A bifunctional small molecule that targets the selective degradation of circulating proteins.

Abstract

The present invention relates to a bifunctional small molecule comprising a circulating protein-binding moiety (CPBM) linked via a linker group to a cell receptor-binding moiety (CRBM), which is a membrane receptor for degrading cells such as hepatocytes or other degrading cells. In certain embodiments, (CPBM) is a moiety that binds to immunoglobulin G. In certain embodiments, (CRBM) is a moiety that binds to the asialoglycoprotein receptor of hepatocytes (asialoglycoprotein receptor-binding moiety, or ASGRBM).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 498,852, filed on 28 April 2023, and U.S. Provisional Patent Application No. 63 / 517,984, filed on 7 August 2023, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Various diseases are associated with elevated levels of certain circulating proteins that contribute to disease progression. For example, elevated levels of multiple circulating pro-inflammatory cytokines (i.e., signaling proteins that promote inflammatory effects) contribute to various systemic inflammatory conditions and autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and atherosclerosis. Some studies also link chronic inflammation to an increased risk of heart disease, stroke, cancer, and Alzheimer's disease. Specifically, elevated levels of cytokines such as TNFα or MIF are associated with rheumatoid arthritis (RA), atherosclerosis, and other diseases.

[0003] In summary, diseases and / or conditions related to circulating proteins affect the lives of millions of people. There is a strong need for new therapies to address these conditions.

[0004] Current strategies targeting circulating proteins involve the use of inhibitory antibodies that possess excellent specificity and affinity for the target protein. Despite these advantages, antibody-based therapies have several drawbacks, primarily related to their high molecular weight and / or peptide structure, potential for inducing immunogenicity, their high cost, short efficacy period, and low oral bioavailability. The small molecule-based strategies according to the present invention have the potential to combine the beneficial properties of antibody-based therapies while simultaneously overcoming their most significant drawbacks.

[0005] The high prevalence of inflammatory diseases in the population places a considerable economic burden on healthcare systems. The current high demand and high cost of antibody-based therapies are reflected in the global sales of TNF-α antibodies, which amount to as much as US$34.4 billion. In contrast, the bifunctional small molecules according to the present invention can be readily prepared by organic synthesis and have the potential to significantly reduce manufacturing, storage, and processing costs. Similarly, these bifunctional chemical constructs are easier to mass-produce and ultimately meet the high therapeutic demand. [Overview of the project]

[0006] Conceptually, the present invention relates to a bifunctional small molecule that can be used to remove circulating proteins that mediate pathological and / or conditional states in a subject. The present invention aims to establish a general small molecule strategy that targets the selective degradation of disease-related circulating proteins. The bifunctional molecular construct comprises a protein-targeting motif derived from a known small molecule ligand of the protein of interest. The inventors generally refer to this portion as the circulating protein-binding moiety (CPBM). The other end of the bifunctional molecule is a cell receptor-binding moiety (CRBM) that binds to a cell surface receptor and results in the internal translocation of the circulating protein and the bifunctional molecule. These two motifs are covalently linked via a linker, such as a polyethylene glycol (PEG) linker of adjustable length, and optionally include one or more connector molecules that connect the linker to the CPBM and / or CRBM.

[0007] The bifunctional compound claimed herein selectively binds to a target immunoglobulin G ("IgG") protein in circulation (which may be a pathogenic form of IgG), forming an IgG protein complex, which then binds to a cell receptor, is endocytotic, and degraded. As a result of this mechanism, the target IgG protein is removed from circulation by hepatocytes, macrophages, or other cell types, thus leading to a decrease in the level of the target IgG protein and potentially reducing the corresponding disease symptoms. In certain cases, the removal of the target IgG protein may result in a significant reduction in symptoms, or even a cure or elimination of the disease or condition.

[0008] The approach according to the present invention is inherently advantageous compared to the classical antibody-based strategies of the prior art for targeting disease-associated circulating proteins. The small molecule-based approach of the present invention overcomes the limitations of traditional antibody-based strategies, including the lack of oral bioavailability, the requirement for cryogenic storage, immunogenicity, and high cost.

[0009] Furthermore, since disease-related proteins are eliminated by degradation within hepatocytes rather than simply being inhibited by reversibly blocking protein-receptor interactions, the present invention is expected to have a more sustained effect compared to conventional inhibitory approaches. The bifunctional molecular constructs according to the present invention also have broad applications in that they can target different disease-related proteins simply by switching the protein-targeting motif in the construct. Therefore, previously discovered non-inhibitory protein conjugates may be potentially therapeutically useful in these small molecules.

[0010] In one embodiment, the present invention provides a compound useful for removing circulating IgG proteins related to a pathological condition or state in a patient or subject, which conform to a general chemical structure. [ka] [CPBM] is a circulating protein binding moiety that binds to each of the circulating IgG proteins specified herein, which are associated with and / or mediate disease states and are to be removed by the action of hepatocytes or other cells on circulating IgG proteins (the compound preferably selectively binds to circulating IgG proteins in the plasma of the subject or patient), [CRBM] is a cell receptor binding moiety, preferably an [ASGPRBM] group, which is a binding moiety that binds to hepatocytes or other cells via the asialocrypoprotein receptor or other receptor identified herein, preferably on the surface of hepatocytes or other degraded cells in a patient or subject. Each [CON] is an optional connector chemical part that either connects directly to the [CPBM] or [CRBM] if present, or connects the [linker] to the [CPBM] or [CRBM]. The [linker] is a chemical moiety having a valency of 1 to 15 that is covalently bonded to one or more [CRBM] groups and / or [CPBM] groups via [CON] (including a [MULTICON] group), and the [linker] itself optionally contains one or more [CON] groups or [MULTICON] groups. k' is an integer between 1 and 15. j' is an integer between 1 and 15. h and h' are each independent integers between 0 and 15. i L However, these are integers from 0 to 15. However, h, h', and i L The subject matter includes compounds, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, provided that at least one of the following is at least one.

[0011] In various embodiments, the [linker] has a valency of 1 to 10. In various embodiments, the [linker] has a valency of 1 to 5. In various embodiments, the [linker] has a valency of 1, 2, or 3. The [MULTICON] group can connect one or more [CRBM] or [CPBM] groups to one or more [linkers].

[0012] In one embodiment, [CPBM] is a part: [ka] It is either or includes it.

[0013] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0014] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0015] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0016] In another embodiment, [CPBM] is as follows: [ka] It is either a part of it or includes it.

[0017] In another embodiment, [CPBM] is as follows: [ka] is part of or includes it.

[0018] In another embodiment, [CPBM] is as follows:

Chemical formula

[0019] In another embodiment, [CPBM] is as follows:

Chemical formula

[0020] In one embodiment, [CRBM] is [ASGPRBM], with the chemical structure:

Chemical formula

[0021] In one embodiment, R1 and R3 are each independently optionally substituted with 1 to 3 halogen groups, 1 to 3 C1-C4 alkyl groups, or O-C1-C4 alkyl groups. [ka] It is a group, and each alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, and K is independently an integer from 0 to 4 in each occurrence, or R1 and R3 each have their own independent chemical structure: [ka] A base that follows, R 7 However, it is an O-C1-C4 alkyl group that is optionally substituted with 1 to 3 halo groups or 1 to 2 hydroxyl groups, and K' is independently an integer from 0 to 4 at each occurrence, or R 7 However, -NR N3 R N4 base or [ka] And K is a base that is independently an integer between 0 and 4 at each occurrence, or R1 and R3 are independent of each other, and their structure is: [ka] A base that follows such that K is independently 0 to 4 at each occurrence, or [ka] It is the basis, CYC [ka] and a ring selected from the group consisting of C3-C8 saturated carboncyclic structures, linker X, R C , and -(CH2) K Each of these is bonded to an open valence atom in the CYC containing NH, R C However, it is absent, H, a C1-C4 alkyl group optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, or structure: [ka] A group that follows the formula, where R4, R5, and R6 are each independently H, halogen, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K These are C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -C(O)-C1-C4 alkyl groups, in which case the alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R C but, [ka] And, R N , R N1 , and R N2Each of these is independently a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. K is an integer between 0 and 4, independently at each occurrence. K' is an integer between 0 and 4, independently at each occurrence. R N3 However, it is a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. R N4 However, it is a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups, or R N4 but, [ka] (K is 1) [ka] However, it is a linker group that includes at least one [CPBM] group and connects the [CPBM] group to [CRBM] via one or more optional [CON] groups, or [ka] However, the linker group is a linker group that includes at least one functional group covalently bonded to at least one [CPBM] group or an optional [CON] group, R2 is [ka] And R N1 And K is the same as above, R AM However, H, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -(CH2) K -NRN3 R N4 (R N3 is H or C1-C3 alkyl, where one of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups. R N4 However, it is a C1-C3 alkyl group optionally substituted with H, 1-3 halo groups or 1 or 2 hydroxyl groups, or R N4 but, [ka] (K is 1) or R2 is [ka] And, R TA However, H, CN, NR N1 R N2 ,-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K These are C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -C(O)-C1-C4 alkyl, where each alkyl is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R TA However, C3-C 10 An aryl group or a 3- to 10-membered heteroaryl group containing up to 5 heteroatoms, wherein the aryl group or the heteroaryl group is CN, NR, etc. N1 R N2 ,-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -(CH2) KIt is optionally substituted with 1 to 3 substituents selected from the group consisting of C(O)-C1-C4 alkyl groups, where each alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R TA but, [ka] is, or R TA However, each is optionally substituted with 1 to 3 halogen groups and optionally substituted with 1 to 3 C1-C3 alkyl groups. [ka] is a base, or R TA but, [ka] And, R N , R N1 , and R N2 Each of these is independently a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. Each -(CH2) K Each group is optionally substituted with 1 to 4 C1-C3 alkyl groups, each optionally substituted with 1 to 3 fluorine groups or 1 to 2 hydroxyl groups. K is independently between 0 and 4 for each occurrence.

