (t, J = 5.90 Hz,2 H), 3.11 - 3.18 (m, 3 H), 2.10 (s, 3 H), 1.99 (s, 3 H), 1.89 (s, 3 H), 1.77 (s, 3 H).

[0184] Preparation of Intermediate 98:

[0185] Pd / C (9.00 g, 10% purity) in reaction bottle (purged with Ar for three times) was addedTHF (180 ml) slowly, then a solution of TFA (16.7 g, 147 mmol, 1.00 equiv.) and Intermediate 97 (90.0 g,147.0 mmol, 1.00 equiv.) in THF (720 ml) was added to the reaction slowly under N2. The reaction was degassed and purged with N2and Hz for three times, then stirred at 25 °C for 3 h under Hz atmosphere(40 psi). TLC (DCM: MeOH = 10: 1, Rf= 0.20) indicated Intermediate 97 was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was dissolved in THF (100 ml), filtered carefully through siliceous earth under N2atmosphere, the cake was washed with THF (100 ml * 2), and the filtrate was concentrated under reduced pressure to get the residue. The residue was diluted with water (1000 ml), washed with DCM (300 ml * 3), the aqueous layer was lyophilized to affordIntermediate 98 (80.0 g, 139.0 mmol, 95.1% purity, 91.8% yield, TFA salt) as a white solid. LCMS: RT = 0.484 min, MS cal.: 478.22, mass observed: [M + H]+= 478.9.1H NMR (400 MHz, DMSO-d6δ) ppm 7.91 (br t, J = 9.03 Hz, 4 H), 5.21 (d, J = 3.26 Hz, 1 H), 4.96 (dd, J = 11.17, 3.39 Hz, 1 H), 4.54 (d, J = 8.53 Hz, 1 H),3.98 - 4.08 (m, 3 H), 3.85 - 3.93 (m, 1 H), 3.75 - 3.84 (m, 1 H), 3.59 (hr t, J = 5.14 Hz, 3 H), 3.50 - 3.56 (m, 6H), 2.98 (br s, 2 H), 2.10 (s, 3 H), 2.00 (s, 3 H), 1.89 (s, 3 H), 1.78 (s, 3 H).

[0186] Preparation of Intermediate 100:

[0187] To a mixture of 99 (60.0 g, 495.0 mmol, 1.00 equiv.) in DMSO (166 ml) was added aqueousNaOH (5.0 M, 9.91 ml, 0.10 equiv.) dropwise at 0-15 °C for over 5 min. After addition, the mixture was stirred at 0-15 ºC for 5 min, then 99a (254.0 g, 1.98 mol, 287 mL 4.00 equiv.) was added to the reaction mixture dropwise at 20 "C. The resulting mixture was stirred at 25 ºC for 16 h. TLC (DCM: MeOH = 10: 1, Rf= 0.7) indicated Intermediate 99 was consumed completely, and one major new spot with lower polarity was detected. The resulting reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (400 ml), quenched by addition of water (400 ml), and extracted with EtOAc (400 ml * 3). The combined organic layers were washed with brine (300 ml * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford Intermediate 100 (100.0 g, 197.8 mmol, 96.0% purity, 40.0% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 3.51 - 3.61(m, 7 H), 3.17 (s, 5 H), 2.39 (t, J = 6.02 Hz, 6 H), 1.40 (s, 27 H).

[0188] Preparation of Intermediate 101:

[0189] To a solution of Intermediate 100 (40.0 g, 79.1 mmol, 1.00 equiv.) in MeCN (400 ml) was added HOBt (10.7 g, 79.1 mmol, 1.00 equiv.). Then 100a (16.5 g, 79.1 mmol, 1.00 equiv.) and DCC (16.3 g,79.1 mmol, 1.00 equiv.) were added. The reaction was stirred at 25 °C for 16 h. TLC (PE: EA = 1: 1, Rf=0.80) indicated Intermediate 100 was consumed completely, and one major new spot with lower polarity was detected. MeCN was evaporated to get the residue. The residue was purified by column chromatography (SiO2, PE: EA = 10: 1 to 1: 1) to afford Intermediate 101 (40.0 g, 57.4 mmol, 82.9% purity,72.5% yield) as a white solid. LCMS: RT = 1.151 min, MS cal.: 696.38, mass observed: [M + H]+= 697.3, [M+ Na]+= 719.3.1H NMR (400 MHz, DMSO-d6) δ ppm 7.26 - 7.40 (m, 6 H), 7.06 (s, 1 H), 5.03 (s, 2 H), 3.49 -3.61 (m, 14 H), 2.39 (br t, J = 6.02 Hz, 6 H), 1.40 (s, 27 H).

[0190] Preparation of Intermediate 102:

[0191] A solution of Intermediate 101 (30.0 g, 43.0 mmol, 1.00 equiv.) in HCOOH (300 ml) was stirred at 25 °C for 16 h. TLC (PE: EA = 1: 1, Rf= 0.04) indicated Intermediate 101 was consumed completely, and one major new spot with larger polarity was detected. Solvent was evaporated under reduced pressure, then co-evaporated with toluene (50 ml * 3) under reduced pressure, and dried under reduced pressure to get the residue. The residue was purified by prep-HPLC (A: 0.1% FA condition / H2O, B: MeCN) to afford Intermediate 102 (20.0 g, 37.8 mmol, 98.2% purity, 87.9% yield).1H NMR (400 MHz,DMSO-d6) δ ppm 12.17 (br s, 3 H), 7.26 - 7.43 (m, 6 H), 7.06 (s, 1 H), 5.02 (s, 2 H), 3.49 - 3.65 (m, 14 H),2.42 (br t, J = 6.27 Hz, 6 H). LCMS: RT = 0.790 min, MS cal.: 528.20, mass observed: [M + H]+= 529.2.

[0192] Preparation of Intermediate 103:

[0193] To a stirring solution of Intermediate 102 (20.0 g, 37.8 mmol, 1.00 equiv.) andIntermediate 98 (78.5 g, 132 mmol, 3.50 equiv., TFA salt) in DMF (400 ml) was added HOBT (20.4 g, 151 mmol, 4.00 equiv.), EDCI (29.0 g, 151 mmol, 4.00 equiv.) and DIEA (22.0 g, 170 mmol, 4.50 equiv.) successively. The reaction was stirred at 25 ºC for 2 h. TIC (DCM: MeOH = 10: 1, Rf= 0.4) indicatedIntermediate 102 was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was slowly poured into a stirring cold 0.5 mol / L HCI solution (900 ml), and stirred for 10 min. White precipitate was formed and filtered, the aqueous phase was extracted with DCM (600 ml* 2) twice. The combined organic layers were washed with 5% NaHCO3(450 ml), dried over Na2SO4, and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100: 1 to 5: 1) to afford Intermediate 103 (58.0 g, 30.4 mmol, 82.7% purity, 80.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 ppm 7.92 (br t, J = 5.14 Hz, 3 H), 7.81 (d, J = 9.03 Hz, 3 H), 7.28 - 7.39 (m, 6 H), 7.13 (s, 1 H), 5.21 (d, J = 3.26 Hz, 3 H), 5.02 (s, 2 H), 4.97 (dd, J =11.17, 3.39 Hz, 3 H), 4.54 (d, J = 8.53 Hz, 3 H), 4.03 (s, 9 H), 3.84 - 3.92 (m, 3 H), 3.75 - 3.81 (m, 3 H), 3.45 -3.61 (m, 37 H), 3.39 (br s, 3 H), 3.18 - 3.23 (m, 6 H), 2.30 (br t, J=6.15 Hz, 6 H), 2.10 (s, 9 H), 2.00 (s, 9 H), 1.89 (s, 9 H), 1.77 (s, 9 H). LCMS: RT = 3.455 min, MS cal.: 1908.81, mass observed: [M + 2H]2+= 955.7.

[0194] Preparation of Intermediate 104:

[0195] Pd / C (4.6 g, 25.13 mmol, 10% purity, 1.00 equiv.) in reaction bottle (purged with N2for three times) was added MeOH (230 ml) slowly, then a solution of TFA (2.75 g, 24.1 mmol, 1.00 equiv.) and Intermediate 103 (46.0 g, 24.1 mmol, 1.00 equiv.) in MeOH (230 ml) was added to the reaction slowly under N2atmosphere. The reaction was degassed and purged with N2and Hz for three times, stirred at 25 ºC for 2 h under Hz atmosphere (15 psi). TLC (DCM: MeOH = 10: 1, Rf= 0.3) indicated Intermediate 103 was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was dissolved in MeOH (250 ml), filtered carefully through siliceous earth under N2atmosphere, the cake was washed with MeOH (250 ml * 2), and the filtrate was concentrated under reduced pressure to afford Intermediate 104 (crude, 42.0 g, 22.4 mmol, 94.1% purity, 92.2% yield, TFA salt) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 (br t, J = 5.44 Hz, 6 H), 7.81 - 7.88 (m, 3 H), 7.73 - 7.77 (m, 1 H),5.19 - 5.26 (m, 3 H), 4.97 (dd, J = 11.13, 3.38 Hz, 3 H), 4.52 - 4.61 (m, 3 H), 3.99 - 4.06 (m, 10 H), 3.84 - 3.93(m, 4 H), 3.74 - 3.82 (m, 4 H), 3.46 - 3.61 (m, 42 H), 3.38 - 3.42 (m, 8 H), 3.19 - 3.24 (m, 6 H), 2.28 - 2.34 (m,6 H), 2.08 - 2.12 (m, 9 H), 1.98 - 2.02 (m, 9 H), 1.87 - 1.90 (m, 9 H), 1.75 - 1.80 (m, 9 H). LCMS: RT = 1.585 min, MS cal.: 1774.78, mass observed: [M + H]+= 1775.7, [M + 2H]2+= 888.7.

[0196] Preparation of Intermediate 105:

[0197] DIEA (8.62 g, 66.6 mmol, 3.00 equiv.), EDCI (6.69 g, 33.3 mmol, 1.50 equiv.) and HOBt(6.38 g, 33.3 mmol, 1.50 equiv.) were added to the solution of Intermediate 104 (42.0 g, 22.2 mmol, 1.00 equiv., TFA salt) and 104a (7.77 g, 33.3 mmol, 1.50 equiv.) in DMF (420 ml). The mixture was stirred at 25 ºC for 2.0 h. LCMS indicated Intermediate 104 was consumed completely, several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was slowly poured into a stirring 0.5 mol / L MCI solution (cold, 500 ml). The aqueous phase was extracted with DCM (500 ml * 3). The combined organic layers were washed with 5% NaHCO3(500 ml), dried over Na2SO4, then concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH= 100: 1 to 5: 1) to afford Intermediate 105 (34.0 g, 17.1 mmol, 93.3% purity, 77.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.88 - 7.94 (m, 3 H), 7.78 - 7.83 (m, 3 H), 7.71 - 7.76 (m, 1 H), 7.21 - 7.26 (m, 1 H), 5.19 - 5.23 (m, 3 H), 4.94 - 5.02 (m, 3 H), 4.51 - 4.59 (m, 3 H), 4.00 - 4.06 (m, 9 H), 3.91 - 3.93(m, 2 H), 3.84 - 3.90 (m, 3 H), 3.72 - 3.81 (m, 5 H), 3.46 - 3.63 (m, 46 H), 3.37 - 3.43 (m, 9 H), 3.18 - 3.23 (m,6 H), 2.27 - 2.34 (m, 6 H), 2.09 - 2.12 (m, 9 H), 1.98 - 2.01 (m, 9 H), 1.88 - 1.90 (m, 9 H), 1.75 - 1.79 (m, 9 H). LCMS: RT = 0.501 min, MS cal.: 1989.87, mass observed: [M + 2H]2+= 996.3.

[0198] Preparation of Target A043:

[0199] To a solution of Intermediate 105 (34.0 g, 12.6 mmol, 1.00 equiv.) in MeOH (400 ml) was added NaOMe (5.4 M in MeOH, 9.91 ml, 4.26 equiv.) at 0 °C. Then the solution was stirred at 0 °C for 0.5 h. LCMS indicated Intermediate 105 was consumed completely, several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was adjusted pH to 6 with 1.0 M HCI solution at 0 °C, and washed with DCM (250 ml * 3) for three times, the aqueous layer was lyophilized to afford Target A043 (crude, containing NaCI, 20.0g, 12.4 mmol, 96.3% purity) as a white solid.1H NMR (400 MHz,DMSOd6) 6 ppm 7.92 - 7.98 (m, 3 H), 7.73 - 7.77 (m, 1 H), 7.61 - 7.65 (m, 3 H), 7.22 - 7.27 (m, 1 H), 4.59 -4.64 (m, 3 H), 4.55 - 4.58 (m, 3 H), 4.49 - 4.52 (m, 3 H), 4.25 - 4.31 (m, 3 H), 3.90 - 3.94 (m, 2 H), 3.68 - 3.81 (m, 9 H), 3.63 - 3.67 (m, 4 H), 3.59 - 3.62 (m, 6 H), 3.58 - 3.62 (m, 7 H), 3.38 - 3.41 (m, 13 H), 3.17 - 3.24 (m,7 H), 2.28 - 2.34 (m, 7 H), 1.78 - 1.82 (m, 9 H). LCMS: RT = 0.501 min, MS cal.: 1611.77, mass observed: [M + H]+= 1612.8, [M + 2H]2+= 807.2.

[0200] Preparation of Intermediate 107:

[0201] Peptide was synthesized using standard Fmoc chemistry (Rink AM resin).1) Resin preparation: To the vessel containing Rink Amide AM resin (624.80 g, 200.00 mmol, 0.32 mmol / g) and DMF (2 L) was bubbled with N2for 2 h at 25 °C Then 20% piperidine in DMF (4 L) was added and the mixture was bubbled with N2for 30 min at 25 °C. The mixture was filtered and washed with DMF(4 L) * 5 before proceeding to next step.2) Coupling: A solution of Fmoc-Thr(tBu)-OH (238.00 g, 600.00 mmol, 3.00 equiv.), DIC (75.60 g,600.00 mmol, 3.00 equiv.), HOBt (81.20 g, 600.00 mmol, 3.00 equiv.) in DMF (2 L) was added to the resin with N2bubbling for 1 h at 25 °C. The coupling reaction was monitored by ninhydrin test. The resin was then washed with DMF (4 L) * 5.3) Deprotection: 20% piperidine in DMF (2 L) was added to the resin and the mixture was bubbled with N2for 30 min at 25 ºC. The resin was then washed with DMF (4 L) * 5.4) Steps 2 and 3 were repeated for the following amino acids elongation: Number # 2-14, Table 15.5) After all the steps were completed, the resin was washed with DMF (4 L) * 5, MeOH (4 L) * 5, then dried under reduced pressure to afford resin-bound peptide (Rink AM resin, 450.5 g, 200 mmol).Table 15: The list of amino acids and the corresponding reagents used on SPPS.

[0202] Peptide cleavage and cyclization.1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 5 L) was added to the flask containing the sidechain protected resin-bound peptide (Rink AM resin, 450.5 g, 200 mmol) at 25 °C and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (30 L). After filtration, the solid was washed with isopropyl ether (5 L) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 106 (320.0 g, crude) as a white solid.4) To the mixture of Intermediate 106 (320.0 g, crude) in HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 70 L) was added 0.1 M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 °C for 5 min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 107 (109.0 g, 90.7% purity, 30.4% yield) as a white solid. LCMS: RT = 10.492 min, MS calcd.: Mav= 1623.85, mass observed: [M + H]' = 1625.57, [M + 2H]2+= 813.02.5) Another 200 mmol resin was performed to afford Intermediate 107 as 107.8 g.

[0203] Preparation of BH0002640 (Fdl-GN3):

[0204] A mixture of Target A043 (15.0 g, crude, 9.30 mmol, 1.00 equiv.) and Intermediate 107 (8.86 g, 5.46 mmol, 1.00 equiv.) in NH4HCO3(0.2 M, 100 ml, 3.67 equiv.) and t-BuOH (100 ml) was addedCUSO4.5H2O (0.4 M, 13.64 ml, 1.00 equiv.) and sodium ascorbate (4.32 g, 21.8 mmol, 4.00 equiv.). The resulting reaction was degassed and purged with N2for three times. Then the mixture was stirred at 25"C for 0.5 h under N2atmosphere. LC-MS showed Target A043 was consumed completely, several new peaks were shown on LC-MS and desired compound was detected. The resulting reaction mixture was lyophilized to get a residue. The residue was purified by prep-HPLC (A: 0.075% HOAc in H2O, B: MeCN) to afford BH0002640 (7.0 g, 2.16 mmol, 98.4% purity, 23.2% yield, 0.42% TFA content, < 0.05% HOAc content, 2.00% water content) as a white solid. LCMS: RT = 1.554 min, MS cal.: 3234.47, mass observed: [M + H]+= 3235.44, [M + 2H]2+= 1618.72.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.71 (br s, 2 H), 8.66 (br s,2 H), 8.19 - 8.39 (m, 5 H), 8.15 (br d, J = 7.28 Hz, 1 H), 8.05 (br s, 2 H), 7.95 (br t, J = 5.65 Hz, 3 H), 7.70 - 7.87 (m, 6 H), 7.62 (d, J = 9.03 Hz, 3 H), 7.52 (br d, J = 8.03 Hz, 1 H), 7.42 (br d, J = 7.53 Hz, 1 H), 7.22 - 7.29(m, 4 H), 7.18 (br s, 1 H), 7.11 (br s, 1 H), 7.07 (br s, 1 H), 7.01 (q, J = 7.45 Hz, 2 H), 6.88 - 6.94 (m, 3 H), 4.87(br s, 2 H), 4.61 - 4.82 (m, 7 H), 4.52 (br s, 5 H), 4.45 (br t, J = 5.14 Hz, 3 H), 4.31 - 4.41 (m, 3 H), 4.28 (d, J =8.53 Hz, 5 H), 4.09 - 4.18 (m, 2 H), 3.94 - 4.09 (m, 3 H), 3.91 (s, 3 H), 3.75 - 3.82 (m, 6 H), 3.73 (br d, J = 8.53Hz, 4 H), 3.67 - 3.70 (m, 2 H), 3.64 (br d, J = 2.76 Hz, 4 H), 3.51 - 3.59 (m, 27 H), 3.43 (br d, J = 3.01 Hz, 3 H), 3.39 (br t, J = 5.77 Hz, 10 H), 3.30 (br t, J = 6.15 Hz, 6 H), 3.20 (q, J = 5.94 Hz, 9 H), 3.09 (br d, J = 14.31 Hz,4 H), 2.92 (br s, 10 H), 2.73 (br s, 1 H), 2.58 (br t, J = 7.53 Hz, 3 H), 2.30 (br t, J = 6.27 Hz, 6 H), 2.18 (br s, 4 H), 1.90 - 1.98 (m, 1 H), 1.86 (s, 1 H), 1.80 (s, 12 H), 1.26 - 1.58 (m, 6 H), 1.15 (br d, J = 6.78 Hz, 3 H), 1.03(br d, J=6.27 Hz, 3 H), 0.81 (br d, J = 6.27 Hz, 3 H), 0.77 (br d, J = 6.02 Hz, 6 H), 0.66 - 0.74 (m, 6 H), 0.63 (br d, J = 6.53 Hz, 3 H).EXAMPLE 23. Procedure for Preparation of BH-0003924.

[0205] Intermediate 108 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 16.Table 16: The list of amino acids and the corresponding reagents used on SPPS.

[0206] Cleavage and Cyclizaiton.1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 ml) was added to the flask containing the side-chain protected resin-bound peptide Intermediate 108 (Rink AM resin, 1.87 g, 0.50 mmol) at 25 ºC and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (150 ml). After filtration, the solid was washed with isopropyl ether (150 ml) twice, and the crude peptide was dried under reduced pressure for2 h to afford Intermediate 108 (793 mg, crude) as a white solid.

[0207] To a mixture of Intermediate 108 (793 mg, crude) in MeCN / H2O (4 / 6, v / v / , 500 ml) was added CH2I2(15.0 equiv.) and Et3N (6.00 equiv.), then the mixture was stirred at 25 °C for 8 h under N2.The mixture was quenched by addition of 1 M HCI. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford BH-0003924 (94.0 mg, 96.4% purity,11.4% yield) was obtained as a white solid after lyophilization. LCMS: RT = 1.41 min, MS calcd.: Mav= 1585.80, mass observed: [M + H]+= 1586.80, [M + 2H]2+= 793.6.EXAMPLE 24. Procedure for Preparation of BH-0003925.

[0208] Intermediate 109 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0048] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 17.Table 17: The list of amino acids and the corresponding reagents used on SPPS.

[0209] BH-0003925 (peptide cleavage, disulfide formation) was synthesized by following the procedure mentioned in section

[0049] . 0.50 mmol resin afforded BH-0003925 (80.6 mg, 97.8% purity,8.60% yield) was obtained as a white solid after lyophilization. LCMS: RT = 1.38 min, MS calcd.: Mav= 1833.05, mass observed: [M + H]+= 1834.0, [M + 2H]2+= 917.2.EXAMPLE 25. Procedure for Preparation of BH-0003174.

[0210] Intermediate 120 (resin-bound peptide) was synthesized by following the procedure mentioned in section

[0059] . SPPS (0.50 mmol loading resin) was performed with amino acids elongation shown in Table 18.Table 18: The list of amino acids and the corresponding reagents used on SPPS.

[0211] BH-0003174 (peptide cleavage, disulfide formation) was synthesized by following the procedure mentioned in section

[0060] . 0.5 mmol resin afforded BH-0003174 (93 mg, 94.6% purity, 11.6% yield) as a white solid. LCMS: RT = 0.81 min, MS calcd.: Mav= 1521.76, mass observed: [M + H]+= 1521.76, [M + 2H]2+= 761.50EXAMPLE 26. Procedure for Preparation of BH-0003747. VDNKFNKEQQNAFYEILHLPNLNEEQRNAFIQSLKDDPSQSANLLAEAKKLNDAQAPK

[0212] BH-0003747 was synthesized by following the procedure mentioned in section

[0059] .SPPS (1.00 mmol resin) was performed with amino acids elongation shown in Table 19, Number # 1-58.Table 19: The list of amino acids and the corresponding reagents used on SPPS.

[0213] Peptide cleavage.1) Cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 250 ml) was added to the flask containing the side-chain protected resin-bound peptide, 7.89 g, 1.00 mmol) at 25 ºC and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (600 ml). After filtration, the solid was washed with isopropyl ether (600 ml) twice, and the crude peptide was dried under reduced pressure for2 h to afford BH-0003747 (6.53 g, crude) as a white solid.4) The crude BH-0003747 was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford BH-0003747 (547.1 mg, 97.8% purity, 8.05% yield) as a white solid. LCMS: RT = 0.72 min, MS calcd.: Mav = 6640.26, mass observed: [M + 4H]4+= 1660.80, [M + 5H]5+= 1328.90,[M + 6H]6+= 1107.70, [M + 7H]7+= 949.52, [M + 8H]8+= 830.90, [M + 9H]9+= 738.80, [M + 11H]11+= 604.61, [M + 12H]12+=554.30.EXAMPLE 27. Procedure for Preparation of BH-0003784.

[0214] Intermediate 121 was synthesized by following the procedure mentioned in section

[0059] SPPS (1.00 mmol resin) was performed with amino acids elongation shown in Table 20, Number # 1-59.Table 20: The list of amino acids and the corresponding reagents used on SPPS.

[0215] Peptide cleavage and fragment coupling.1) Cleavage from resin: A solution of 20% HFIP / DCM (50 ml) was added to the resin above at room temperature and stirred for 1 h. After filtration, the filtrate was collected and concentrated under reduced pressure to afford fully protected peptide Intermediate 121 (6.51 g, crude) as a white solid.2) Fragments coupling: To the mixture of Intermediate 121 (1.40 g, crude, 122.0 μmol, 1.00 equiv.),Target A101 (120.9 mg, 244.0 mmol, 2.00 equiv.), HOBt (49.4 mg, 366.0 mmol, 3.00 equiv.) in DMF (2.0 ml) was added EDCI (69.9 mg, 366.0 mmol, 3.00 equiv.) at 0 ºC. The resulting reaction was stirred for 8 h at 25 "C. The reaction was added into flask with cold 0.1 M HCI (30 ml), and the precipitate was filtered off to afford the crude as Intermediate 122.3) Deprotection: A solution ofTFA / TIS / H2O / 3-mercaptopropanoic acid (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 20 ml) was added to the flask containing Intermediate 122 (crude) in step 2, and the resulting mixture was stirred for 1 h at 25 °C. The mixture was precipitated with cold isopropyl ether (100 ml), then filtered off, and the solid was washed with isopropyl ether (50 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 123 (845 mg, crude) as a white solid.5) The crude Intermediate 123 was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 123 (120 mg, 13.8% yield) as a white solid.

[0216] Preparation of BH0003784 (dick reaction):

[0217] Click reaction BH0003784 was synthesized using the same procedure as BH0003610, which was performed by following the procedure mentioned in

[0050] -

[0051] .

[0218] 30.2 mgof Target A093 afforded BH0003784 (92 mg, 90.7% purity, 58.5% yield) as a white solid. LCMS: RT =1.26 min, MS calcd.: Mav= 8463.21, mass observed: [M + 5H]5+= 1693.6, [M + 6H]6+= 1411.6, [M + 7H]7+= 1210.1, [M + 8H]8+= 1058.9, [M + 9H]9+= 941.5, [M + 10H]10+=847.3,[M + 11H]11+= 770.5, [M + 12H]12+=706.2, [M + 13H]13+= 652.1, [M + 14H]14+= 605.5.EXAMPLE 28. Procedure for Preparation of Target A041Jntermediate 2.