[0022] In various embodiments, any of the alkyl groups described herein, which are optionally substituted with 1 to 3 halogen groups, are substituted with 1, 2, or 3 fluorine (F) atoms.

[0023] In various embodiments, [ka] And, RC , [ka] And K is the same as above.

[0024] In some embodiments of the present invention, X in the [CRBM] / [ASGPRBM] group is OCH2 or CH2O, and R N1 It is preferably H.

[0025] In various embodiments, the [CRBM] / [ASGPRBM] group has the following chemical structure: [ka] A base that follows, R1, R2, and R3 are groups, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, as defined herein.

[0026] In some embodiments, the carbohydrate portion of the [ASGPRBM] group has an α-configuration at the anomeric center. In some embodiments, the carbohydrate portion of the [ASGPRBM] group has a β-configuration at the anomeric center.

[0027] In some embodiments, [CRBM] has the chemical structure: [ka] It is an [ASGPRBM] group that conforms to or contains such a group.

[0028] In some embodiments, the [CRBM] / [ASGPRBM] group has the following chemical structure: [ka] It is a base that follows, R A However, it is a C1-C3 alkyl group that is optionally substituted with 1 to 5 halogen groups. Z A However, -(CH2) IM, -O-(CH2) IM , S-(CH2) IM , NR M -(CH2) IM , C(O)-(CH2) IM -, a PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) residues, or -C(O)(CH2) IM NR M where IM and R M are the same as above, Z B is absent, -(CH2) IM -, -C(O)-(CH2) IM -, or -C(O)-(CH2) IM -NR M -where IM and R M are the same as above.

[0029] In various embodiments, R1 and R3 are each independently a group according to the chemical structure: [Chemical formula] and R C , [Chemical formula] [[ID=4​​​​​​​​​In other embodiments, the present invention relates to methods for treating a pathological condition or state in which circulating proteins are associated with or contribute to the overall symptoms of the pathological condition and / or state or the pathological condition or state. These pathological conditions and / or states include, among many others described herein, autoimmune diseases and numerous inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer's disease, atherosclerosis, heart disease, stroke, and cancer (including leukemia). A therapeutic method according to the present invention involves 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, suppress, and / or treat the pathological condition or state by removing circulating proteins associated with the pathological condition and / or state from the circulation of the patient or subject.

[0032] In additional embodiments, the present invention relates to pharmaceutical compositions comprising an effective amount of the compound according to the present invention in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally in combination with at least one additional bioactive agent.

[0033] In other embodiments, the present invention relates to methods for treating a pathological condition or state in which circulating proteins are associated with the overall symptoms related to the pathological condition or state. These pathological conditions and / or states include, among many others described herein, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Alzheimer's disease, atherosclerosis, heart disease, stroke, and cancer (including leukemia). The method involves 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, suppress, and / or treat the pathological condition or state by removing circulating proteins associated with the pathological condition and / or state. [Modes for carrying out the invention]

[0034] According to the present invention, conventional chemical synthesis methods and pharmaceutical formulation methods, as well as pharmacology, molecular biology, microbiology, and recombinant DNA techniques within the scope of the art, can be used. Such techniques are well known and are described in full elsewhere in this document.

[0035] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, up to one-tenth of the lower limit (for example, in the case of a group containing several carbon atoms), and any other specified values ​​or intervening values ​​within that specified range, are included within the present invention unless the context otherwise explicitly indicates otherwise. The upper and lower limits of these smaller ranges may independently be included within the smaller range and are also included within the present invention, subject to any specific excluded limitations within the described range. Where a described range includes one or both of the limiting values, ranges excluding one or both of the limiting values ​​they include are also included within the present invention.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. Any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of the present invention, but preferred methods and materials are described herein.

[0037] As used herein and in the appended claims, the singular forms "a," "an," "and," and "the" refer to multiple subjects unless the context otherwise explicitly indicates.

[0038] Furthermore, the following terms shall have the definitions set forth below. If a particular term is not defined below, it shall be understood to have the meaning within the scope of its typical use in the context of those skilled in the art.

[0039] As used herein, the term “compound” refers to any specific compound disclosed herein unless otherwise indicated, including its tautomers, positional isomers, geometric isomers, stereoisomers, and, where applicable, optical isomers (enantiomers), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms). In its use in this context, the term “compound” generally refers to a single compound, but may also include other compounds, e.g., stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomer-enriched mixtures of the disclosed compound. In this context, the term also refers to prodrug forms of a compound modified to facilitate the administration and delivery of the compound to the active site. Note that, in describing the compounds, a number of substituents, linkers, and connector molecules, as well as variables associated with them, will be described, among other things. The use of a bond presented as –---- means the presence or absence of a single bond, depending on the context of the described chemistry, including the attachment of a bond to another part. The use of a bond presented as ------- means that, depending on the chemical context described, a single or double bond is intended. Those skilled in the art will understand that the molecules described herein are stable compounds as outlined below.

[0040] The terms “patient” or “subject” are used throughout this specification in context to describe an animal, generally a mammal, preferably a human, that is provided with treatment using the compositions of the present invention, including preventive treatment (prevention, in particular when this term is used in relation to reducing the likelihood of metastasis of an existing cancer). In the case of treatment of an infection, condition, or pathology that is specific to a particular animal, such as a human patient or a patient of a particular sex, e.g., a human male or female patient, the term patient refers to that particular animal. The compounds of the present invention are useful in the treatment of numerous pathologies, including autoimmune conditions and / or conditions, as well as inflammatory conditions and / or conditions, and cancer, and are particularly useful in reducing the likelihood of metastasis or recurrence of cancer.

[0041] The term “effective” is used herein to describe the amount of compound or composition used to produce or bring about an effect, whether the intended result relates to the suppression of the action of a condition (e.g., autoimmune diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), among many others, atherosclerosis, heart disease, or stroke, or cancer, including leukemia) on the subject or the treatment or prevention of the subject, unless otherwise indicated. This term encompasses all other effective amount or effective concentration terms (including the term “therapeutic effective”) described herein.

[0042] As used herein, terms such as “to treat,” “to treat,” and “treatment” include, in particular, autoimmune diseases including rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), atherosclerosis, heart disease, stroke, and cancer (including leukemia), including recurrence and / or metastasis of cancer, improvement of a condition by reducing or suppressing at least one symptom of a condition or state, suppression of one or more signs of a condition (e.g., atherosclerosis, heart disease, cancer growth, reduction of cancer cells or tissue), and the condition or state or pathology. This refers to any action that benefits patients at risk of a condition or state in which MIF proteins can be eliminated, such as the prevention of signs of the condition, the reduction of its likelihood, or the delay of its progression (in particular, including the prevention or delay of the onset of conditions or states secondary to conditions or states including, among others, atherosclerosis, worsening of tissue and inflammation in rheumatoid arthritis, further damage to cardiovascular tissue in heart disease, further damage to central nervous system tissue in stroke, cancer, cancer recurrence or metastasis, or cancer recurrence or metastasis). The treatments used herein encompass both prophylactic and therapeutic treatments, depending on the context of the treatment. The term “prophylactic,” where used, means reducing the likelihood or severity of occurrence within the context of the treatment of a condition or state described elsewhere herein.

[0043] Where used in this application, the terms “about” and “approximately” are used interchangeably. Any numerical values ​​used in this application, with or without “about” or “approximately,” are intended to encompass any normal variation of values ​​as understood by those skilled in the art.

[0044] The terms “immunoglobulin G binding moiety” or “circulating protein binding moiety,” including “IgGBM,” refer to one end of a bifunctional compound according to the present invention that can bind to circulating proteins associated with or contributing to pathological conditions or states described elsewhere herein. In the present invention, CPBM can bind to circulating proteins, form a complex with the compound, and deliver the bound protein to hepatocytes or other cells, in which case the other end of the bifunctional molecule, including an asialoglycoprotein receptor binding moiety (ASGPRBM) or a cell receptor binding moiety (CRBM), such as those described elsewhere herein, can each bind to the surface of hepatocytes or other cells. Upon binding to cells, the bifunctional molecule bound to the circulating protein is translocated internally by the cell via phagocytosis / endocytosis, in which case the cell destroys the protein via lysosomal degradation or other degradation pathways. The terms “immunoglobulin G binding moiety” or “IgGBM” are used to describe the portion that binds to circulating IgG immunoglobulin and forms a complex with the bifunctional molecule according to the present invention, which is ultimately destroyed in hepatocytes. In certain cases, the terms IgGBM and other cell-binding moieties are used synonymously when describing the present invention.

[0045] CPBM groups, such as IgGBM, bind to their respective circulating proteins, forming complexes with the bifunctional compounds according to the present invention. The bifunctional compounds complexed with the bound circulating proteins can then bind to cell receptors on the cell, which can take up the complexed compound using the cell's phagocytosis / endocytosis mechanism and remove the protein via a degradation process. It should be noted that the CPBM, which is a peptide that binds to IgGBM, is covalently linked to the other part of the bifunctional molecule according to the present invention via a terminal amine or carboxylic acid group of the peptide. In preferred embodiments, the carboxylic acid is amidated, often with a free amine group (substituted with two H) and at least one C1-C 10 An alkyl group, more often an alkylated amine group with at least one C1-C3 alkyl group, forms a non-reactive amide group, thereby allowing the free amine at the other end of the peptide to be covalently linked to the other part of the bifunctional molecule. In other embodiments, the amine terminus has a C2-C amine group. 10 The carboxylic acid group is rendered unreactive by terminal capping with an acyl group, preferably a C2-C4 acyl group, which allows the carboxylic acid group to react with the amine, in many cases, to form an amide.