[0219] Preparation of Target A041_lntermediate 2;

[0220] To a solution of Intermediate 104A (100 mg, 263.57 umol, 1 equiv.) in DMF (2 ml) was added HATU (110.24 mg, 289.93 umol, 1.1 equiv.) and DIEA (102.19 mg, 790.71 umol, 137.73 uL, 3 equiv.) at 0ºC and the reaction was stirred for 0.5 h at 0ºC. Then Intermediate 104 (514.85 mg, 289.93 umol, 1.1 equiv.) was added at 0 °C and the reaction was stirred 0.5 h at 0 ºC. TLC showed the reaction was completed. The reaction was poured into H2O (20 ml) and extracted with DCM (10 ml x 2). The combined organic layer was washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO2, dichloromethane: methanol = 100: 1 to 10: 1) to give Target 041_lntermediate 2(310 mg, 145.05 umol, 55.03% yield, 100% purity) as yellow solid. LCMS: RT = 2.596 min, MS cal.: 2135.9, found: [M / 3 + H]+= 713.2.1H NMR (400 MHz, MeOH-d4) 6 ppm = 5.34 (d, J =3.07 Hz, 3 H), 5.07 (dd, J=11.18, 3.07 Hz, 3 H), 4.65 (d, J =8.55 Hz, 3 H), 4.00 - 4.20 (m, 12 H), 3.91 - 3.99 (m, 3 H), 3.86 (s, 2 H), 3.60- 3.79 (m, 59 H), 3.54 - 3.59 (m, 6 H), 3.39 (br t, J =4.93 Hz, 8 H), 2.42 - 2.48 (m, 6 H), 2.15 (s, 9 H), 2.03 (s,9 H), 1.95 (d, J =5.92 Hz, 18 H). Theoretical number of H: 149, found: 141, exchangeable H: 8.EXAMPLE 29 Procedure for Preparation of Target A042.

[0221] Preparation of Intermediate 124:[02221 To a solution of Intermediate 104B (100 mg, 343.29 umol, 1 equiv.) in DMF (20 ml) was added HATU (143.58 mg, 377.62 umol, 1.1 equiv.) and DIEA (133.10 mg, 1.03 mmol, 179.38 uL, 3 equiv.) at 0 °C and the reaction was stirred for 0.5 h at 0 ºC. Then Intermediate 104 (609.61 mg, 343.29 umol, 1 equiv.) was added at 0 °C and the reaction was stirred for 0.5 h at 0 ºC. TLC showed the reaction was completed. The reaction was poured into H2O (50 ml) and extracted with DCM (30 ml x 2). The combined organic layer was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO2, dichloromethane: methanol = 100: 1 to 10: 1) to give Intermediate 124 (200 mg,97.60 umol, 28.43% yield) as white solid. LCMS: RT = 1.821 min, MS cal.: 2049.1, found: [M / 2 + H]+= 1025.6.1H NMR (400 MHz, MeOH-d4 ) = δ.534 (d, J = 3.1 Hz, 3H), 5.07 (dd, J = 3.3, 11.2 Hz, 3H), 4.65 (d, J= 8.5 Hz, 3H), 4.17 - 4.00 (m, 13H), 3.97 - 3.91 (m, 3H), 3.77 - 3.60 (m, 52H), 3.58 - 3.53 (m, 6H), 3.39 (br t,J = 5.0 Hz, 8H), 2.45 (t, J = 6.0 Hz, 6H), 2.15 (s, 9H), 2.03 (s, 9H), 1.95 (d, J = 5.8 Hz, 18H). Theoretical number of H: 141, found: 133, exchangeable H: 8.

[0223] Preparation of Target A042[02241 To a solution of Intermediate 124 (230 mg, 112.25 umol, 1 equiv.) in MeOH (3 ml) was added NaOMe (3.03 mg, 56.12 umol, 0.5 equiv.). The mixture was stirred at 20 ºC for 1 h. LCMS showedReactant 1 was consumed and one new peak of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give Target A042 (183.04 mg, 109.56 umol, 97.60% yield) as yellow oil. LCMS: RT = 0.553 min, MS cal.: 1669.81, [M / 2+H]+= 836.3.1H NMR (400 MHz,MeOD) δ = 4.44 (d, J = 8.4 Hz, 3H), 4.00 - 3.91 (m, 6H), 3.88 (s, 2H), 3.84 (d, J = 2.9 Hz, 3H), 3.76 (t, J = 6.4Hz, 7H), 3.70 - 3.67 (m, 14H), 3.61 - 3.61 (m, 1H), 3.67 - 3.60 (m, 33H), 3.59 - 3.54 (m, 8H), 3.51 (t, J = 6.1Hz, 4H), 3.42 - 3.36 (m, 8H), 2.55 (t, J = 6.2 Hz, 2H), 2.45 (t, J = 6.0 Hz, 6H), 1.99 (s, 9H). Theoretical number of H: 123, found: 106, exchangeable H: 17.EXAMPLE 30 Procedure for Preparation of Target A044

[0225] Preparation of Intermediate 91:[0226J To a solution of Intermediate 104C (80 mg, 422.90 umol, 1.0 equiv.) in DMF (10 ml) was added HATU (176.88 mg, 465.19 umol, 1.1 equiv.) and DIEA (163.97 mg, 1.27 mmol, 220.98 uL, 3.0 equiv.) at OºC and the reaction was stirred for 0.5 h at OºC. Intermediate 104 (750.99 mg, 422.90 umol, 1.0 equiv.) was added to the reaction mixture at O ºC and the reaction was stirred for 0.5 h at OºC. TLC showed the reaction was completed. The reaction was poured into H2O (100 ml) and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine (40 ml), dried over anhydrous Na2SO4filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 10 / 1) to give Intermediate 125 (270 mg, 32.79% yield) as colorless oil. LCMS: RT = 1.750 min, MS cal.: 1946.9, [M / 2+H]4= 974.5.1H NMR (400 MHz,MeOH-d4) 6 = 5.32 (d, J = 3.1 Hz, 3H), 5.06 (dd, J = 3.5, 11.2 Hz, 3H), 4.63 (d, J = 8.3 Hz, 3H), 4.16 - 4.00 (m,14H), 3.95 - 3.95 (m, 1H), 3.95 - 3.90 (m, 5H), 3.73 - 3.60 (m, 39H), 3.56 - 3.52 (m, 6H), 3.42 - 3.36 (m, 8H),2.43 (t, J = 6.0 Hz, 6H), 2.13 (s, 9H), 2.01 (s, 9H), 1.93 (d, J = 6.1 Hz, 18H) Theoretical number of H:133, found: 125, exchangeable H: 8.

[0227] Preparation of Target A044

[0228] To a solution of Intermediate 125 (270.00 mg, 138.68 umol, 1.0 equiv.) in MeOH (3 mL) was added NaOMe (7.49 mg, 138.68 umol, 1.0 equiv.). The mixture was stirred at 20 ºC for 1 h. LCMS showed Reactant 1 was consumed, and one new peak of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give Target A044 (205.41 mg, 130.95 umol, 94.43% yield) as a white solid. LCMS: RT = 1.833 min, MS cal.: 1567.75, [M / 2+H]+= 785.0.1H NMR(400MHz, MeOD) δ = 4.44 (d, J =8.4 Hz, 3H), 4.08 (s, 2H), 4.00 - 3.91 (m, 8H), 3.84 (d, J =3.1 Hz, 3H), 3.79 -3.73 (m, 8H), 3.73 - 3.68 (m, 18H), 3.66 - 3.60 (m, 20H), 3.59 - 3.53 (m, 8H), 3.52 - 3.48 (m, 3H), 3.44 - 3.38(m, 8H), 2.45 (t, J =6.0 Hz, 6H), 1.99 (s, 9H). Theoretical number of H: 113, found: 96, exchangeable H: 17.EXAMPLE 31. Procedure for Preparation of Target A094

[0229] Preparation of Intermediate 126:

[0230] To a solution of Intermediate 96a (5.00 g, 12.84 mmol, 1.00 equiv.) in DCM (500 ml) was added FeCl3(6.25 g, 38.53 mmol, 2.23 ml, 3.00 equiv.). The mixture was stirred at 25 "C for 3 h. TLC(DCM: MeOH = 10:1, Starting material Rf= 0.6, product Rf= 0.7) showed the one new point was detected and the reactant was consumed. The reaction mixture was diluted with DCM (100 ml) and extracted withH2O (500 ml * 5). The combined organic layers were washed with brine (200 ml * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford Intermediate 126 (4.10 g, crude) as white solid, which was used in the next step without further purification.

[0231] Preparation of Intermediate 127:

[0232] To a solution of Intermediate 126 (4.10 g, 12.45 mmol, 1.00 equiv.) and Intermediate126A (2.59 g, 12.45 mmol, 1.00 equiv.) in DCM (80 ml) was added TMSOTf (830.17 mg, 3.74 mmol, 674.94 uL, 0.30 equiv.) and 4A molecular sieves (4.10 g) at 0 "C. The mixture was stirred at 25 "C for 12 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was diluted with H2O(200 ml) and extracted with DCM (200 ml *3). The combined organic layers were washed with brine (200 ml * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 30 / 1) to give Intermediate127 (3.60 g, 6.70 mmol, 53.79% yield) as a yellow solid. LCMS: RT = 1.970 min, MS cal.: 537.2, found: [M - H]+= 536.2.1H NMR (400 MHz, DMSO-d6) 6 = 7.810-7.787 (d, J = 9.2 Hz, 1H), 7.373 - 7.322 (m, 6H),5.212(s, 1H), 5.203(s, 1H), 5.078 - 4.934 (m, 1H), 4.490 - 4.469 (d, J = 8.4 Hz, 1H), 3.722 - 3.697(m, 5H),3.431 - 3.406 (m, 1H), 2.373-2.337 (m, 2H), 2.097 (s, 3H), 1.990 (s, 3H), 1.888 (s, 3H), 1.738 (s, 3H), 1.574- 1.488 (m, 4H). Theoretical number of H: 35, found: 35.

[0233] Preparation of Intermediate 128:

[0234] To a solution of Intermediate 127 (3.00 g, 5.58 mmol, 1.00 equiv.) in THF (90 mL) was added Pd / C (1.00 g, 10% purity) and TFA (63.63 mg, 558.08 umol, 41.32 uL, 0.10 equiv.). The solution was degassed and purged with Hz for 3 times, and stirred at 25 °C for 1 h under Hz atmosphere. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to afford Intermediate 128 (2.40 g, 5.36 mmol, 96.11% yield) as yellow oil, which was used in the next step without further purification. LCMS: RT = 0.926 min, MS cal.: 447.17, found: [M + H]+= 448.2.1H NMR (400 MHz, DMSO-d6) 6 = 11.974 (s, 1H), 7.814 - 7.791 (d, J = 9.2 Hz, 1H), 7.245 -7.159 (m, 1H), 5.210(s, 1H), 4.972 - 4.936 (m, 1H), 4.490 - 4.470 (d, J = 8 Hz, 1H), 4.019 (s, 3H), 3.689 -3.580 (m, 7H), 2.097 (s, 3H), 1.770 (s, 3H), 1.763 (s, 3H), 1.493 - 1.486 (m, 4H). Theoretical number of H:29, found: 29.

[0235] Preparation of Intermediate 129:

[0236] To a solution of Intermediate 100 (38.00 g, 75.15 mmol, 1.00 equiv.) in CH2CI2(323 ml) was added Na2CO3(31.86 g, 75.15 mmol, 25% purity, 1.00 equiv.) while stirring. Then CbzCI (39.74 g,232.97 mmol, 3.00 equiv.) was added dropwise and the reaction mixture was stirred for 24 h at 20 ºC. TLC(Petrolum ether: ethyl acetate = 5:1, the starting material Rf= 0.5, product Rf= 0.3) showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: ethyl acetate= 100 / 1 to 10: / l) to give Intermediate 129 (104.71 g, 163.67 mmol, 72.59% yield) as colouless oil.

[0237] Preparation of Intermediate 130:

[0238] To a solution of Intermediate 129 (25.7 g, 40.17 mmol, 1.00 equiv.) in HCOOH (400 ml) was added formic acid (5.55 g, 120.51 mmol, 4.55 ml, 3.00 equiv.), then the reaction was stirred for 18 h at 20 °C. After completed, four parallel reactions were combined for work up. The reaction solution was concentrated under reduced pressure to give Intermediate 130 (17.00 g, 89.76% yield) as colorless oil, which was used into next step directly without further purification.

[0239] Preparation of Intermediate 131:

[0240] To a solution of Intermediate 130 (1.00 g, 2.12 mmol, 1.00 equiv.) in DMF (10 ml) was added HATU (2.42 g, 6.36 mmol, 3.00 equiv.) and DIEA (1.92 g, 14.85 mmol, 2.59 ml, 7.00 equiv.) at 0 ºC.The mixture was stirred at 0 °C for 0.5 h. Then Intermediate 130A (1.11 g, 6.36 mmol, 1.11 ml, 3.00 equiv.) was added and the mixture was stirred at 25 °C for 0.5 h. LCMS showed reactant was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (10 ml) and extracted with DCM (10 ml * 3). The combined organic layers were washed with brine10 ml (5 ml * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 10 / 1) to affordIntermediate 131 (1.9 g, 2.02 mmol, 95.28% yield) as a yellow solid. LCMS: RT = 2.264 min, MS cal.: 939.55, found: [M + H]+= 940.8.

[0241] Preparation of Intermediate 132:

[0242] To a solution of Intermediate 131 (2.00 g, 2.13 mmol, 1.00 equiv.) in DCM (20 ml) andTFA (4 ml) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 ºC for 1 h under N2atmosphere. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to give Intermediate 132 (1.30 g, 2.03 mmol, 95.51% yield) as yellow oil. LCMS: RT = 1.170 min, MS cal.: 639.4, found: [M + H]+= 640.5.1H NMR(400 MHz, DMSO-ds) 6 = 8.052-8.024 (m, 3H), 7.854 - 7.757 (m, 9H), 7.384 - 7.306 (m, 5H), 6.546 (s, 1H),4.984 (s, 2H), 3.652 - 3.483 (m, 9H), 3.130 - 3.082 (m, 6H), 2.791 - 2.742 (m, 6H), 2.321 - 2.290 (m, 6H),1.697 - 1.627 (m, 6H). Theoretical number of H: 53, found: 53.

[0243] Preparation of Intermediate 133:

[0244] To a solution of Intermediate 128 (2.00 g, 4.47 mmol, 3.00 equiv.) in DMF (10 ml) was added HATU (1.70 g, 4.47 mmol, 3.00 equiv.) and DIEA (577.71 mg, 4.47 mmol, 778.58 uL, 3.00 equiv) at0 °C for 0.5 h. Then Intermediate 132 was added at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was diluted with H2O(200 ml) and extracted with DCM (200 ml *3). The combined organic layers were washed with brine (200 ml * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 100 / 1 to 30 / 1) to give Intermediate133 (1.20 g, 622.40 umol, 41.77% yield) as yellow solid. LCMS: RT = 1.900 min, MS cal.: 1928.06, found: [M / 2+ H]+= 965.1.1H NMR (400 MHz, DMSO-d6) δ = 7.829 - 7.807 (m, 6H), 7.739 - 7.711 (m, 3H), 7.354 - 7.314 (m, 6H), 5.214 - 4.982 (m, 3H), 4.973 - 4.945 (m, 5H), 4.492 - 4.471 (d, J = 8.4 Hz, 3H), 4.021 -3.011(m, 46H), 2.287 - 2.272 (t, J = 3 Hz, 7H), 2.035 (s, 9H), 1.888 (s, 9H), 1.777 (s, 9H), 1.769 (s, 9H), 1.514 -1.461 (m, 19H). Theoretical number of H: 134, found: 134.

[0245] Preparation of Intermediate 134:

[0246] To a solution of Intermediate 133 (1.00 g, 518.66 umol, 1.00 equiv.), Pd / C (500 mg, 518.66 umol, 10% purity, 1.00 equiv.) and TFA (59.14 mg, 518.66 umol, 38.40 uL, 1.00 equiv.) in THF (30 ml) was degassed and purged with Hz for 3 times, and then the mixture was stirred at 25 ºC for 0.5 h under Hz atmosphere. LCMS showed reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to afford Intermediate 134 (760.00 mg, 423.66 umol, 81.68% yield) as yellow oil, which was used in the next step without further purification. LCMS: RT = 1.673 min, MS cal.: 1792.85, found: [M / 2 + H]+= 898.2.[02471 Preparation of Intermediate 135:

[0248] To a solution of Intermediate 100a (93.29 mg, 445.96 umol, 1.00 equiv.) in DMF (8 ml) was added HATU (169.57 mg, 445.96 umol, 1.00 equiv.) and DIEA (57.64 mg, 445.96 umol, 77.68 uL, 1.00 equiv.) at 0 °C for 0.5 h. Then Intermediate 134 (800.00 mg, 445.96 umol, 1.00 equiv.) was added, and the mixture was stirred at 25ºC for 0.5 h. LCMS showed the desired mass and the reactant was consumed.The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase:[water(TFA)-ACN];B%: 30%-50%,8min) to afford Intermediate 135 (200.00 mg, 100.75 umol, 22.59% yield) as yellow solid. LCMS: RT = 1.982 min, MS cal.: 1983.9, found: [M / 2 + H]+= 993.5.1H NMR (400 MHz,DMSO-dc) 5 = 7.855 - 7.812 (m, 6H), 7.751 - 7.723 (m, 3H), 7.364 - 7.328 (m, 6H), 5.212 - 5.021 (m, 3H),4.978 - 4.942 (m, 6H), 4.487 - 4.466 (d, J = 8.4 Hz, 3H), 4.020 -3.854 (m, 9H), 3.685 -3.522 (m, 26H), 3.045- 3.015 (t, J = 6 Hz, 13H), 2.292 - 2.260 (t, J = 6.4 Hz, 7H), 2.035 (s, 9H), 1.888 (s, 9H), 1.777 (s, 9H), 1.769(s, 9H), 1.514 - 1.461 (m, 19H). Theoretical number of H: 137, found: 137.

[0249] Preparation of Intermediate 136:

[0250] To a solution of Intermediate 135 (180.00 mg, 90.68 umol, 1.00 equiv.) in THF (3 ml) was added Pd / C (150 mg, 90.68 umol, 10% purity, 1.00 equiv.) and TFA (15.51 mg, 136.01 umol, 10.07 uL, 1.50 equiv.) at 25 ºC and the reaction was stirred for 0.5 h at 25 ºC. LCMS showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give Intermediate 136 (80.00 mg, 43.22 umol, 47.67% yield) as white solid. LCMS: RT = 1.685 min, MS cal.: 1849.8, [M / 2+H]+= 926.6.

[0251] Preparation of Intermediate 137:

[0252] To a solution of oxalyl dichloride (13.06 mg, 102.91 umol, 9.01 uL, 1.20 equiv.) in DCM(0.30 ml) was added Intermediate 10 (20.00 mg, 85.76 umol, 1.00 eq) and DMF (0.10 mL), and the reaction mixture was stirred at 0 "C for 1 h. TLC (DCM: MeOH = 10:1, Starting material Rf= 0.3, product Rf= 0.4) showed the reaction was completed. Then TEA (19.68 mg, 194.49 umol, 27.07 uL, 3.00 equiv.) and Intermediate 136 (120.00 mg, 64.83 umol, 1.00 equiv.) in DCM (2 ml) was added dropwise to the above solution at 0 ºC, then the mixture was stirred at 25 "C for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to afford Intermediate 137 (125 mg, crude) as yellow oil. LCMS: RT = 1.724 min, MS cal.: 2064.96, found: [M / 2 + H]+= 1034.3.

[0253] Preparation of Target AO94:

[0254] To a solution of Intermediate 137 (119.80 mg, 57.98 umol, 1.00 equiv.) in MeOH (2 ml) was added NaOMe (3.13 mg, 57.98 umol, 1.00 equiv.). The mixture was stirred at 25 °C for 17 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column:C18-1150*30mm*5um;mobile phase: [water( NH4HCO3)-ACN];B%: 5%-35%,10min) to afford Target A094 (26 mg, 15.40 umol, 26.57% yield) as white solid. LCMS: RT = 1.078 min, MS cal.: 1686.87, found: [M / 2+H] + = 845.1.1H NMR (400 MHz, CD3OD) 5 = 4.37 (m, 2H), 4.36 - 4.33 (m, 2H), 3.97 - 3.87 (m, 8H), 3.84 (br s,3H), 3.80 - 3.64 (m, 28H), 3.60 (br s, 2H), 3.58 (br s, 2H), 3.49 (br s, 8H), 3.26 - 3.20 (m, 12H), 2.43 (br s, 6H), 2.21 (br t, J = 6.3 Hz, 6H), 2.04 - 1.95 (m, 9H), 1.75 - 1.63 (m, 12H), 1.58 (br d, J = 6.0 Hz, 6H).Theoretical number of H: 126, found: 106, exchangeable H: 20.EXAMPLE 32. Procedure for Preparation of Target A099

[0255] Preparation of Intermediate 96

[0256] To a solution of Intermediate 95a (50 g, 335.15 mmol, 1 eq) in MeOH (500 mL) was addedCbzCI (62.89 g, 368.66 mmol, 52.41 mL, 1.1 eq) and TEA (78.00 g, 770.84 mmol, 107.29 mL, 2.3 eq). The mixture was stirred at 25 ºC for 12 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. TLC (Dichloromethane: Methanol = 10:1 Rf= 0.7) indicated Reactant1 was consumed completely and one new spot formed. The reaction mixture was diluted with H2O (500 ml) and extracted with EtOAc (300 ml * 2). The combined organic layers were washed with brine (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 1 / 0 to 10 / 1) to giveIntermediate 96 (52 g, 183.54 mmol, 54.76% yield) as colorless oil. LCMS: RT = 1.522 min, MS cal.: 283.14, found: [M+H]+= 284.2.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.22 - 7.33 (m, 5 H), 5.34 (br s, 1 H), 5.03(s, 2 H), 3.62 - 3.68 (m, 2 H), 3.56 (s, 4 H), 3.49 - 3.53 (m, 4 H), 3.33 (q, J = 5.04 Hz, 2 H), 2.18 - 2.57 (m, 1H). Theoretical number of H: 21, found: 21.[02571 Preparation of Intermediate 126

[0258] To a solution of Intermediate 96a (20 g, 51.37 mmol, 1 eq) in DCM (2000 mL) was added FeCl3(25.00 g, 154.10 mmol, 8.93 mL, 3 eq). The mixture was stirred at 25ºC for 3 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was diluted with water(2000 mL) and extracted with water (2000 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue Intermediate 126 (14 g, 42.51 mmol, 82.77% yield) as white oil. LCMS: RT = 1.421 min, MS cal.: 329.11, found: [M+H]+= 330.2.1H NMR (400 MHz, CDCI3-d) δ = 6.00 (d, J = 6.8Hz, 1H), 5.47 (t, J = 3.0 Hz, 1H), 4.92 (dd, J = 3.3, 7.4 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.21 - 4.17 (m, 1H), 4.14 - 4.08 (m, 1H), 4.04 - 3.98 (m, 1H), 2.13 (s, 3H), 2.09 - 2.04 (m, 9H). Theoretical number of H: 19, found:19.

[0259] Preparation of Intermediate 97:

[0260] To a solution of Intermediate 126 (13.5 g, 41.00 mmol, 1 eq), Intermediate 96 (11.61 g,41.00 mmol, 1 eq) in DCM (280 ml) was added TMSOTf (2.73 g, 12.30 mmol, 2.22 mL, 0.3 eq) and 4A molecular sieves (14 g, 41.00 mmol, 1 eq) at 0ºC. The mixture was stirred at 25ºC for 16.5 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with water (300 ml) and extracted with DCM (300 ml * 3). The combined organic layers were washed with brine (300 ml * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1 to 0 / 1) to give Intermediate 97 (22 g, 35.91 mmol, 87.60% yield) as a white solid. LCMS: RT = 1.857 min, MS cal.: 612.3, found: [M+H]+= 613.4.1HNMR (400MHz, MeOD-d6) δ = 7.41 - 7.27 (m, 5H), 5.32 (d, J = 2.9 Hz, 1H), 5.11 - 5.03 (m, 3H), 4.85 (s, 4H),4.89 - 4.81 (m, 1H), 4.64 (d, J = 8.5 Hz, 1H), 4.18 - 4.05 (m, 4H), 4.00 (d, J = 6.6 Hz, 1H), 3.91 (td, J = 4.0,11.4 Hz, 1H), 3.72 (ddd, J = 4.0, 6.6, 11.0 Hz, 1H), 3.65 - 3.62 (m, 2H), 3.55 (t, J = 5.5 Hz, 2H), 2.13 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.92 (s, 3H). Theoretical number of H: 40, found: 38, exchangeable H: 2.

[0261] Preparation of Intermediate 98;

[0262] To a solution of Intermediate 97 (2 g, 3.26 mmol, 1 eq) in THF (20 mL) was added TFA (37.22 mg, 326.47 umol, 24.17 uL, 0.1 eq) and Pd / C (500 mg, 3.26 mmol, 10% purity, 1 eq). The mixture was stirred at 25 ºC for 1 h. LCMS showed the desired mass was detected and the reactant was consumed.The reaction mixture was filtered and concentrated under reduced pressure to give Intermediate 98 (1.5 g, 3.13 mmol, 96.02% yield) as yellow oil. LCMS: RT = 0.369 min, MS cal.: 478.2, found: [M+H]+= 479.4. 1H NMR (400MHz, MeOD-d4) = 5. δ34 (d, J = 2.8 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.64 - 4.56 (m, 1H), 4.16 - 4.00 (m, 4H), 3.95 (td, J = 4.2, 11.2 Hz, 1H), 3.75 - 3.69 (m, 3H), 3.65 - 3.61 (m, 6H), 3.01 - 2.90 (m, 2H), 2.14 (s, 3H), 2.02 (s, 3H), 1.95 - 1.92 (m, 6H). Theoretical number of H: 34, found: 31, exchangeable H: 3.

[0263] Preparation of Intermediate 139:

[0264] To a solution of Intermediate 138 (50 g, 548.80 mmol, 1 eq), Intermediate 139a (154.74 g, 1.21 mol, 175.25 mL, 2.2 eq) in DMSO (500 mL) was added NaOH (439.00 g, 548.80 mmol, 5% purity, 1 eq). The mixture was stirred at 25 ºC for 24 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. TLC (Petroleum ether: Ethyl acetate = 1: 1 Rf= 0.67) indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was diluted with H2O (500 ml) and extracted with EtOAc (300 ml * 2). The combined organic layers were washed with brine (300 ml * 2), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 / 0 to 1 / 1) to give Intermediate 139 (37.6 g, 108.22 mmol, 19.72% yield) as a colorless oil. LCMS: RT=2.826 min, MS cal.: 333.22, found: [M+CH3]+= 348.3.1H NMR (400 MHz, CHLOROFORM-d) 6 = 5.30(s, 1H), 3.73 - 3.61 (m, 4H), 3.52 - 3.39 (m, 2H), 3.36 - 3.29 (m, 1H), 3.16 - 3.09 (m, 1H), 2.96 - 2.76 (m, 1H),2.47 (t, J = 6.4 Hz, 3H), 1.45 (s, 18H) Theoretical number of H: 34, found: 31, exchangeable H: 3.