[0046] In one embodiment, [CPBM] is a part: [ka] It is either or includes it.

[0047] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0048] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0049] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0050] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0051] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0052] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0053] In another embodiment, [CPBM] is part: [ka] It is either or includes it.

[0054] The term “cell receptor binding moiety” refers to a portion of the bifunctional compound according to the present invention that can bind to receptors on cells capable of degrading circulating proteins according to the present invention. These are portions that bind to asialoglycoprotein receptors, LRPR, LDLR, RcγRI, FcRN, transferrin receptors, or macrophage scavenger receptors (e.g., membrane receptors of degrading cells) as described separately herein. Many of these binding moieties are peptides covalently linked to other portions of the bifunctional compound according to the present invention via terminal amine or carboxylic acid groups. With respect to the CPBM group described above, in preferred embodiments, the carboxylic acid is amidated, often with a free amine group (substituted with two H) or at least one C1-C 10 An alkyl group, more often an alkylated amine group with at least one C1-C3 alkyl group, forms a non-reactive amide group, thereby allowing the free amine at the other end of the peptide to be covalently linked to the other part of the bifunctional molecule. In other embodiments, the amine terminus has a C2-C amine group. 10 The carboxylic acid group is rendered unreactive by terminal capping with an acyl group, preferably a C2-C4 acyl group, which allows the carboxylic acid group to react with the amine, in many cases, to form an amide.

[0055] The term “asiaroglycoprotein receptor binding site” (“ASGPRBM”) refers to a binding site that binds to hepatocyte asiaroglycoprotein receptors. This binding site is also a component of the claimed bifunctional compound as a CRBM group covalently bonded to a CPBM group via a CON group, a linker, or directly. The ASGPRBM group selectively binds to hepatocyte asiaroglycoprotein receptors on the surface of hepatocytes. It is through this site that the bifunctional compound, when complexed with the circulating protein, binds to hepatocytes. Upon binding to hepatocytes, the circulating protein is taken up by hepatocytes or other cells via phagocytic mechanisms, where it is degraded by lysosomal degradation.

[0056] Exemplary ASGPRBM groups for use in the compounds according to the present invention include, inter alia, the chemical structure:

Chemical formula

[0057] In one embodiment, R1 and R3 are each independently optionally substituted with 1 to 3 halogen groups, 1 to 3 C1-C4 alkyl groups, or O-C1-C4 alkyl groups. [ka] It is a group, and each alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, and K is independently an integer from 0 to 4 in each occurrence, or R1 and R3 each have their own independent chemical structure: [ka] A base that follows, R 7 However, it is an O-C1-C4 alkyl group that is optionally substituted with 1 to 3 halo groups or 1 to 2 hydroxyl groups, and K' is independently an integer from 0 to 4 at each occurrence, or R 7 However, -NR N3 R N4 base or [ka] And K is a base that is independently an integer between 0 and 4 at each occurrence, or R1 and R3 are independent groups that follow the structure: R1 and R3 are independent of each other, and their structure is: [ka] A base that follows such that K is independently 0 to 4 at each occurrence, or [ka] It is the basis, CYC [ka] and a ring selected from the group consisting of C3-C8 saturated carboncyclic structures, linker X, RC , and -(CH2) K Each of these is bonded to an open valence atom in the CYC containing NH, R C However, it is absent, H, a C1-C4 alkyl group optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups, or structure: [ka] A group that follows the formula, where R4, R5, and R6 are each independently H, halogen, CN, NR N1 R N2 , -(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K These are C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -C(O)-C1-C4 alkyl groups, in which case the alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R C but, [ka] And, R N , R N1 , and R N2 Each of these is independently a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. K is an integer between 0 and 4, independently at each occurrence. K' is an integer between 0 and 4, independently at each occurrence. R N3 However, it is a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. R N4However, it is a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups, or R N4 but, [ka] (K is 1) [ka] However, it is a linker group that includes at least one [CPBM] group and connects the [CPBM] group to [CRBM] via one or more optional [CON] groups, or [ka] However, the linker group is a linker group that includes at least one functional group covalently bonded to at least one [CPBM] group or an optional [CON] group, R2 is [ka] And R N1 And K is the same as above, R AM However, H, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)-C1-C4 alkyl, -(CH2) K -NR N3 R N4 (R N3 is H or C1-C3 alkyl, where one of the alkyl groups is optionally substituted with 1-3 halogen groups or 1-2 hydroxyl groups. R N4 However, it is a C1-C3 alkyl group optionally substituted with H, 1-3 halo groups or 1 or 2 hydroxyl groups, or R N4 but, [ka] (K is 1) or R2 is [ka] And, R TA However, H, CN, NR N1 R N2 ,-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C4 alkyl, -(CH2) K COOH, -(CH2) K These are C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -C(O)-C1-C4 alkyl, where each alkyl is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R TA However, C3-C 10 An aryl group or a 3- to 10-membered heteroaryl group containing up to 5 heteroatoms, wherein the aryl group or the heteroaryl group is CN, NR, etc. N1 R N2 ,-(CH2) K OH, -(CH2) K OC1-C4 alkyl, C1-C3 alkyl, -O-C1-C3-alkyl, -(CH2) K COOH, -(CH2) K C(O)O-C1-C4 alkyl, OC(O)-C1-C4 alkyl, and -(CH2) K It is optionally substituted with 1 to 3 substituents selected from the group consisting of C(O)-C1-C4 alkyl groups, where each alkyl group is optionally substituted with 1 to 3 halogen groups or 1 to 2 hydroxyl groups, or R TA but, [ka] is, or R TAHowever, each is optionally substituted with 1 to 3 halogen groups and optionally substituted with 1 to 3 C1-C3 alkyl groups. [ka] is a base, or R TA but, [ka] And, R N , R N1 , and R N2 Each of these is independently a C1-C3 alkyl group optionally substituted with H, or 1-3 halogen groups or 1-2 hydroxyl groups. Each -(CH2) K Each group is optionally substituted with 1 to 4 C1-C3 alkyl groups, each optionally substituted with 1 to 3 fluorine groups or 1 to 2 hydroxyl groups. K is independently 0 to 4 for each occurrence. 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.

[0058] In some embodiments, the carbohydrate portion of the [ASGPRBM] group has an α-configuration at the anomeric center. In some embodiments, the carbohydrate portion of the [ASGPRBM] group has a β-configuration at the anomeric center.

[0059] In some embodiments, [CRBM] has the chemical structure: [ka] It is an [ASGPRBM] group that conforms to or contains such a group.

[0060] [CON] is a connector portion (including [MULTICON]) as otherwise described herein, and [LINKER] is a linking portion as otherwise described herein that links [CPBM] to a [CRBM] group and optionally includes one or more connector portions (either by optionally connecting two or more chemical parts to provide the linking portion, or by connecting the linking portion to the [CPBM] group or the [CRBM] group), or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0061] In various embodiments, X is -OC(R) when X has a length of 2 atoms. N1 )(R N1 ), C(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 ), C(R N1 )(R N1 )-S-, N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X has a length of 3 atoms, then -OC(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1 )-,-OC(R N1 )(R N1 )-O-, -OC(R N1 )(R N1 )-S-, -OC(R N1 )(R N1 )-N(R N1 )-,-SC(R N1 )(R N1 )-C(RN1 )(R N1 ), C(R N1 )(R N1 )-SC(R N1 )(R N1 )-, C(R N1 )(R N1 )-C(R N1 )(R N1 )-S, -SC(R N1 )(R N1 )-S-, -SC(R N1 )(R N1 )-O-, -SC(R N1 )(R N1 )-N(R N1 )-, N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 ), N(R N1 )-C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) and If X has a length of 4 atoms, then -OC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-OC(R N1 )(R N1 )-(R N1 )(R N1 )-,-OC(RN1 )(R N1 )-OC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-SC(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-(R N1 )(R N1 )-SC(R N1 )(R N1 )-,-SC(R N1 )(R N1 )-SC(R N1 )(R N1 )-, N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 )-, C(R N1 )(R N1 )-N(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ), C(R N1 )(R N1 )-C(R N1 )(R N1 )-N(R N1 ), N(R N1 )-C(R N1 )(R N1 )-N(R N1 ), or C(R N1 )(R N1 )-C(R N1 )(R N1 )-C(R N1 )(R N1 ) and R N1 This is the same as above. In most cases, RN1 H is H.

[0062] In various embodiments, X is OCH2 or CH2O, and R N1 H is H.

[0063] In various embodiments, the [CRBM] / [ASGPRBM] group has the following chemical structure: [ka] A base that follows, R1, R2, and R3 are groups, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, as defined herein.

[0064] In various embodiments, the [CRBM] / [ASGPRBM] group has the following chemical structure: [ka] It is a base that follows, R A However, it is a -C1-C3 alkyl group that is optionally substituted with 1 to 5 halogen groups. Z A However, -(CH2) IM -O-(CH2) IM , S-(CH2) IM , NR M -(CH2) IM , C(O)-(CH2) IM - A PEG group containing 1 to 8 ethylene glycol (CH2CH2O or OCH2CH2) units, or -C(O)(CH2) IM NR M IM and R M This is the same as above, Z B However, absent, -(CH2) IM -, -C(O)-(CH2) IM -, or -C(O)-(CH2) IM -NR M - and IM and R M This is the same as above.

[0065] In various embodiments, Z A This is a PEG group containing 1 to 4 ethylene glycol units. In various embodiments, Z A This is a PEG group containing 2 to 4 ethylene glycol units. In various embodiments, R A R is a C1-C3 alkyl group optionally substituted with 1 to 5 fluorine atoms. In various embodiments, R A R is a -CH3 group optionally substituted with 1 to 3 fluorine atoms. In various embodiments, R A This is a -CH2CH3 molecule that is selectively substituted with 1 to 3 fluorine atoms.

[0066] Please note that the above [CRBM] and [ASGPRBM] groups may also be represented as follows. [ka]

[0067] In the structure described above, the anomeric center of the carbohydrate portion has a β-configuration. In some embodiments, the anomeric center of the carbohydrate portion may have an α-configuration.

[0068] The terms “tumor” or “cancer” are used throughout this specification to refer to cancerous or malignant neoplasms, which are pathological processes resulting in the formation and proliferation of abnormal tissues that grow by cell proliferation, often more rapidly than normal, and continue to grow after the stimulus that initiated the new proliferation has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, recur after attempts to remove them, and are likely to cause death to the patient unless properly treated. As used herein, the term tumor is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors and solid tumors. Neoplasms include, but are not limited to, morphological irregularities of cells in the tissue of the subject or host compared to normal proliferation in the same histological type, as well as pathological proliferation of cells in the tissue of the subject. In addition, neoplasms include benign and malignant tumors (e.g., colon tumors), which are either invasive or non-invasive. Malignant neoplasms (cancers) are distinguished from benign neoplasms by exhibiting a greater degree of anaplasia or loss of cell differentiation and orientation, and by possessing invasive and metastatic characteristics.Examples of neoplasms or tumors from which the target cells of the present invention may originate include carcinomas (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, particularly Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; and central nervous system tumors. Tumors (e.g., glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliomas, gangliogliomas, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma); germline tumors (e.g., intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed tumors, particularly carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, e.g., Wilms' tumor and teratoma (Beers). and Berkow (eds.), The Merck Manual of Diagnosis and Therapy, 17th sup.th ed. (Whitehouse Station, NJ: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991). All of these neoplasms can be treated using the compounds according to the present invention.

[0069] Representative common cancers treated with the compounds of the present invention include, for example, prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer, and lymphoma, all of which can be treated with one or more compounds of the present invention. Due to the activity of this compound, the present invention has general applicability to treat substantially all cancers in any tissue, and therefore, the compounds, compositions, and methods of the present invention are generally applicable to the treatment of cancer and to reducing the likelihood of cancer development and / or metastasis of existing cancers.

[0070] In certain embodiments of the present invention, the cancer to be treated is metastatic cancer, recurrent cancer, or drug-resistant cancer (including, in particular, multidrug-resistant cancer). Separately, metastatic cancer can be found in substantially all tissues of a cancer patient in the later stages of the disease, and typically, metastatic cancer can be found in the lymphatic system / lymph nodes (lymphoma), bone, lung, bladder tissue, kidney tissue, liver tissue, and substantially any tissue (including the brain (brain cancer / tumor)). Therefore, the present invention is generally applicable and can be used to treat any cancer in any tissue, regardless of etiology.

[0071] The term "tumor" is used to describe malignant or benign growths or tumors.

[0072] The term "autoimmune disease" refers to a disease or illness that occurs when living tissues are attacked by their own immune system. The immune system is a complex body structure normally designed to "find and destroy" invaders, including infectious pathogens. In diseases known as autoimmune diseases, MIF levels are often elevated. This invention aims to suppress or reduce elevated MIF levels in patients with autoimmune diseases (as well as inflammatory diseases and conditions and cancer), thereby improving many of the symptoms and side effects of these conditions and conditions. Examples of autoimmune diseases that often present with high levels of MIF include, among many others, systemic lupus erythematosus, Sjögren's syndrome, Hashimoto's thyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes mellitus, polymyositis, scleroderma, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, and pulmonary fibrosis.

[0073] A more complete list of autoimmune diseases that can be treated with the compounds and pharmaceutical compositions according to the present invention includes, among others, Addison's disease, APS type 1, 2, and 3, autoimmune pancreatitis (AIP), type 1 diabetes mellitus, autoimmune thyroiditis, Oud's thyroiditis, Graves' disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjögren's syndrome, autoimmune enteropathy, celiac disease, Crohn's disease, microscopic colitis, ulcerative colitis, and autophospholipid syndrome. Aplastic syndrome (AP1S), aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cryoglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, painful steatosis, adult-onset Still's disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-associated arthritis, eosinophilic fasciitis, Felty syndrome AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixed connective tissue disease (MCTD), relapsing rheumatoid arthritis, Parry-Romberg syndrome, Personage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemic lupus erythematosus, undifferentiated connective tissue disease (UCTD), dermatomyositis, fibromyalgia, myositis, inclusion body myositis, myasthenia gravis Neurogenic myotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, anti-NMDA receptor encephalitis, Barlow concentric sclerosis, Bickerstaff brainstem encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, pattern II, Oschtran syndrome, childhood autoimmune streptococcal infection-associated neuropsychiatric disorders PANDAS, progressive inflammatory neuropathy, restless leg syndrome, generalized rigidity syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, woody conjunctivitis, Mollen's ulcer, neuromyelitis optica, opsoclonus-myoclonus syndrome, optic neuritis, scleritis, Suzak syndrome, sympathetic ophthalmitis, Tolosa-Hunt syndrome, autoimmune cochlear disease (AIED),This includes Meniere's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis, granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), Kawasaki disease, leukocytosis-destroying vasculitis, lupus vasculitis, rheumatic vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immunodeficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud's disease, primary immunodeficiency disorders, and pyoderma gangrenosum.

[0074] The term "inflammatory disease" is used to describe diseases or illnesses that have acute inflammation as their main symptom, but more often have chronic inflammation. Inflammatory diseases include, among other things, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease; including other ataxias), and immune response disorders that cause inflammation (e.g., T cell maturation, B cell and T cell homeostasis, counters damaging inflammation). Dysregulation of inflammation), chronic inflammatory diseases (e.g., inflammatory bowel disease (including Crohn's disease), rheumatoid arthritis, lupus, multiple sclerosis, chronic obstructive pulmonary disease / COPD, pulmonary fibrosis, cystic fibrosis, Sjögren's disease); hyperglycemic disorders, diabetes mellitus (types I and II) (affecting lipid metabolism, islet function, and / or islet structure), pancreatic β-cell death, and related hyperglycemic disorders (including severe insulin resistance, hyperinsulinemia, insulin-resistant diabetes mellitus (e.g., Mendenhall syndrome, Werner syndrome, pyelonephrosis, and lipoatrophic diabetes mellitus)), and dyslipidemia (e.g., hyperlipidemia, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein (HDL), elevated triglycerides, and metabolic syndrome) as shown in obese subjects. Syndrome, liver disease, kidney disease (apoptosis in atherosclerotic plaque, glomerular disease), cardiovascular disease (particularly complications during infarction, ischemia, stroke, pressure overload, and reperfusion), muscle degeneration and muscular atrophy, low-grade inflammation, gout, silicosis, atherosclerosis and related conditions, e.g., cardiac and neurological signs (both central and peripheral) (including stroke, age-related dementia and sporadic Alzheimer's disease, as well as psychiatric conditions (including depression)), stroke and spinal cord injury, and arteriosclerosis. Elevated MIF is observed very frequently in these diseases, and these conditions and / or states are made responsive to therapy using the compounds and / or pharmaceutical compositions according to the present invention. It should be noted that there is some overlap between certain autoimmune diseases and the inflammatory diseases described herein.

[0075] The term "linker" refers to a chemical substance comprising a complex linker that optionally connects a circulating protein-binding portion (CPBM) to a cell receptor-binding portion (CRBM) containing an asial glycoprotein receptor-binding portion (ASGPRBM) via at least one (preferably one or two) connector portions [CON] in the compound according to the present invention via covalent bonds. The linker between these two active portions of the molecule, namely the CPBM group and the CRBM / ASGPRBM group, is in the range of approximately 5 Å to 50 Å or more in length, approximately 6 Å to 45 Å in length, approximately 7 Å to 40 Å in length, approximately 8 Å to 35 Å in length, approximately 9 Å to 30 Å in length, approximately 10 Å to 25 Å in length, approximately 7 Å to 20 Å in length, approximately 5 Å to 16 Å in length, approximately 5 Å to 15 Å in length, approximately 6 Å to 14 Å in length, approximately 10 Å to 20 Å in length, approximately 11 Å to 25 Å in length, etc. Linkers based on ethylene glycol units and having lengths of 2–15 glycol units, 1–8 glycol units, 1, 2, 3, 4, 5, and 6 glycol units may be preferred, although certain linkers may be much longer. By having linkers having lengths otherwise disclosed herein, the CPBM and CRBM / ASGPRBM groups are positioned to advantageously utilize the biological activity of the compounds according to the present invention in binding to receptors, including asialoclycoprotein receptors, on hepatocytes and other cells, thereby potentially resulting in selective targeted degradation of circulating proteins within lysosomal degradation mechanisms or other degradation mechanisms of hepatocytes. The selection of linker components is based on their demonstrated properties of biocompatibility, solubility in aqueous and organic media, and low immunogenicity / antigenicity. Numerous linkers may be used as described elsewhere herein, but linkers based on polyethylene glycol (PEG) bonds, polypropylene glycol bonds, or polyethylene glycol-co-polypropylene oligomers (up to about 100 units, about 1-100, about 1-75, about 1-60, about 1-50, about 1-35, about 1-25, about 1-20, about 1-15, 2-10, about 4-12, about 1-8, 1-3, 1-4, 2-6, 1-5, etc.) may be preferred as linkers due to the chemical and biological properties of these molecules. The use of polyethylene (PEG) bonds with 2-15 ethylene glycol units is preferred.When describing the 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., methylene groups or amide groups are preferred) may be covalently bonded to any end of the linker group to the CRBM / ASGPRBM group, the [CON] group, another linker group, or the CPBM group.