[0265] Preparation of Intermediate 140:

[0266] To a solution of Intermediate 239(30 g, 86.34 mmol, 1 eq) in DCM (500 ml) was added Na2CO3(36.61 g, 86.34 mmol, 315 ml, 25% purity, 1 eq) and CbzCI (44.19 g, 259.03 mmol, 36.82 ml, 3 eq).The mixture was stirred at 25°C for 14 hr. LCMS showed the desired mass of product was detected andthe reactant was consumed completely. TLC (PE: EA = 2: 1, Rf= 0.6) indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with water 200 mL and extracted with DCM 200 mL * 3. The combined organic layers were washed with brine 200 ml dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=4 / l to 3 / 1) to obtained Intermediate 140 (28 g, 58.14 mmol, 67.34% yield) as a white solid. LCMS: RT = 2.826 min, MS cal.: 481.27, found: [M+H]+= 482.4.1H NMR (400 MHz, CHLOROFORM-d) 6 = 7.37 - 7.28 (m, 5H), 5.30 (br d, J = 7.9 Hz, 1H), 5.09 (s, 2H), 4.12 (d, J = 7.2 Hz, 1H),3.94 - 3.86 (m, 1H), 3.60 - 3.52 (m, 2H), 3.48 - 3.42 (m, 2H), 2.45 (t, J = 6.3 Hz, 4H), 2.05 (s, 1H), 1.63 - 1.52(m, 1H), 1.43 (s, 17H), 1.26 (t, J = 7.2 Hz, 1H). Theoretical number of H: 39, found: 38, exchangeable H: 1.[02671 Preparation of Intermediate 141:[02681 A mixture of Intermediate 140 (28 g, 58.14 mmol, 1 eq) in HCOOH (500 ml) was stirred at 25ºC for 17 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was dried over and concentrated under reduced pressure to give Intermediate 141 (21.24 g, 57.50 mmol, 98.90% yield) as yellow oil. LCMS: RT = 0.514 min, MS cal.: 369.14, found: [M+H]+= 370.3.1H NMR (400 MHz, CHLOROFORM-d) 6 = 8.15 (s, 1H), 7.42 - 7.27 (m, 5H),5.32 - 5.19 (m, 1H), 5.09 (s, 2H), 4.02 - 3.85 (m, 1H), 3.77 - 3.62 (m, 3H), 3.61 - 3.41 (m, 3H), 2.58 (t, J = 6.1Hz, 3H). Theoretical number of H: 23, found: 19, exchangeable H: 4.

[0269] Preparation of Intermediate 142:

[0270] To a solution of Intermediate 141 (1.4 g, 3.79 mmol, 1 eq) in DMF (25 ml) was added HATU (2.88 g, 7.58 mmol, 2 eq) and DIEA (2.94 g, 22.74 mmol, 3.96 ml, 6 eq) at 0ºC. The mixture was stirred at OºC for 0.5 h, then was added intermediate 98 (3.63 g, 7.58 mmol, 2 eq) at OºC, then was stirred at 25ºC for 1 h. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water (20 ml) and extracted with DCM (30 ml * 3).The combined organic layers were washed with brine (30 ml * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column:Welch Xtimate C18 250*70mm#10um;mobile phase: [water( NH4HCO3)-ACN];B%: 20%-50%,20min) to give Intermediate 142 (1.7 g, 1.32 mmol, 34.76% yield) as yellow oil. LCMS: RT = 1.862 min, MS cal.: 1289.55, found: [M+H]+= 1290.9.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.39 - 7.33 (m, 5H), 5.36 - 5.30(m, 2H), 5.20 - 5.20 (m, 1H), 5.20 - 5.13 (m, 2H), 5.10 (br s, 2H), 4.79 (br d, J = 8.5 Hz, 2H), 4.20 - 4.04 (m, 7H), 3.98 - 3.82 (m, 7H), 3.66 - 3.52 (m, 22H), 3.51 - 3.47 (m, 5H), 2.50 - 2.39 (m, 5H), 2.17 (br s, 2H), 2.15(s, 5H), 2.04 (s, 7H), 1.99 (s, 7H), 1.95 - 1.95 (m, 1H). Theoretical number of H: 87, found: 82, exchangeableH: 5.

[0271] Preparation of Intermediate 143:

[0272] To a solution of Intermediate 142 (1 g, 775.01 umol, 1 eq) in THF (40 ml) was added TFA(88.37 mg, 775.01 umol, 57.38 uL, 1 eq). The mixture was stirred at 25ºC for 1 hr under 15 psi. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. TLC (DCM: MEOH = 10:1, Rf= 0.6) indicated Reactant 1 was consumed completely and one new spot formed.The reaction was clean according to TLC. The reaction mixture was filtered and concentrated under reduced pressure to give Intermediate 143 (896 mg, 774.96 umol, 99.99% yield) as yellow oil. LCMS: RT = 1.499 min, MS cal.: 1155.52, found: [M+H]+= 1156.8.1H NMR (400 MHz, METH ANO L-d4) δ = 5.37 - 5.31(m, 2H), 5.10 - 5.02 (m, 2H), 4.67 - 4.57 (m, 2H), 4.18 - 3.91 (m, 10H), 3.86 - 3.46 (m, 32H), 3.42 - 3.35 (m,4H), 2.53 - 2.47 (m, 4H), 2.18 - 2.12 (m, 6H), 2.07 - 2.00 (m, 6H), 1.97 - 1.91 (m, 12H). Theoretical number of H: 81, found: 80, exchangeable H: 1.

[0274] To a solution of Intermediate 100a (452.35 mg, 2.16 mmol, 1 eq) in DMF (10 ml) was added HATU (863.28 mg, 2.27 mmol, 1.05 eq) and DIEA (838.38 mg, 6.49 mmol, 1.13 ml, 3 eq). The5 mixture was stirred at O’C for 0.5 h. Intermediate 143 (2.5 g, 2.16 mmol, 1 eq) was added at O’C, and the mixture was stirred at 25’C for Ih. TLC (PE / EA = 0: 1, Rf = 0.6) indicated Reactant 1 was consumed completely and one new spot formed. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was dried by Ns. The residue was purified by column chromatography (SiOs, DCM / MEOH = 100 / 1 to 5 / 1) to give Intermediate 144 (1.2 g, 890.63 umol,10 41.19% yield) as faint yellow solid. LCMS: RT = 1.793 min, MS cal.: 1346.58, found: [M+H] * = 1347.9.XHNMR (400 MHz, METHANOL-d4) 6 = 7.36 (br d, J = 6.3 Hz, 5H), 5.33 (br d, J = 2.8 Hz, 2H), 5.16 - 5.04 (m,4H), 4.64 (d, J = 8.5 Hz, 2H), 4.14 (br t, J = 6.0 Hz, 7H), 3.97 - 3.89 (m, 2H), 3.81 (s, 2H), 3.74 - 3.58 (m, 19H),3.41 - 3.37 (m, 3H), 2.44 (br t, J = 5.6 Hz, 4H), 2.14 (s, 6H), 2.02 (s, 6H), 1.94 (d, J = 6.6 Hz, 12H), 1.41 - 1.34(m, 10H). Theoretical number of H: 90, found: 84, exchangeable H: 6.416

[0276] To a solution of Intermediate 144 (1.4 g, 1.04 mmol, 1 eg) in THF (2 ml) was added Pd / C(700 mg, 1.04 mmol, 10% purity, 1 eg) and TFA (118.48 mg, 1.04 mmol, 76.93 uL, 1 eg). The mixture was stirred at 20ºC for 1 hr under 15 psi. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give Intermediate 145 (1.24 g, 1.02 mmol, 98.36% yield) as yellow oil. LCMS: RT = 1.449 min, MS cal.: 1212.54, found: [M+H]+= 1213.9.1H NMR (400 MHz, METH ANO L-d4) 6 = 5.35 (d, J = 3.1 Hz, 2H),5.09 - 5.04 (m, 3H), 4.64 - 4.57 (m, 2H), 4.15 (br d, J = 6.6 Hz, 10H), 3.99 - 3.93 (m, 2H), 3.75 - 3.69 (m,10H), 3.67 - 3.62 (m, 10H), 3.56 (br d, J = 5.3 Hz, 5H), 3.39 (br t, J = 5.4 Hz, 5H), 2.46 (br t, J = 5.9 Hz, 4H), 2.15 (s, 6H), 2.03 (s, 6H), 1.95 (d, J = 5.4 Hz, 12H) Theoretical number of H: 84, found: 77, exchangeable H:7.[02771 Preparation of Intermediate 146:

[0278] To a solution of Intermediate 10 (1.2 g, 820.95 umol, 83% purity, 1 eg) in DMF (5 mL) was added HATU (327.76 mg, 861.99 umol, 1.05 eg) and DIEA (318.30 mg, 2.46 mmol, 428.98 uL, 3 eg). The mixture was stirred at 0ºC for 0.5 h. Intermediate 145 (201.04 mg, 861.99 umol, 1.05 eg) was added at 0ºC, and the mixture was stirred at 25ºC for Ih. TLC (PE / EA =0: 1, Rf= 0.6) indicated Reactant 1 was consumed completely and one new spot formed. LC-MS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was dried by N2and purified by column chromatography (SiO2, DCM / MEOH = 100 / 1 to 5 / 1) to give Intermediate 146 (1.11 g, 777.07 umol, 94.66% yield) as faint yellow solid. LCMS: RT = 1.800 min, MS cal.: 1427.63, found: [M / 2+H]+= 715.0.1H NMR (400 MHz, METHANOL-d4) δ = 5.50 (s, 2H), 5.34 (d, J = 2.9 Hz, 2H), 5.10 - 5.04 (m, 2H), 4.64(d, J = 8.3 Hz, 2H), 4.20 - 4.01 (m, 11H), 3.95 (s, 4H), 3.74 - 3.62 (m, 26H), 3.55 (br d, J = 5.5 Hz, 7H), 3.42 -3.34 (m, 6H), 3.27 - 3.19 (m, IH), 2.46 (t, J = 6.0 Hz, 4H), 2.15 (s, 6H), 2.03 (s, 6H), 2.00 - 1.90 (m, 12H).Theoretical number of H: 97, found: 91, exchangeable H: 6.

[0279] Preparation of Target A099:

[0280] To a solution of Intermediate 146 (500 mg, 350.03 umol, 1 eq) in MeOH (2 ml) was addedNaOMe (9.46 mg, 175.02 umol, 0.5 eq). The mixture was stirred at 25 ºC for 1 hr. LCMS showed Reactant1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was adjust pH to 7-8 and filtered. The residue was purified by prep-HPLC (column: Waters Xbridge BEHC18 100*30mm*10um;mobile phase: [water(TFA)-ACN];B%: 5%-30%,8min) to give Target A099 (145 mg, 123.28 umol, 35.22% yield) as a white solid. LCMS: RT = 1.589 min, MS cal.: 1175.57, found: [M / 2+H]+= 589.0.1H NMR (400 MHz, METH ANO L-d4) δ = 4.44 (d, J = 8.4 Hz, 2H), 4.13 (s, 1H), 4.06 (s, 2H), 3.95 (s,6H), 3.83 (d, J = 3.0 Hz, 2H), 3.75 - 3.60 (m, 34H), 3.55 (s, 10H), 3.38 (t, J = 5.4 Hz, 6H), 2.45 (t, J = 6.1 Hz, 4H), 1.98 (s, 6H). Theoretical number of H: 85, found: 73, exchangeable H: 12.EXAMPLE 33. Procedure for Preparation of Target A100

[0281] Preparation of Intermediate 148:

[0282] To a solution of intermediate 147 (9 g, 47.56 mmol, 1 eq) in DCM (135 ml) was added Na2CO3(20.16 g, 47.56 mmol, 63 ml, 25% purity, 1 eq) and CbzCI (24.34 g, 142.67 mmol, 20.28 ml, 3 eq).The mixture was stirred at 25ºC for 14 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with H2O 10 mL and extracted with DCM 90 mL (30 mL* 3). The combined organic layers were dried over Na2SO4filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 100 / 1 to 1 / 1) to give intermediate 148 (11.03 g, 34.11 mmol, 71.72% yield) as a colorless oil. LCMS: RT = 2.208 min, MS cal.: 323.17, found: [M+H] * = 268.2.1H NMR (400 MHz, CHLOROFORM-d) 6 = 7.39 - 7.34 (m, 5H), 5.33 - 5.27 (m, 1H), 5.13 - 5.08 (m, 2H), 3.67 (s, 2H), 3.57 - 3.48(m, 2H), 3.44 - 3.31 (m, 2H), 2.47 (t, J = 6.2 Hz, 2H), 1.45 (s, 9H). Theoretical number of H: 25, found: 25.

[0283] Preparation of Intermediate 149;

[0284] A mixture of Intermediate 148 (11 g, 34.02 mmol, 1 eq) and HCOOH (171 ml) was stirred at 25ºC for 17 hr. LCMS showed Reactant 1 was consumed completely and one peak with the desired Ms were detected. The reaction mixture was concentrated under reduced pressure to give intermediate 149 (8.9 g, 33.30 mmol, 97.89% yield, 100% purity) as a yellow oil. LCMS: RT = 1.1.138 min, MS cal.: 267.11, found: [M+H]+= 268.2.1H NMR (400MHz, ACN-d4) δ = 7.41-7.32 (m, 5H), 5.21 (s, 1H), 5.08 (s, 1H), 3.72 -3.69 (t, J = 6.4 Hz, 2H), 3.54 - 3.51 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (t, J = 5.6 Hz, 2H), 2.57 - 2.54 (t, J = 6.0 Hz, 2H). Theoretical number of H: 17, found: 15, exchangeable H: 2.

[0285] Preparation of Intermediate 150:

[0286] To a solution of Intermediate 149 (2.5 g, 9.35 mmol, 1 eq) in DMF (25 mL) was added HATU (3.91 g, 10.29 mmol, 1.1 eq) and DIEA (3.63 g, 28.06 mmol, 4.89 mL, 3 eq) at 0ºC for 0.5 hr. Then the solution of intermediate 98 (4.92 g, 10.29 mmol, 1.1 eq) in DMF (50 mL) was added at 0ºC and the reaction was stirred for 1 hr at 25ºC. LCMS showed the reaction was completed. The reaction mixturewas poured into H2O (50 ml) and extracted with DCM (100 ml x3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give crude product. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol = 100 / 1 to 1 / 1) to give intermediate 150 (3.36 g, 4.62 mmol, 49.36% yield) as yellow oil. LCMS: RT = 1.762 min, MS cal.: 727.3, found: [M+H]+= 728.5. 1H NMR (400 MHz, CHLOROFORM-d) 6 = 7.38 - 7.30 (m, 3H), 6.83 - 6.69 (m, 1H), 6.39 - 6.31 (m, 1H), 5.60(br s, 1H), 5.37 - 5.27 (m, 2H), 5.19 - 5.07 (m, 2H), 4.78 (d, J = 8.5 Hz, 1H), 4.21 - 4.04 (m, 2H), 3.97 - 3.33(m, 15H), 3.22 - 3.13 (m, 1H), 2.96 (s, 1H), 2.88 (s, 1H), 2.80 (s, 1H), 2.45 (br t, J = 5.6 Hz, 1H), 2.21 - 1.92 (m, 8H), 1.52 - 1.39 (m, 3H). Theoretical number of H: 49, found: 44, exchangeable H: 5.

[0287] Preparation of Intermediate 151:

[0288] To a solution of intermediate 150 (1.2 g, 1.65 mmol, 1 eq) in THF (10 ml) was added TFA (282.02 mg, 2.47 mmol, 183.13 ul, 1.5 eq) and Pd / C (0.6 g, 1.65 mmol, 10% purity, 1 eq). The mixture was stirred at 25ºC for 1 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate 151 (1.12 g, 1.58 mmol, 95.99% yield, TFA) as yellow oil. LCMS: RT = 0.783 min, MS cal.: 593.28, found: [M+H]+= 594.2.1H NMR (400 MHz, METHANOL-d4) δ = 4.62 - 4.56 (m, 1H), 4.19 - 3.94(m, 5H), 3.80 - 3.63 (m, 14H), 3.60 - 3.56 (m, 2H), 3.43 - 3.36 (m, 2H), 3.19 - 3.14 (m, 2H), 2.54 - 2.49 (m, 2H), 2.14 (s, 3H), 2.03 (s, 3H), 1.95 (d, J= 2.9 Hz, 6H). Theoretical number of H: 43, found: 40, exchangeableH: 3.

[0289] Preparation of Intermediate 152:

[0290] To a solution of intermediate 100a (271.36 mg, 1.30 mmol, 1.1 eq) in DMF (5 ml) was added DIEA (457.20 mg, 3.54 mmol, 616.18 uL, 3 eq) and HATU (493.21 mg, 1.30 mmol, 1.1 eq) at 0ºC.The mixture was stirred at 0ºC for 0.5 hr, then intermediate 151 (0.7 g, 1.18 mmol, 1 eq) was added at0°C. The mixture was stirred at 25ºC for 1 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The residue was purified by prep-HPLC (column: WatersXbridge BEH C18 250*70mm*10um;mobile phase: [water( NH4HCO3)-ACN];B%: 15%-45%,18min) to give intermediate 152 (0.7 g, 891.94 umol, 75.64% yield) as a yellow solid. LCMS: RT = 1.546 min, MS cal.: 784.34, found: [M+H]+= 785.5.1H NMR (400 MHz, METHANOL-d4) δ = 7.42 - 7.26 (m, 5H), 5.37 - 5.31(m, 1H), 5.11 (s, 3H), 4.67 - 4.59 (m, 1H), 4.20 - 3.88 (m, 5H), 3.82 - 3.75 (m, 2H), 3.74 - 3.58 (m, 9H), 3.55- 3.45 (m, 4H), 3.41 - 3.35 (m, 4H), 2.49 - 2.40 (m, 2H), 2.13 (s, 3H), 2.02 (s, 3H), 1.94 (d, J = 7.3 Hz, 6H). Theoretical number of H: 52, found: 48, exchangeable H: 4.

[0291] Preparation of Intermediate 153:

[0292] To a solution of intermediate 152 (150 mg, 191.13 umol, 1 eq) in MeOH (2 ml) was added Pd / C (75 mg, 191.13 umol, 10% purity, 1 eq) and TFA (32.69 mg, 286.70 umol, 21.23 uL, 1.5 eq). The mixture was stirred at 25"C for 1 hr. LCMS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate 153 (146 mg, 190.93 umol, 99.89% yield, TFA) was obtained as a yellow oil. LCMS: RT = 1.145 min, MS cal.: 650.3, found: [M+H]+= 651.5.1H NMR (400 MHz, METHANOL-d4) δ = 5.35(d, J = 3.0 Hz, 1H), 5.09 - 5.03 (m, 1H), 4.61 (d, J = 8.5 Hz, 1H), 4.15 (d, J = 6.5 Hz, 5H), 3.72 (s, 3H), 3.68 (s,7H), 3.59 - 3.53 (m, 4H), 3.45 - 3.37 (m, 4H), 2.47 (t, J = 5.9 Hz, 2H), 2.15 (s, 3H), 2.03 (s, 3H), 1.94 (d, J = 4.9 Hz, 6H). Theoretical number of H: 46, found: 40, exchangeable H: 6.

[0293] Preparation of Intermediate 154:

[0294] To a solution of Intermediate 10 (128 mg, 548.84 umol, 1.1 eq) in DCM (1 ml) was addedOxalyl chloride (80.68 mg, 658.60 umol, 60.66 uL, 1.2 eq) and DMF (4.01 mg, 54.88 umol, 4.22 uL, 0.1 eq).The mixture was stirred at OºC for 1 h. TLC showed intermediate 10 was consumed and one new spot was formed. The intermediate 153 (306 mg, 470.28 umol, 1 eq) and DIEA (182.34 mg, 1.41 mmol, 245.74 ul,3 eq) was dissolved in the mixture at 0ºC. The mixture was stirred at 0ºC for 0.5 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was concentrated under reduced pressure to remove solvent to give intermediate 154 (400 mg, 461.96 umol, 98.23% yield) as yellow oil. LCMS: RT = 1.492 min, MS cal.: 865.4, found: [M+H]+= 866.6.

[0295] Preparation of Target A100:

[0296] To a solution of Intermediate 154 (300 mg, 346.47 umol, 1 eq) in MeOH (3 ml) was addedNaOMe (18.72 mg, 346.47 umol, 1 eq). The mixture was stirred at 25ºC for 12 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters XbridgeBEH C18 100*30mm*10um;mobile phase: [water(TFA)-ACN];B%: 15%-30%,8min) to give Target A100(145 mg, 196.01 umol, 84.86% yield) as yellow oil. LCMS: RT = 1.571 min, MS cal.: 739.36, found: [M- GalNaC]+= 537.2.1H NMR (400MHz, MeOD-d») 6 = 4.44 (d, = 8.5 Hz, 1H), 4.07 (s, 2H), 3.95 - 3.90 (m, 3H),3.83 (d, J = 3.1 Hz, 1H), 3.75 - 3.70 (m, 8H), 3.69 - 3.61 (m, 14H), 3.58 - 3.48 (m, 6H), 3.38 (br t, J = 4.8 Hz,6H), 2.49 - 2.44 (m, 2H), 2.01 - 1.97 (m, 3H). Theoretical number of H: 53, found: 46, exchangeable H: 7.EXAMPLE 34. Procedure for Preparation of Target A101

[0298] To a solution of Intermediate 155 (500.00 mg, 1.56 mmol, 1.00 equiv.) in DMF (5 mL) was added HATU (650.74 mg, 1.71 mmol, 1.10 equiv.) and DIEA (603.25 mg, 4.67 mmol, 813.01 uL, 3.00 equiv.) at 0 ºC and the reaction was stirred at 0 ºC for 0.5 h. Then Target A092 (500.31 mg, 1.71 mmol, 1.10 equiv.) in DMF (5 ml) was added at 0ºC. The mixture was stirred at 25ºC for 0.5 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was poured into H2O(10 ml) and extracted with DCM (10 ml x 5). The combined organic layer was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to afford Intermediate 156 (658.13 mg, 1.10 mmol, 71.01% yield) as yellow oil. LCMS: RT = 0.478 min, MS cal.: 595.7, found: [M + H-100]4= 496.4.1H NMR (400 MHz, CDCI3) δ = 7.07 (br d, J = 1.5 Hz, 1H), 6.19 (br s, 1H), 5.14 (br t, J = 9.0 Hz, 1H), 4.15 (d, J = 2.3Hz, 4H), 3.89 (d, J = 5.4 Hz, 2H), 3.84 (s, 5H), 3.77 (t, J = 5.8 Hz, 2H), 3.69 - 3.59 (m, 7H), 3.54 (t, J = 5.2 Hz, 2H), 3.31 (br d, J = 4.4 Hz, 2H), 3.23 - 3.13 (m, 1H), 2.54 (t, J = 5.8 Hz, 2H), 2.45 (t, J = 2.3 Hz, 2H), 1.50 -1.40 (m, 12H). Theoretical number of H: 45, found: 44, exchangeable H: 1.

[0299] Preparation of Target A101:

[0300] To a solution of Intermediate 122 (900.00 mg, 1.51 mmol, 1.00 equiv.) in EtOAc (2 ml) was added HCI / EtOAc (4 M, 10.00 ml, 26.47 equiv.), and the mixture was stirred 0.5 h at 25 ºC. LCMS showed the desired mass and the reactant was consumed. The reaction solution was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18-1150*30mm*5um; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%,10min) to afford Target A101 (360 mg, 726.44 umol, 48.08% yield) as yellow oil. LCMS: RT = 1.46 min, MS cal.: 495.6, found: [M + H]+= 496.4.1H NMR (400 MHz, CD3OD) 6 = 4.16 (d, J = 2.1 Hz, 6H), 3.84 (s, 2H), 3.80 (s, 6H), 3.76 (t, J = 6.1 Hz,2H), 3.69 - 3.57 (m, 11H), 2.91 (br s, 2H), 2.86 (t, J = 2.3 Hz, 2H), 2.53 (t, J = 6.1 Hz, 2H). Theoretical number of H: 37, found: 33, exchangeable H: 4.EXAMPLE 35. Procedure for preparation of BH0003664.

[0302] Peptide was synthesized using standard Fmoc chemistry (Rink AM resin).1) Resin preparation: To the vessel containing Rink Amide AM resin (1.56 g, 0.50 mmol, 0.32 mmol / g) and DMF (20 ml) was bubbled with N2for 2 h at 25 °C. Then 20% piperidine in DMF (40 ml) was added and the mixture was bubbled with N2for 30 min at 25 °C. The mixture was filtered and washed with DMF(20 ml) * 5 before proceeding to next step.2) Coupling: A solution of Fmoc-Thr(tBu)-OH (0.60 g, 1.50 mmol, 3.00 equiv.), HBTU (0.558 g, 1.43 mmol, 2.85 equiv.), DIEA (0.39 g, 3.00 mmol, 6.00 equiv.) in DMF (20 ml) was added to the resin with N2bubbling for 30 min at 25 °C. The coupling reaction was monitored by ninhydrin test. The resin was then washed with DMF (40 ml) * 5.3) Deprotection: 20% piperidine in DMF (40 ml) was added to the resin and the mixture was bubbled with N2for 30 min at 25 ºC. The deprotection reaction was monitored by ninhydrin test. The resin was then washed with DMF (40 ml) * 5.4) Steps 2 and 3 were repeated for the following amino acids elongation: Number # 2-13, Table 21.5) Coupling succinic anhydride: A solution of succinic anhydride (3.00 equiv.), DIEA (0.39 g, 3.00 mmol, 6.00 equiv.) in DMF (20 ml) was added to the resin with N2bubbling for 30 min at 25 °C. The coupling reaction was monitored by ninhydrin test. The resin was then washed with DMF (40 ml) * 5.6) Coupling 2,3,5,6-tetrafluorophenol: A solution of 2,3,5,6-tetrafluorophenol (10.00 equiv.), DIC 10.00 equiv.) in DMF (20 ml) was added to the resin with N2bubbling for 30 min at 25 °C The coupling reaction was monitored by ninhydrin test. The resin was then washed with DMF (40 ml) * 5, isopropylether (40 ml) * 5, then dried under reduced pressure to afford resin-bound peptide Intermediate 157 (Rink AM resin, 1.30 g, 0.50 mmol).Table 21: The list of amino acids and the corresponding reagents used on SPPS.