[0076] Alternative linkers include, for example, polyamino acid linkers with a maximum length of 100 amino acids (of any type, preferably D- or L-amino acids, preferably naturally occurring L-amino acids) (about 1-75, about 1-60, about 1-50, about 1-45, about 1-35, about 1-25, about 1-20, about 1-15, 2-10, about 4-12, about 5-10, about 4-6, about 1-8, about 1-6, about 1-5, about 1-4, about 1-3 lengths) that optionally contain one or more linking groups (preferably one or two linking groups at one or both ends of the polyamino acid linker).

[0077] A preferred linker has the following chemical structure: [ka] Those who follow, Alternatively, examples include polypropylene glycol or polypropylene-co-polyethylene glycol linker having 1 to 100, 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, or about 1 to 3 alkylene glycol units. R a is either H, C1-C3 alkyl, or alkanol, or R 3 Together with (proline), it forms a cyclic ring, R 3Preferably, alanine (methyl), arginine (propylene guanidine), asparagine (methylene carboxamide), aspartic acid (ethaneic acid), cysteine ​​(thiol, reduced or oxidized dithiol), glutamine (ethyl carboxamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethyl methyl thioether), phenylalanine (benzyl), proline, hydroxyproline (R 3 However, R a A side chain derived from a D-amino acid or L-amino acid (preferably a naturally occurring L-amino acid) selected from the group consisting of serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methylene indole), tyrosine (methylenephenol), or valine (isopropyl), where R 3 The base is shown in parentheses, m (in the context of this usage) is an integer between 1 and 100, 1 and 75, 1 and 60, 1 and 55, 1 and 50, 1 and 45, 1 and 40, 2 and 35, 3 and 30, 1 and 15, 1 and 12, 1 and 10, 1 and 8, 1 and 6, 1, 2, 3, 4, or 5.

[0078] In another embodiment, the linker according to the present invention comprises a polyethylene glycol linker containing 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 a lysine group or other amino acid moiety (which may consist of 1 to 10 amino acids that can be bound to a CPBM group and / or a CRBM / ASGPRBM group) is attached at one or both ends of the linker. Yet another linker comprises an amino acid residue (D or L) attached to the CPBM moiety and / or CRBM / ASGPRBM moiety, as separately described herein. In another embodiment, as separately described herein, the amino acid has 1 to 15 methylene groups that separate the amino group from the acid (acyl) group when providing a linker to the MIFBM and / or ASGRBM group, and this linker comprises 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 amino acid groups, which are linked together via peptide bonds to form this linker. This linker has the chemical structure: [ka] Represented by, R am is a C1-C3 alkyl group optionally substituted with H or 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 between 1 and 100, 1 and 75, 1 and 60, 1 and 55, 1 and 50, 1 and 8, 1 and 6, 1, 2, 3, 4, or 5.

[0079] In various embodiments, the linker has the chemical formula: [ka] in accordance with Z and Z' are independent of each other, bonded, -(CH2) i -O, -(CH2) i -S, -(CH2) i -NR, [ka] And, (CH2) i If the base is present in Z or Z', it is coupled to a connector (CON), CPBM, or CRBM / ASGPRBM. Each R is H, or a C1-C3 alkyl or alkanol group. Each R 2 These are independently H or C1-C3 alkyl groups. Each Y is independently a combination, O, S, or NR. Each i is independently 0-100, 0-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 0, 1, 2, 3, 4, or 5. D is [ka] or It is a combination, provided that Z, Z', and D are not simultaneously combined. j is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5. m' is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5. n is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5 (n is preferably 2), X 1 It is O, S, or NR, R is H, or a C1-C3 alkyl or alkanol group, or a pharmaceutical salt thereof.

[0080] In one embodiment, other linkers included herein have the following chemical structure: [ka] The linkers that follow this rule are listed below. Each n and n' is independently 1-25, 1-15, 1-12, 2-11, 2-10, 2-8, 2-6, 2-5, 2-4, and 2-3, or 1, 2, 3, 4, 5, 6, 7, or 8. Each n'' is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5, or 6 (preferably 2, 3, 4, or 5).

[0081] A linker can also form a complex linker, comprising two or more linker segments (based on the linkers described above) that are directly bonded to each other or bonded via [CON] groups. A particular linker containing a [CON] group connecting a first (PEG) linker group and a second (PEG) linker group has the following structure: [ka] or [ka] Includes, Each n and n' is independently 1-25, 1-15, 1-12, 2-11, 2-10, 2-8, 2-6, 2-5, 2-4, and 2-3, or 1, 2, 3, 4, 5, 6, 7, or 8. Each n'' is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5, or 6 (preferably 3).

[0082] Each of these linkers may also contain an alkylene group with 1 to 4 methylene groups at the distal end of each linker group to facilitate the linking of the linker groups.

[0083] Other linkers containing the connector group [CON] include those with the chemical formula: Examples of groups represented by PEG-[CON]-PEG include: Each PEG linker is independently a polyethylene glycol group containing 1 to 12 ethylene glycol units, and [CON] is a connector group described separately herein. In various embodiments, [CON] is [ka] That is the case.

[0084] The term "connector," symbolized as "CON" or [CON] in the general formula, is used to describe a chemical moiety optionally included in the bifunctional compounds according to the present invention, formed from the reaction product of an activated linker and a CPBM moiety (preferably activated for covalent bonding between the linker and its moiety) or from the reaction product of a CRBM / ASGPRBM group and an activated linker. A connector group is often a moiety resulting from the easy condensation of two or more distinct chemical fragments containing reactive groups that can provide connector groups, as otherwise described herein, for generating the bifunctional or polyfunctional compounds according to the present invention. A connector may be distinguishable from a linker in that it is the result of a specific chemical reaction used to provide the bifunctional compounds according to the present invention, and the reaction products of these groups may result in a distinguishable connector group or a portion of a connector group distinguishable from a linker group; however, in certain specific cases, the connector group may be incorporated into and become integrated with the linker group, as otherwise described herein.

[0085] Furthermore, it should be noted that connector groups may be linked to several linkers in order to provide multifunctionality within the same molecule (i.e., two or more CPBM moieties and / or two or more CRBM / ASGPRBM moieties). In particular, with respect to more common connector groups such as amide groups, oxygen (ether), sulfur (thioether), or amine bonds, urea or carbonate-OC(O)O- groups, or those otherwise described herein, it should be noted that there may be some overlap between the description of connector groups and the description of linker groups, such as when the connector group is actually incorporated or forms part of a linker. Furthermore, if the connector (or linker) is symbolized as: [ka] Note that at locations indicated as being linked to another base using , it may be connected to a CPBM, CRBM / ASGPRBM, or linker.

[0086] If two or more such groups (symbols) are present in the linker or connector, one of the CRBM / ASGPRBM group, linker group, or CPBM group may be bonded to one of these groups. If the symbol is not used, the linker may be located in one or more positions in the region where open valences exist.

[0087] In various embodiments, preferred [CON] connector groups used in the present invention include the following chemical groups: [ka] This includes, R CON1 and R CON2 Each of these independently represents H, methyl, or a bond (for bonding to another part), or structure: [ka] It is a diamide group that follows the formula, X 2 However, CH2, O, S, NR 4, C(O), S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O, X 3 However, O, S, NR 4 And, R 4 However, it is an H, C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group, R 1 However, it is H or a C1-C3 alkyl group (preferably H), n" is independently 0-8, often 1-7, or 1, 2, 3, 4, 5, or 6 (preferably 3), Alternatively, the connector group [CON] has the following chemical structure: [ka] It is a base that follows, R 1CON , R 2CON , and R 3CON Each of them independently represents H, -(CH2) MC1 ,-(CH2) MC1a C(O) XA (NR 4 ) XA -(CH2) MC1a ,-(CH2) MC1a (NR 4 ) XA C(O) XA -(CH2) MC1a , or -(CH2) MC1a O-(CH2) MC1 -C(O)NR 4 -However, R 1CON , R 2CON , and R 3CON The condition is that H is not at the same time, Each MC1 is an integer between 1 and 4, independently. Each MC1a is an independent integer between 0 and 4. R 4 However, it is either an H, a C1-C3 alkyl or alkanol group, or a -C(O)(C1-C3) group.

[0088] In various embodiments, MC1 is 1 or 2. In various embodiments, MC1a is 0, 1, or 2.

[0089] The triazole group shown above may be a preferred connector group. Additional preferred connector groups are: [ka] And, It is connected to at least one CPBM and / or at least one CRBM / ASPRGBM (preferably three CRBM / ASPRGBM portions). This connector base may be used to form GN3 as otherwise described herein.

[0090] Note 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. Note that in certain cases, a diamide group may also function independently as a linker group within the given context.

[0091] In some embodiments, at least one of [CON] and [linker] is [ka] or including the same. In some embodiments, at least one of [CON] is [ka] Includes. In some embodiments, the [linker] is [ka] It is either or includes it.

[0092] Additional galactose-based and talose-based ASGPR binding moieties In one embodiment, the present invention relates to a compound useful for removing circulating proteins related to a pathological condition or state in a patient or subject, which conforms to the general chemical structure of Formula II. [ka] Formula II

[0093] As used herein, the term “extracellular protein-targeting ligand” is used interchangeably with the term “CPBM” (cell protein binding site). As used herein, the term “ASGPR ligand” is used interchangeably with the “asiaroglycoprotein receptor (ASGPR) binding site” as defined herein.

[0094] In the compound of formula II, each [CON] is an optional connector chemical moiety that either directly connects to [CPBM] or [CRBM] if present, or connects [linker-2] to [CPBM] or [CRBM].

[0095] In the compound of formula II, [Linker-2] is a chemical moiety having a valency of 1 to 15 that is covalently bonded to one or more [CRBM] groups and / or [CPBM] groups via [CON] (including a [MULTICON] group), and [Linker-2] itself optionally contains one or more [CON] groups or [MULTICON] groups. k' is an integer between 1 and 15. j' is an integer between 1 and 15. h and h' are each independent integers between 0 and 15. i L It is an integer from 0 to 15, However, h, h', and i L A pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, provided that at least one of them is at least one.

[0096] The [MULTICON] group can connect one or more [CRBM] or [CPBM] groups to one or more [linker-2] groups. 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, [linker-2] is the linker as defined herein. A Linker B Linker C Linker D , and / or one or more combinations thereof.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] In the compound of formula II, X 1 O, S, N(R) b ), and C(R 4 )(R 4 ) are 1 to 5 adjacent atoms selected independently from X 1 If X is a single atom, 1 O, S, N(R 6 ), or C(R 4 )(R 4 ) and X 1If X has two atoms, 1 One or fewer atoms are O, S, or N(R) 6 ) and X 1 If X has 3, 4, or 5 atoms, 1 Two or fewer atoms are O, S, or N(R) 6 ) and R 3 Each instance independently contains hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocyclic, -OR 8 , and -NR 8 R 9 Selected from, R 4 Each instance independently involves hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 , -NR 6 R 7 Selected from, R 6 and R 7 Each instance independently includes hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from, R 8 and R 9 Each instance of a character is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0101] In terms of chemical structure, throughout this application, the “extracellular protein-targeting ligand” corresponds to the aforementioned [CPBM].

[0102] A. Galactose-based ASGPR-binding cell receptor binding portion of formula II In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0103] In one embodiment, the compound of formula II has one of the following structures. [ka]

[0104] In various embodiments, the ASGPR ligand is C 1 Position or C 5 Rank (R 1 Position or R 5 It is linked at any of the positions to form a decomposition compound. In various embodiments, the ASGPR ligand is C 6 They are linked at a certain position to form a decomposition compound. For example, the ASGPR ligand [ka] In that case, non-limiting examples of ASGPR-binding compounds of formula II include: [ka] Examples include disubstituted or trisubstituted versions thereof, or pharmaceutically acceptable salts thereof, where disubstituted or trisubstituted refers to the number of additional galactose derivatives bonded to the linker moiety.

[0105] In any of the embodiments herein referenced for use in a degrading agent, the ASGPR ligand is typically C 5 A targeting ligand for an extracellular protein at a specific position (for example, this is adjacent to C 6Linked to a carbon hydroxyl or other functional moiety that can be used for binding purposes. The linker and extracellular protein targeting ligand are C 1 If connected via a position, the carbon is appropriately functionalized to link with, for example, a hydroxyl, amino, allyl, alkyne, or hydroxyl-allyl group.

[0106] In various embodiments, the ASGPR ligand is used for ASGPR binding in the liver. 3 Position or C 4 Because the chelating site chelates with calcium, C 3 Position or C 4 They are not linked at the 11th position. In certain embodiments, ASGPR ligands useful for incorporation into the compound of formula II are selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0107] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] [ka] [ka] [ka]

[0108] B. Formula II: Talos-based ASGPR-binding cell receptor binding portion In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0109] In one embodiment, the compound of formula II is an extracellular proteolytic compound in which the ASGPR ligand is a ligand described herein. [ka]

[0110] In one embodiment, in the compound of formula II, the ASGPR ligand is located at the C1 or C5 position (R 1 Position or R 5 It is linked at any of the positions (C6) to form a decomposition compound. In one embodiment, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is [ka] In that case, non-limiting examples of ASGPR-binding compounds of formula II include: [ka] Examples include disubstituted or trisubstituted versions thereof, or pharmaceutically acceptable salts thereof, where disubstituted or trisubstituted refers to the number of additional galactose derivatives bonded to the linker moiety. In certain embodiments, the compound of formula II is selected from the following: [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0111] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0112] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0113] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0114] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0115] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0116] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0117] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0118] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR b COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0119] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0120] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0121] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0122] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0123] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] In a particular embodiment, R 2-NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), these R 2 Each group is optionally substituted with one, two, three, or four independent substituents as described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0124] In a particular embodiment, the compound of formula II is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0125] In a particular embodiment, the ASGPR ligand useful for incorporation into the compound of formula II is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0126] C. ASGPR ligand / binding site in compound of formula II In a particular embodiment, in a compound of formula II, R 1 It is hydrogen.

[0127] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0128] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0129] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0130] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0131] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0132] In a particular embodiment, in a compound of formula II, R 1 teeth, [ka] That is the case.

[0133] In a particular embodiment, in a compound of formula II, R 1 It is a C0-C6 alkyl-cyano that is optionally substituted with 1, 2, 3, or 4 substituents.

[0134] In a particular embodiment, in a compound of formula II, R 1 This is an alkyl group optionally substituted with 1, 2, 3, or 4 substituents.

[0135] In a particular embodiment, in a compound of formula II, R 1is an alkenyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is an alkynyl optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 is a haloalkyl that is optionally substituted with 1, 2, 3, or 4 substituents. In certain embodiments, in the compound of formula II, R 1 It is F.

[0136] In a particular embodiment, in a compound of formula II, R 1 It is Cl.

[0137] In a particular embodiment, in a compound of formula II, R 1 It is Br.

[0138] In a particular embodiment, in a compound of formula II, R 1 This is an aryl molecule optionally substituted with one, two, three, or four substituents.

[0139] In a particular embodiment, in a compound of formula II, R 1 This is an arylalkyl that is optionally substituted with 1, 2, 3, or 4 substituents.

[0140] In a particular embodiment, in a compound of formula II, R 1 It is a heteroaryl compound that is optionally substituted with 1, 2, 3, or 4 substituents.

[0141] In a particular embodiment, in a compound of formula II, R 1 This is a heteroarylalkyl that is optionally substituted with 1, 2, 3, or 4 substituents.

[0142] In a particular embodiment, in a compound of formula II, R 1 It is a heterocycle that is optionally substituted with 1, 2, 3, or 4 substituents.

[0143] In a particular embodiment, in a compound of formula II, R 1 It is a heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents.

[0144] In a particular embodiment, in a compound of formula II, R 1 It is a haloalkoxy that is optionally substituted with 1, 2, 3, or 4 substituents.

[0145] In a particular embodiment, in a compound of formula II, R 1 These are -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR compounds, each optionally substituted with 1, 2, 3, or 4 substituents. 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0-C6 alkyl-S(O)2R 3 , C0-C6alkyl-N(R 8 )-C(O)R 3 , C0-C6alkyl-N(R 8 )-S(O)R 3 , C0-C6alkyl-N(R 8 )-C(S)R 3 , C0-C6alkyl-N(R 8 )-S(O)2R 3 C0-C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, or C0-C6 alkyl-OS(O)2R 3 That is the case.

[0146] In a particular embodiment, in a compound of formula II, R 2This is an aryl molecule optionally substituted with one, two, three, or four substituents.

[0147] In a particular embodiment, in a compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3, or 4 substituents.

[0148] In a particular embodiment, in a compound of formula II, R 2 This is a heteroaryl compound containing one or two heteroatoms independently selected from N, O, and S, which are optionally substituted with one, two, three, or four substituents.

[0149] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0150] In a particular embodiment, in a compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3, or 4 substituents.

[0151] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 -S(O)-R 3 That is the case.

[0152] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 -C(S)-R 3 That is the case.

[0153] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 -S(O)(NR6 )-R 3 That is the case.

[0154] In a particular embodiment, in a compound of formula II, R 2 -N=S(O)(R) is optionally substituted with 1, 2, 3, or 4 substituents. 3 )2.

[0155] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 C(O)NR 9 S(O)2R 3 That is the case.

[0156] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 -S(O)2-R 10 That is the case.

[0157] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 8 -C(NR 6 )-R 3 That is the case.

[0158] In a particular embodiment, in a compound of formula II, R 2 It is hydrogen.

[0159] In a particular embodiment, in a compound of formula II, R 2 R 10 That is the case.

[0160] In a particular embodiment, in a compound of formula II, R 2 is alkyl-C(O)-R 3 That is the case.

[0161] In a particular embodiment, in a compound of formula II, R 2is -C(O)-R 3 That is the case.

[0162] In a particular embodiment, in a compound of formula II, R 2 It is an alkyl group.

[0163] In a particular embodiment, in a compound of formula II, R 2 It is a haloalkyl compound.

[0164] In a particular embodiment, in a compound of formula II, R 2 is -OC(O)R 3 That is the case.

[0165] In a particular embodiment, in a compound of formula II, R 2 -NR 8 -C(O)R 10 That is the case.

[0166] In a particular embodiment, in a compound of formula II, R 2 is an alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

[0167] In a particular embodiment, in a compound of formula II, R 2 This is an allele that is optionally substituted with 1, 2, 3, or 4 substituents.