[0303] Peptide cleavage and cyclization.1) Cleavage solution (TFA / TlS / H2O, 95 / 2.5 / 2.5, v / v / v, 20 ml) was added to the flask containing the side-chain protected resin-bound peptide Intermediate 157 (Rink AM resin, 1.30 g, 0.50 mmol) at 25 °C and stirred for 2 h.2) After filtration, the filtrate was collected.3) The filtrate was precipitated with cold isopropyl ether (100 ml). After filtration, the solid was washed with isopropyl ether (100 ml) twice, and the crude peptide was dried under reduced pressure for 2 h to afford Intermediate 158 (1.10 g, crude) as a white solid.4) To a mixture of Intermediate 158 (1.10 g, crude) in HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 500 ml) was added 0.1 M I2 / AcOH dropwise until a yellow color persisted, then the mixture was stirred at 25 °C for 5 min. The mixture was quenched by addition of 0.1 M aq. Na2S2O3dropwise until the yellow color disappeared. After filtration, the filtrate was purified by prep-HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to afford Intermediate 159 (40.0 mg, 98.5% purity, 4.5% yield) as a white solid. LCMS: RT = 1.835 min, MS calcd.: Mav= 1777.87, mass observed: [M + H]+= 1778.65, [M + 2H]2+= 889.32.

[0304] Preparation of BH0003664:

[0305] A mixture of Intermediate 159 (40.0 mg, 21.98 μmol, 1.20 equiv.) and Target A011A (30.0 mg, 18.32 μmol, 1.00 equiv.), DIEA (4.73 mg, 36.64 μmol, 6.38 μL, 2 equiv.) in DMF (1 ml) was stirred at25 ºC for 1 h. After completion monitored by LC-MS, the reaction was filtered off and purified by prep-HPLC (A: 0.075% TFA / H2O; B: MeCN), followed by lyophilization to afford BH0003664 (16.9 mg, 94.9% purity, 28.3% yield) as a white solid. LCMS: RT = 1.379 min, MS calcd.: Mav= 3249.53, mass observed: [M+ 2H]2+= 1625.6, [M + 3H]3+= 1084.1, [M + 4H]4+= 813.0.EXAMPLE 36. Procedure for Preparation of Target A239

[0306] Preparation of Intermediate 161

[0307] To a mixture of intermediate 160 (100 g, 665.90 mmol, 89.29 ml, 3.00 equiv.) and TsO(42.32 g, 221.97 mmol, 1.00 equiv.) in DCM (400 ml) was added TEA (33.69 g, 332.95 mmol, 46.34 ml,1.50 equiv.) in DCM (100 ml) in one portion at 0ºC under N2. The mixture was stirred at 25ºC for 12 hours.TLC indicated TsCI was consumed completely and one new spot formed. The reaction was clean according to TLC. The residue was poured into water (w / w = 1 / 1) (1000 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (500 ml * 2). The combined organic phase was washed with brine (300 ml * 1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 2 / 1 to 1 / 2) to afford Intermediate 161 (105 g, 344.99 mmol, 31.08% yield) as a yellow oil. LCMS: RT =0.646 min, MS cal.: 304.36, [M+H]+= 305.0.1H NMR(400 MHz, CDCI3) 6 = 7.82 - 7.8 (d, J = 8.0 Hz, 2H), 7.36 - 7.34 (d, J = 8.0 Hz 2H), 4.18 - 4.16 (t, J = 4.8 Hz, 2H), 3.73 - 3.70 (m, 4H), 3.62 - 3.58 (m, 6H), 3.33 - 3.25 (m, 3H), 2.11 (s, 1H). Theoretical number of H: 20, found: 20.

[0308] Preparation of Intermediate 162

[0309] Equip a 1000 ml three-necked round bottom flask, addition funnel and thermometer, N2balloon etc. MeCN (600 mL) was charged to the 1000 mL three-necked round bottom flask, then Intermediate 161 (50 g, 164.28 mmol, 1.00 equiv.) and Nal (24.62 g, 164.28 mmol, 1.00 equiv.) was added at 25ºC. At 25ºC (inner temperature), NaN3(18.16 g, 279.28 mmol, 1.70 equiv.) was slowly added to the reaction mixture at 25ºC within 0.5 hours. After the addition, the mixture was stirred at 80ºC for 12 hours.LCMS showed Intermediate 161 was consumed completely and one main peak with desired desired mass was detected. The reaction mixture was added H2O (50 ml), then was added sat. Na2CO3adjust to pH > 9. The aqueous phase was extracted with EtOAc (100 ml * 5), the combined organic layers were dried over Na2SO4, and the solvent was concentrated at 45°C under reduce pressure. H2O (2.5 L) was added to the aqueous phase then NaOH (2 M) was added to it until pH > 12, then NaCIO (50 mL) was added slowly to the aqueous phase at 0ºC, it was quenched at 25ºC for 18 h. When the pH > 12, it was discarded to a special bucket. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 2 / 1 to 1 / 2) to afford intermediate 162 (28 g, 159.83 mmol, 97.29% yield) as a yellow oil. LCMS: RT =0.447 min, MS cal.: 175.19, [M+H]+= 176.1.1H NMR (400 MHz, CDCI3) δ = 3.74 - 3.69 (m, 4H), 3.62 - 3.60(m, 4H), 3.40 - 3.38 (m, 3H), 2.45 - 2.42 (t, J = 6.0, 2H). Theoretical number of H: 13, found H: 13.

[0310] Preparation of Intermediate 163

[0311] Equip a 2000 mL three-necked round bottom flask, addition funnel and thermometer, N2balloon etc. DCM (500 mL) was charged to the 2000 mL three-necked round bottom flask, thenIntermediate 162 (60 g, 342.49 mmol, 1.00 equiv.) and TEA (69.31 g, 684.99 mmol, 95.34 mL, 2.00 equiv.) was added at 25ºC. At 0ºC (inner temperature), MsCI (58.85 g, 513.74 mmol, 39.76 mL, 1.50 equiv.) inDCM (100 ml) was added dropwise to the reaction mixture at 0ºC within 0.5 h. After the addition, the mixture was stirred at 0ºC for 1 hr. LCMS showed Intermediate 162 was consumed completely and one main peak with desired mass was detected. The reaction mixture was washed with 3% HCI (50 mL) and extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford Intermediate 163 (86 g, 339.55 mmol, crude, yellow oil), used for next step without further purification. LCMS: RT =0.661 min, MS cal.:253.28, [M+NH4]+= 271.0.

[0312] Preparation of Intermediate 164

[0313] To a mixture of Intermediate 163 (86 g, 339.55 mmol, 1.00 equiv.) and Nal (203.59 g, 1.36 mol, 4.00 equiv.) in acetone (600 mL) in one portion at 25ºC under N2. The mixture was stirred for 12 hours. LCMS showed Intermediate 163 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (100 mL). The aqueous phase was extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (50 mL * 1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1 to 0 / 1) to afford Intermediate 164 (83 g, 291.14 mmol, 85.74% yield) as a yellow oil. LCMS: RT =0.742 min, MScal.: 285.08, [M + NH4]+= 303.0.1H NMR (400 MHz, CDCl3) = 3.79 - 3 δ.60 (m, J = 6.0, 2H), 3.71 - 3.69 (m,6H), 3.41 - 3.4 (m, 2H), 2.29 - 2.25 (m, 2H). Theoretical number of H: 12, found H : 12.

[0314] Preparation of Intermediate 166

[0315] To a solution of Intermediate 165 (40 g, 185.50 mmol, 1.00 equiv., MCI) in Py (200 ml) was added propionic anhydride (193.13 g, 1.48 mol, 191.22 ml, 8.00 equiv.). The mixture was stirred at20°C for 12 h. LCMS showed the desired compound was detected and the reactant was consumed. The mixture was diluted with IM MCI (100 ml) and extracted with EtOAc (100 mL*3), the combined organic layers were dried over NajSO*, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 1 / 1) to give Intermediate 166 (19.7 g, 42.87 mmol, 23.11% yield) as colorless oil. LCMS: RT=0.815 min, MS cal.:459.2, found: MS= 386.4.

[0316] Preparation of Intermediate 167.

[0317] To a solution of Intermediate 166 (5 g, 10.88 mmol, 1.00 equiv.) in DCM (50 ml) was added TiCl4(2.72 g, 14.36 mmol, 1.32 equiv.). The mixture was stirred at 25ºC for 12 h. TIC (PE: EA = 2:1, Rf= 0.5) showed the reactant was consumed and one main spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / 9 to 0 / 1) to give Intermediate 167 (4.5 g, crude) as a yellow solid.

[0318] Preparation of Intermediate 168

[0319] To a solution of Intermediate 167 (4 g, 9.48 mmol, 1.00 equiv.) in Tol. (100 ml) was addedAIBN (467.09 mg, 2.84 mmol, 0.30 equiv.) and Bu3SnH (5.52 g, 18.96 mmol, 5.02 ml, 2.00 equiv.) at 20ºC.The mixture was refluxed for 2 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was added to saturated solution of KF (50 ml) and extracted with EtOAc(50 ml * 3). The combined organic layers were washed with brine (50 ml * 3), dried over Na2SO4filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to give Intermediate 168 (1.28 g, 3.31 mmol, 35.2 % yield) as a white solid. LCMS: RT=1.8O4 min, MS cal.: 387.2, [M+H]4= 388.3.1H NMR (400MHz, MeOD-d4) δ = 5.43 (d, J = 2.4 Hz, 1H), 4.99 (dd, J = 3.2, 11.1 Hz, 1H), 4.34 (dt, j = 5.2, 11.1 Hz,1H), 4.12 - 4.08 (m, 1H), 4.02 - 3.88 (m, 2H), 3.31 (s, 2H), 2.45 (q, J = 7.6 Hz, 2H), 2.35 - 2.29 (m, 2H), 2.28- 2.12 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H), 1.13 - 1.03 (m, 9H). Theoretical number of H: 29, found H : 28, exchangeable: 1.[03201 Preparation of Intermediate 169.

[0321] To a solution of Intermediate 168 (3.5 g, 9.03 mmol, 1.00 equiv.) in MeOH (30 ml) was added NaOMe (488.05 mg, 9.03 mmol, 1.00 equiv.). The mixture was stirred at 25ºC for 12 h. TLC (DCM:MeOH =10: 1, Rf= 0.3) showed the reactant was consumed and one new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 5 / 1) to give Intermediate 169 (1.6 g, 7.30 mmol, 80.78% yield) as a white solid.1H NMR (400MHz, MeOD-d4) δ = 4.17 (dt, J = 5.2, 10.7 Hz, 1H), 3.96 (dd, J= 5.2, 10.9 Hz, 1H), 3.88 (d, J = 2.8 Hz, 1H), 3.80 - 3.73 (m, 1H), 3.72 - 3.66 (m, 1H), 3.54 (dd, J = 3.2, 10.6Hz, 1H), 3.46 - 3.39 (m, 1H), 3.10 (t, J = 10.8 Hz, 1H), 2.31 - 2.20 (m, 2H), 1.19 - 1.12 (m, 3H). Theoretical number of H: 17, found H: 13, exchangeable: 4.

[0322] Preparation of Intermediate 170.

[0323] To a solution of Intermediate 169 (440 mg, 2.01 mmol, 1.00 equiv.) in DMF (10 ml) was added [(IS, 4R)-7, 7-dimethyl-2-oxo-norbornan-l-yl]methanesulfonic acid; hydrate (251.19 mg, 1.00 mmol, 0.50 equiv.) and 2A (1.05 g, 10.03 mmol, 1.23 ml, 5.00 equiv.). The mixture was stirred at 70ºC for12 h. LCMS showed the desired mass was detected and the reactant was consumed. The reaction mixture was diluted with NaHCO3(10 ml) and extracted with EtOAc (10 ml * 3). The combined organic layers were washed with brine (5 ml *3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 30 / 1 to 10 / 1) to give Intermediate 170 (450 mg, 1.74 mmol, 86.47% yield) as a yellow solid. LCMS: RT=0.522 min, MS cal.: 259.1, [M+H]+= 260.3.1H NMR (400MHz, MeOD-d4) = 4.24 ( δd, J = 4.8 Hz, 1H), 4.13 - 3.98 (m, 2H), 3.90 - 3.69(m, 4H), 3.08 (t, J = 10.8 Hz, 1H), 2.31 - 2.20 (m, 2H), 1.52 (s, 3H), 1.35 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H).Theoretical number of H: 21, found H: 19, exchangeable: 2.