[0168] In a particular embodiment, in a compound of formula II, R 2 This is an alkynyl compound optionally substituted with 1, 2, 3, or 4 substituents.

[0169] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 6 -It is Alkenil.

[0170] In a particular embodiment, in a compound of formula II, R 2It is an -O-alkenyl that is optionally substituted with 1, 2, 3, or 4 substituents.

[0171] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 6 - It is Alkinnil.

[0172] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 6 -It is a heteroaryl compound.

[0173] In a particular embodiment, in a compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3, or 4 substituents. 6 - It is Ariel.

[0174] In a particular embodiment, in a compound of formula II, R 2 It is an -O-heteroaryl compound that is optionally substituted with 1, 2, 3, or 4 substituents.

[0175] In a particular embodiment, in a compound of formula II, R 2 It is an -O-aryl compound that is optionally substituted with 1, 2, 3, or 4 substituents.

[0176] In a particular embodiment, in a compound of formula II, R 2 This is an -O-alkynyl molecule optionally substituted with 1, 2, 3, or 4 substituents.

[0177] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0178] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0179] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] R is selected from the following, where R is an optional substituent as defined herein.

[0180] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0181] In a particular embodiment, in a compound of formula II, R 2A teeth, [ka] R is selected from the following, where R is an optional substituent as defined herein.

[0182] In a particular embodiment, in a compound of formula II, R 2A teeth, [ka] Selected from.

[0183] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0184] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0185] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0186] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0187] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0188] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0189] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0190] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0191] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0192] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0193] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0194] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0195] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from. In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0196] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0197] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0198] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0199] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0200] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0201] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0202] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0203] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0204] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0205] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0206] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0207] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0208] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0209] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0210] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0211] In a particular embodiment, in a compound of formula II, R 2 or R 2A teeth, [ka] Selected from.

[0212] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0213] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0214] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0215] In a particular embodiment, in a compound of formula II, R 2 teeth, [ka] Selected from.

[0216] In a particular embodiment, in a compound of formula II, R 2 teeth, In a particular embodiment, in a compound of formula II, R 2 This is a spirocyclic heteroalgebra, for example, but is not limited to, [ka] That is the case.

[0217] In a particular embodiment, in a compound of formula II, R 2 is a silicon-containing heterocycle, for example, but is not limited to, [ka] That is the case.

[0218] In a particular embodiment, in a compound of formula II, R 2 This has been replaced with SF5, for example, not limited to, [ka] That is the case.

[0219] In a particular embodiment, in a compound of formula II, R 2 It is substituted with a sulfoxime, for example, but is not limited to, [ka] That is the case.

[0220] In a particular embodiment, in a compound of formula II, R 10 It is selected from biring complex algebras.

[0221] In a particular embodiment, in a compound of formula II, R 10It is selected from spirocyclic heteroalgebras.

[0222] In a particular embodiment, in a compound of formula II, R 10 -NR 6 - Selected from a complex algebra.

[0223] In a particular embodiment, in a compound of formula II, R 10 teeth, [ka] Selected from.

[0224] In a particular embodiment, in a compound of formula II, R 10 teeth, [ka] Selected from.

[0225] In a particular embodiment, in a compound of formula II, R 10 teeth, [ka] Selected from.

[0226] In a particular embodiment, in a compound of formula II, R 10 teeth, [ka] Selected from.

[0227] In a particular embodiment, in the compound of formula II, the ring is [ka] Selected from.

[0228] In a particular embodiment, in a compound of formula II, R 30 teeth, [ka] Selected from.

[0229] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0230] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0231] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0232] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0233] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0234] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0235] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0236] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0237] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0238] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0239] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0240] In a particular embodiment, in a compound of formula II, R 200 teeth, [ka] That is the case.

[0241] Linker In a non-limiting embodiment, in the compound of formula II, a linker A and linker B Independently, [ka] Selected from, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 Each of them, at each occurrence, independently, each is R 21 The bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the bond, alkyl, -C(O)-, -C(O)O-, -OC(O)O-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-,-P(O)(R 3 )O-, -P(O)(R 3 )-, divalent residues of natural or unnatural amino acids, alkenyls, alkynyls, haloalkyls, alkoxys, and heterocyclics, heteroaryls, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -,-[-(CH2)2-O-] n -,-[O-(CH2)2] n -,-[O-CH(CH3)C(O)] n -,-[C(O)-CH(CH3)-O] n -, -[O-CH2C(O)] n -,-[C(O)-CH2-O] n - Selected from the group consisting of divalent residues of fatty acids, unsaturated or saturated monocarboxylic acids, or divalent residues of dicarboxylic acids, n is independently selected in each case from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. R21 Each instance independently includes hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, and -NR. 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Selected from the group consisting of haloalkyl, heteroalkyl, and heteroaryl compounds, The remaining variables are as defined herein.

[0242] In one embodiment, in a compound of formula II, a linker A It is a bond, a linker B teeth [ka] That is the case.

[0243] In one embodiment, in a compound of formula II, a linker B It is a bond, a linker A teeth [ka] That is the case.

[0244] In one embodiment, in the compound of formula II, the divalent residue of the amino acid is [ka] Selected from, Amino acids can be oriented in any direction, and they can be L-type, D-type, or a mixture thereof.

[0245] In one embodiment, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated by a nucleophilic addition reaction. [ka]

[0246] Non-limiting embodiments of divalent residues of dicarboxylic acids generated from nucleophilic addition reactions include: [ka] It includes.

[0247] In one embodiment, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated from a condensation reaction. [ka]

[0248] Non-limiting embodiments of the divalent residues of dicarboxylic acids generated from condensation include: [ka] It includes.

[0249] Non-limiting embodiments of divalent residues of saturated dicarboxylic acids include: [ka] It includes.

[0250] Non-limiting embodiments of divalent residues of saturated dicarboxylic acids include: [ka] It includes.

[0251] Non-limiting embodiments of the divalent residue of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), and lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2)14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 Selected from CH2-).

[0252] Non-limiting embodiments of the divalent residues of fatty acids include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, pauric acid, oleic acid, elaidic acid, gondic acid, gadolic acid, nervonic acid, myristoleic acid, and erucic acid. [ka]

[0253] Non-limiting embodiments of the divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), alpha-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), γ-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-), Paulic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadolic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2)13 CHCH(CH2)3CH2-), Mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), Myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and Erucic acid (-C(O)(CH2) 11 Selected from CHCH(CH2)7CH2-).

[0254] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from, R 22 Each instance of occurrence is independent, and each is R 21 Alkyl, -C(O)N-, -NC(O)-, -N-, -C(R) 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 ) Selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, The remaining variables are as defined herein.

[0255] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from, R 32 Each instance of occurrence is independent, and each is R 21 Alkyl, N, optionally substituted with 1, 2, 3, or 4 substituents independently selected from + Selected from the group consisting of X-, -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, X- represents an anionic group, such as Br- or Cl. - And, All other variables are as defined herein.

[0256] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from, Each heteroaryl, heterocyclic, cycloalkyl, and aryl can be optionally substituted with one, two, three, or four elements from any combination of halogens, alkyls, haloalkyls, and heteroaryls, heterocyclics, or cycloalkyls, provided that the valence allows it.

[0257] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from, Each heteroaryl, heterocyclic, cycloalkyl, and cycloalkyl can be optionally substituted with one, two, three, or four elements from any combination of halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, if permitted by valence.

[0258] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0259] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0260] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, [ka] Selected from, tt is independently selected from 1, 2, or 3, and ss is 3 minus tt (3-tt).

[0261] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, [ka] Selected from, tt and ss are as defined herein.

[0262] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, [ka] [ka] [ka] [ka] Selected from, Each heteroaryl, heterocyclic, cycloalkyl, and aryl can be optionally substituted with one, two, three, or four elements from any combination of halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein.

[0263] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, [ka] [ka] Selected from, Each heteroaryl, heterocyclic, cycloalkyl, and aryl can be optionally substituted with one, two, three, or four elements from any combination of halogens, alkyls, haloalkyls, and heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein.

[0264] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, [ka] Selected from, Each heteroaryl and aryl can be optionally substituted with one, two, three, or four elements from any combination of halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, where permitted by valence, and tt and ss are as defined herein.

[0265] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0266] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0267] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0268] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0269] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0270] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0271] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0272] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] [ka] Selected from.

[0273] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0274] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0275] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0276] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0277] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0278] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0279] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0280] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0281] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0282] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0283] In a particular embodiment, in the compound of formula II, linker D is [ka] Selected from.

[0284] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0285] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0286] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0287] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0288] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0289] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0290] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0291] In a particular embodiment, the linker A The following can be selected: [ka] Each of them, R 21 It is optionally substituted with 1, 2, 3, or 4 substituents selected from the following.

[0292] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0293] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0294] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0295] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0296] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0297] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0298] In a particular embodiment, in a compound of formula II, a linker A is selected from

[0299] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] [ka] Selected from.

[0300] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0301] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0302] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0303] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0304] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0305] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0306] In a particular embodiment, in a compound of formula II, a linker A teeth, [ka] Selected from.

[0307] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0308] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0309] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0310] In a particular embodiment, in a compound of formula II, a linker B is selected from, and each is R 21 It is optionally substituted with 1, 2, 3, or 4 substituents selected from the following.

[0311] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0312] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0313] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0314] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0315] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0316] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0317] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0318] In a particular embodiment, in a compound of formula II, a linker B teeth, [ka] Selected from.

[0319] In a particular embodiment, in a compound of formula II, a linker B - Linker A teeth, [ka] Selected from.