[0324] Preparation of Intermediate 171:

[0325] To a solution of Intermediate 170 (9 g, 34.71 mmol, 1.00 equiv.) in DMF (90 ml) was added NaH (13.88 g, 347.09 mmol, 60% purity, 10 equiv.) at 0ºC within 10 min. The mixture was stirred at0ºC for 0.5 h, then Intermediate 164 (19.79 g, 69.42 mmol, 2.00 equiv.) was added at 0ºC, and the mixture was stirred at 25ºC for 1 h. LCMS showed the desired mass and the reactant was consumed. The reaction mixture was poured into ice H2O (100 ml) slowly within 10 min, and extracted with DCM (100 ml * 3). The combined organic layers were washed with brine (100 ml * 3), dried over Na2SO4, filtered andconcentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10: 1) to give Intermediate 171 (9 g, 21.61 mmol, 62.26% yield) as yellow oil. LCMS: RT = 1.155 min, MS cal.: 416.2, found: [M + H]+= 417.2.1H NMR (400 MHz, CDCI3) 6 =5.39 - 5.29 (m, 1H), 4.20 - 4.14 (m, 1H), 4.08 - 4.02 (m, 2H), 3.99 - 3.93 (m, 1H), 3.87 (ddd, J = 2.0, 4.8, 6.8Hz, 1H), 3.80 - 3.73 (m, 3H), 3.70 - 3.67 (m, 9H), 3.42 - 3.38 (m, 2H), 3.18 (t, J = 10.8 Hz, 1H), 2.27 - 2.19(m, 2H), 1.55 (s, 3H), 1.35 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H). Theoretical number of H: 32, found H: 32.[03261 Preparation of Intermediate 172:[03271 To a solution of Intermediate 171 (9.8 g, 23.53 mmol, 1.00 equiv.) in THF (200 mL) was added HCI (1 M, 117.66 ml, 5.00 equiv.) and calcium; palladium; carbonate (4.86 g, 2.35 mmol, 4.86 ml,10% purity, 0.10 equiv.). The mixture was stirred at 20ºC for 1 h under H2(15 psi). LCMS showed theReactant was consumed and desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column:Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (HCI)-ACN); gradient: 1%-12% B over 10 min) to give Intermediate 172 (6.8 g, 19.41 mmol, 82.47% yield) as yellow oil. LCMS: RT = 0.300 min, MS cal.: 350.2, found: [M + H]+= 351.2.[03281 Preparation of In...

Claims

CLAIMSWhat is claimed is:

1. A bifunctional compound according to the chemical structure:wherein:[CPBM] is a Circulating Protein Binding Moiety which binds to Immunoglobulin G(IgG) in a subject, wherein IgG mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject, wherein [CPBM] is or comprises a moiety selected from:[CRBM] is a Cellular Receptor Binding Moiety which binds to asialoglycoprotein receptors of hepatocytes or other cell receptors in the subject, wherein [CRBM] is or comprises an [ASGPRBM] group according to the chemical structure:each [CON] is an optional connector chemical moiety which, when present, connects the [LINKER] to [CPBM] or to [CRBM];[LINKER] is a chemical moiety having a valency from 1 to 15, which covalently attaches to one or more [CRBM] or [CPBM] groups, optionally through a [CON], wherein the [LINKER] optionally itself contains one or more [CON] groups; k’ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j’ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h’ are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; iLis 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; with the proviso that at least one of h, h’, and iLis at least 1, or a salt, stereoisomer, or solvate thereof.

2. The compound of claim 1, wherein k’, J’, h, h’, and iLare each independently 1, 2, or 3.

3. The compound of claim 1, wherein:X in [ASGPRBM] is -O-C(RN1)(RN1>, -C(RN1)(RN1)-O-, -S-C(RN1)(RN1)-, -C(RN1)(RN1)-S-, - N(RN1)-C(RN1)(RN1)-, -C(RN1XRN1)-N(RN1)-, or -C(RN1)(RN1)-C(RN1)(RN1)-, when X is 2 atoms in length,X in [ASGPRBM] is -O-C(RN1)(RN1)-C(RN1)(RN1)-, -C(RN1)(RN1)-O-C(RN1)(RN1)-, -O-atoms in length, andX in [ASGPRBM] is -O-C^’XRN’XCCRN’^^-CCRN’XR’^’)-, -C(RN1)(RN1)-O-C(RN1XRN1)-4. The compound of claim 1, wherein X is OCH2or CH2O and wherein RN1is H.

5. The compound of claim 1, wherein the [CRBM] / [ASGPRBM] group is a group according to the chemical structure:or a salt, stereoisomer, or solvate thereof.

6. The compound of claim 1, wherein the [CRBM] / [ ASGPRBM] group is a group according to the chemical structure: or a salt, stereoisomer, or solvate thereof.

7. The compound of claim 1, wherein the [ASGPRBM] group is a group according to the chemical structure:wherein:RAis C1-C3alkyl optionally substituted with 1-5 halo groups;ZAis -(CH2)IM- -O-(CH2)IM-, -S-(CH2)IM-, -NRM-(CH2)IM- -C(O)-(CH2)IM- a PEG group containing from 1 to 8 ethylene glycol residues, or -C(O)(CH2)IMNRM-; andZB is absent, -(CH2)IM-, -C(O)-(CH2)IM-, or -C(O)-(CH2)IM-NRM-.

8. The compound of claim 7, wherein at least one applies:RAis a methyl or ethyl group which is optionally substituted with 1 -3 fluoro groups, or ZA is a PEG group containing from 1 to 4 ethylene glycol residues.

9. The compound of claim 1, wherein R1and R3 are each independently a group according to the chemical structure:

10. The compound of claim 1, wherein R1and R3 of the [CRBM] / [ASGPRBM] group are each independently a moiety selected from the group consisting of11. The compound of claim 1, where R2of the [CRBM] / [ASGPRBM] group is a moiety selected from the group consisting of12. The compound of claim 1, wherein the linker is according to the chemical structure:or a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing between 1 and 100 alkylene glycol units; wherein R» is H, C1-C3alkyl or alkanol or forms a cyclic ring with R3to form a pyrrolidine or hydroxypyrroline group and R3is a side chain derived from a D- or L amino acid selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1 -methylpropane), leucine (2- methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxyproline (R3forms a cyclic ring with R, and the adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidine group), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl); and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

13. The compound of claim 1, wherein the linker is a group according to the chemical formula: wherein:Ram is H or C1-C3alkyl optionally substituted with one or two hydroxyl groups; na is 1-15; and m is an integer ranging from 1 to 100; or wherein the linker is a group according to the chemical formula:wherein:Z and Z’ are each independently a bond, -(CH2)i-O-, -(CH2)i-S-, -(CH2)i-N(R)-,wherein the -(CH2)igroup, if present in Z or Z’, is bonded to a connector group [CON], [MIFBM] / [IgGBM] or [ASGPRBM]; each R is H, or C1-C3alkyl or alkanol; each R2is independently H or C1-C3alkyl; each Y is independently a bond, O, S, or N-R; each i is independently 0 to 100;or a bond, with the proviso that Z, Z’ and D are not each simultaneously bonds; j is an integer ranging from 1 to 100; m’ is an integer ranging from 1 to 100; n is an integer ranging from 1 to 100;X1is O, S, orN-R; and R is H, or C1-C3alkyl or alkanol.

14. The compound of claim 1, wherein the linker is or comprises a group according to the chemical structure:wherein each n and n’ is independently 1 to 25; and each n” is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; or wherein the linker is a group represented by the chemical formula:PEG-[CON]-PEG wherein each PEG is independently a polyethylene glycol group containing from 1-12 ethylene glycol residues and [CON] is a triazole group15. The compound of claim 1, wherein the [CON] is a group according to the structure:wherein RCON1and RCON2are each independently H, methyl, a bond (for attachment to another moiety); or a diamide group according to the structure:wherein:X2is CH2, O, S, NR4, C(O), S(O), S(O)2, -8(O^O, -O8(O)2, or O8(O)2O;X3is O, 8, or NR4;R4is H, C1-C3alkyl or alkanol, or -C(O)(C1-C3alkyl);R1is H or C1-C3alkyl; and n” is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; or the [CON] is a group according to the chemical structure:wherein R1CON, R2CON, and R3CONare each independently H, -(CH2)MCI-, - (CH2)MC1aC(O)XA(NR4)XA-(CH2)MC1a-,-(CH2)MC1a(NR4)XAC(O)XA-(CH2)MC1a-, or - (CHH2)MCO1a-(CH2)MCI-C(O)NR4-, with the proviso that R1CON, R2CONand R3CONare not simultaneously H; each MCI is independently 1, 2, 3, or 4; each MCla is independently 0, 1, 2, 3, or 4; each XA is 0 or 1; andR4is H, C1-C3alkyl or alkanol, or -C(O)(C1-C3alkyl), with the proviso that MCla and XA in a moiety are not all simultaneously 0.

16. The compound of claim 1, wherein the [CON] is a group according to the chemical structure:17, The compound of claim 1, wherein at least one [CON] is or comprise18. The compound of claim 1, wherein [LINKER] is or comprises19. A bifunctional compound according to the chemical structure:of a pharmaceutically acceptable salt thereof, wherein:Extracellular Protein Targeting Ligand is a moiety which binds to Immunoglobulin G (IgG) in a subject, wherein IgG mediates a disease state or condition and is to be removed by the action of hepatocytes or other cells of the subject, wherein Extracellular Protein Targeting Ligand is or comprises a moiety selected from:Xi is 1 to 5 groups independently selected from the group consisting of O, S, N(R6), and C(R4)(R4), wherein if Xi is 1 atom then Xi is O, S, N(R6), or C(R4)(R4), if Xi is 2 atoms then no more than 1 atom of Xi is O, S, or N(R6), if Xi is 3, 4, or 5 atoms then no more than 2 atoms of Xi are O, S, orN(R6);R2is selected from the group consisting of:(i) aryl, heterocycle, and heteroaryl containing 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, each of which aryl, heterocycle, and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents;(iii) -NR8-S(O)-R3, -NR8-C(S)-R3, -NR8-S(OXNR6)-R3, -N=S(OXR3)2, - NR8C(O)NR9S(O)2R3, -NR8-S(O)2-R10, and -NR8-C(NR6)-R3each of which is optionally substituted with 1, 2, 3, or 4 substituents; and(iv) hydrogen, R10, alkyl-C(O)-R3, -C(O)-R3, alkyl, haloalkyl, -OC(O)R3, and -NR8- C(O)R10;R10is selected from the group consisting of aryl, alkyl-NR8-C(O)-R3, alkyl-aryl, alkylheteroaryl with 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR6, alkyl-NR6R8, NR8-NR6-C(O)R3,NR8-S(O)2-R3, alkenyl, allyl, alkynyl, -NR6-alkenyl, -O-alkenyl, -NR6-alkynyl, -O-alkynyl, - NR6-heteroaryl, -NR6-aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, each of which R10is optionally substituted with 1, 2, 3, or 4 substituents;R1and R5are independently selected from the group consisting of hydrogen, heteroalkyl, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6alkyl- OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl- C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)-C(O)R3, C0-C6alkyl-N(R8)-S(O)R3, C0-C6alkyl- N(R8)-C(S)R3, C0-C6alkyl-N(R8)-S(O)2R3C0-C6alkyl-0-C(O)R3, C0-C6alkyl-0-S(O)R3, C0- C6alkyl-O-C(S)R3, -N=S(O)(R3)2, C0-C6alkyN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents;R3at each occurrence is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9;R4is independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR6, -NR6R7, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3;R6and R7are independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR’R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3;R8and R9are independently selected at each occurrence from the group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;Cycle is a 3-8 membered fused cyclic group optionally substituted with 1, 2, 3, or 4 substituents; each Linker* is a bond or moiety that covalently links the [ASGPRBM] group to LinkerB, LinkerBis a bond or moiety that covalently links Linker* group to the Extracellular Protein Targeting Ligand;Linker6is a chemical group that links each Linker* group to the Extracellular Protein Targeting Ligand;LinkerDis a chemical group that links each Linker* group to the Extracellular Protein Targeting Ligand; wherein, when R2is -NR6-alkenyl, -NR6-alkynyl, -NR8-C(O)R10, -NR8-S(O)2-alkenyl, - NR8-S(O)2-alkynyl, -NR6-heteroaryl, or -NR6-aryl, then Extracellular Protein Targeting Ligand does not comprise an oligonucleotide; and the optional substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, Br, I, -NR6R7, heteroalkyl, cyano, nitro, C(O)R3as allowed by valence such that a stable compound results;or a salt, stereoisomer, or solvate thereof.

20. The compound of Claim 19, wherein Linker* is or comprises21. The compound of Claim 19, wherein LinkerBis or comprises22. The compound of Claim 19, wherein Linker” is or comprises23. The compound of Claim 19, wherein LinkerDis or comprises24. A compound selected from the compounds listed in Table 1 of the specification , or a salt, stereoisomer, or solvate thereof.

25. A pharmaceutical composition comprising an effective amount of a compound of any one of preceding claims and a pharmaceutically acceptable carrier, additive, or excipient, optionally further comprising an additional bioactive agent that is effective to treat cancer, autoimmune disease, or inflammatory disease in a patient or that is associated with the upregulation of a circulating protein in the patient.

26. The composition of claim 25, wherein the composition comprises an additional anticancer agent selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286. AV-299, DN-101 , pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HD AC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR- TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK / STAT inhibitor, a checkpoint- 1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601 , ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, [NO 1001 , IPdRi KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311 , romidepsin, ADS- 100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK -304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N -[4-[2-(2-amino-4,7-dihydro-4-oxo-l H - pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11 , CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)- indolylj -quinolone, vatalanib, AG-013736, AVE-0005, lire acetate salt of [D- Ser(Bu t ) 6 ,Azgly 10 ] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t )-Leu-Arg-Pro- Azgly-NH 2 acetate [CjpHwNisOia -(CiH^jx where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKL166, GW-572016, lonafamib, BMS-214662, tipifamib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951 , aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethyl stilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6- mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin- 12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox,gefitinib, bortezimib, paclitaxel, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab, erbitux, cremophor-free paclitaxel, epithilone B, BMS- 247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA- 923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR- 3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl>- rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, 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, hydrocortisone, interleukin- 11 , dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine,hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, immunotherapy agents PDL1 inhibitors, PD1 inhibitors, and CTLA-4 inhibitors.

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