[0320] In a particular embodiment, in a compound of formula II, a linker B - Linker A teeth, [ka] Selected from.

[0321] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0322] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0323] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0324] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0325] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0326] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0327] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] [ka] Selected from.

[0328] In a particular embodiment, in a compound of formula II, a linker C is selected from, and each is R 21It is optionally substituted with 1, 2, 3, or 4 substituents selected from the following.

[0329] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0330] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0331] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0332] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0333] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0334] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0335] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0336] In a particular embodiment, in a compound of formula II, a linker C teeth, [ka] Selected from.

[0337] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, [ka] Selected from.

[0338] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, [ka] Selected from.

[0339] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, [ka] Selected from.

[0340] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, [ka] Selected from.

[0341] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from.

[0342] In a particular embodiment, in a compound of formula II, a linker D teeth, [ka] Selected from, Each is optionally substituted with 1, 2, 3, or 4 substituents, R 21 Selected from.

[0343] In a particular embodiment, in a compound of formula II, a linker B -(Linker A )teeth, [ka] Selected from.

[0344] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )teeth, [ka] Selected from.

[0345] In a particular embodiment, in a compound of formula II, a linker D -(Linker A )teeth, [ka] Selected from.

[0346] In various embodiments, R 4Each instance independently involves hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 , -NR 6 R 7 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from.

[0347] In various embodiments, in the compound of formula II, R 5 These are hydrogen, heteroalkyl, and each is independently and selectively substituted with 1, 2, 3, or 4 substituents. [ka] C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0-C6 alkyl-S(O)2R 3 , C0-C6alkyl-N(R 8 )-C(O)R 3 , C0-C6alkyl-N(R 8 )-S(O)R 3 , C0-C6alkyl-N(R 8 )-C(S)R 3 , C0-C6alkyl-N(R 8 )-S(O)2R 3 C0-C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, and C0-C6 alkyl-OS(O)2R 3 Selected from.

[0348] In various embodiments, in the compound of formula II, R 6 and R 7 Each instance independently includes hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 S(O)R 3 , C(S)R 3 , and S(O)2R 3 Selected from.

[0349] In various embodiments, in the compound of formula II, R 8 and R 9 Each instance of a character is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0350] In various embodiments, the compound of formula II has the structure of formula II-A.

[0351] structure: [ka] Formula II-A A compound of formula II-A having, [CPBM] is a circulating protein binding portion that binds to circulating proteins in the target, and the circulating proteins are to be removed by the action of the target hepatocytes or other cells, which mediate the pathological condition or state. [ASGPBM] is [ka] is an asialoglycoprotein receptor-binding moiety having a structure selected from each [CON], when present, is an optional connector chemical moiety that connects [LIN] to [CPBM] or [ASGPBM], [LIN] is [linker] or [linker-2], each of which is a chemical moiety having 1 to 15 valences that are optionally covalently bonded to one or more [ASGPBM] groups or [CPBM] groups via [CON], and [LIN] itself optionally contains one or more [CON] groups, Z B is absent, (CH2) IM , C(O)-(CH2) IM -, or C(O)-(CH2) IM -NR M and R M is H, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups, R2 is

Chemical formula

Chemical formula

[0352] In various embodiments, in the compound of formula II-A, R2 is -NC(=O)CH3.

[0353] As used herein, the term “organic group” refers to any carbon-containing functional group. Examples include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo(carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur-containing groups such as alkyl and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, O(O)R, C(O)N(R)2, O(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R )C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C 100 ) Hydrocarbyl is an example, where R can be hydrogen (in examples containing other carbon atoms) or a carbon-based portion, and the carbon-based portion can be substituted or unsubstituted.

[0354] As used herein in conjunction with the definitions of molecules or organic groups, the term “substitution” refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. Substitutions can be direct substitutions, where a hydrogen atom is replaced by a functional group or substituent, or indirect substitutions, where an intervening linker group replaces a hydrogen atom and the substituent or functional group is bonded to the intervening linker group. A non-limiting example of a direct substitution is RR-H → RR-Cl (where RR is an organic moiety / fragment / molecule). A non-limiting example of an indirect substitution is RR-H → RR-(LL). zz -Cl(RR is the organic part / fragment / molecule, LL is the intervening linker group, and "zz" is an integer from 0 to 100 (including boundary values)). If zz is 0, LL is absent and a direct substitution occurs. The intervening linker group LL is independently selected at each occurrence 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 These can be linear, branched, cyclic, acyclic, or combinations thereof.

[0355] As used herein, the terms “functional group” or “substituent” refer to a group that may be present on or substituted on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms of the group including hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxyl groups, including carboxylic acid esters; sulfur atoms of the group including thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms of the group including amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms of various other groups. Non-limiting examples of substituents that can be bonded to substituted carbon (or other) atoms include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2 Examples include N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R can be a hydrogen or carbon-based part, for example, R is hydrogen, (C1-C 100) can be a hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups bonded to a nitrogen atom or adjacent nitrogen atoms can combine with the nitrogen atom or adjacent nitrogen atoms to form a heterocyclyl.

[0356] As used herein, the term “alkyl” refers to linear and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of linear alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, 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 forms of alkyl. Typical substituted alkyl groups can be substituted one or more times with any of the groups listed herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0357] As used herein, the term “alkenyl” refers to linear, branched, and cyclic alkyl groups as defined herein, except that they have at least one double bond between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0358] As used herein, the term "alkynyl" refers to linear and branched alkyl groups, except that they have at least one triple bond between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0359] As used herein, the term “acyl” refers to a group containing a carbonyl moiety to which the group is bonded via a carbonyl carbon atom. The carbonyl carbon atom may be bonded to a hydrogen atom to form a “formyl” group, or to another carbon atom which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, etc. An acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group may contain double or triple bonds within the scope of this specification. The acryloyl group is an example of an acyl group. An acyl group may also contain heteroatoms within the scope of this specification. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the scope of this specification. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, this group is called a "haloacyl" group. One example is the trifluoroacetyl group.

[0360] As used herein, the term “cycloalkyl” refers to cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups may have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, including but not limited to norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups, as well as fused rings, including but not limited to dekalinyl groups. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined herein. Typical substituted cycloalkyl groups include, but are not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups, which can be monosubstituted or two or more times and can be substituted with amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination refers to a cyclic alkenyl group.

[0361] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl group as defined herein in which one or more carbon atoms in the ring are replaced by heteroatoms such as O, N, S, and P, each of which may be substituted as described herein if open valence is present, and each may be in any preferred stable oxidation state.

[0362] As used herein, the term “aryl” refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Therefore, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, crisenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group contains about 6 to about 14 carbon atoms in the ring portion of the group. The aryl group can be unsubstituted or substituted as defined herein. Typical substituted aryl groups can be monosubstituted or two or more times, and include, but are not limited to, a phenyl group in which one or more of the 2, 3, 4, 5, or 6 positions of the phenyl ring are substituted, or a naphthyl group in which one or more of the 2 to 8 positions of the phenyl ring are substituted.

[0363] As used herein, the term "aralkyl" refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Typical aralkyl groups include benzyl and phenylethyl groups, as well as condensed (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0364] As used herein, the term “heterocyclyl” refers to aromatic and non-aromatic cyclic compounds containing three or more ring members (one or more of which are heteroatoms, such as N, O, and S, but not limited to these). Thus, heterocyclyls can be cycloheteroalkyls, heteroaryls, or, in the case of polycyclics, any combination thereof. In some embodiments, a heterocyclyl group contains 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings in which the CH2 group in the ring is replaced by one or more C=O groups, as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing C=O groups include, but are not limited to, β-propiolactams, γ-butyrolactams, δ-valerolactams, and ε-caprolactams, and their corresponding lactones. A heterocyclyl group designated as C2-heterocyclyl can be a five-ring having two carbon atoms and three heteroatoms, a six-ring having two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heterocyclyl can be a five-ring having one heteroatom, a six-ring having two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. A heterocyclyl ring may also contain one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzdioxolanyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the scope of this specification. This term also includes polycyclic ring systems containing heteroatoms, such as quinuclidyl, but not limited to these. A heterocyclyl group may be unsubstituted or substituted as discussed herein.Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranil, dihydrobenzofuranil, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adenyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Typical substituted heterocyclyl groups include, but are not limited to, piperidinyl or quinolinyl groups, which can be monosubstituted or substituted two or more times, and are 2, 3, 4, 5, or 6-substituted, or disubstituted with groups such as those listed herein.

[0365] As used herein, the term “heteroaryl” refers to an aromatic ring compound containing five or more ring members (one or more of which are heteroatoms, such as N, O, and S, but not limited to these). For example, a heteroaryl ring can have five to about eight to twelve ring members. Heteroaryl groups are various heterocyclyl groups having aromatic electronic structures. A heteroaryl group designated as C2-heteroaryl can be a five-ring with two carbon atoms and three heteroatoms, a six-ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a five-ring with one heteroatom, a six-ring with two heteroatoms, and so on. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. x-y The heterocyclyl ring specified as such can be any ring containing "x" members to a maximum of "y" members, and containing one or more heteroatoms, including all intermediate integers between "x" and "y", as defined herein. x-y In the specified ring, all non-heteroatom members are carbon.x-y The heterocyclyl ring specified may also be a polycyclic ring system, such as a bicyclic or tricyclic ring system. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. The heteroaryl group may be unsubstituted or substituted with a group as discussed herein. Typical substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

[0366] Additional examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, and ben Zuhydryl, acridinil, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrrolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl ), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl) , benzo[b]furanil (2-benzo[b]furanil, 3-benzo[b]furanil, 4-benzo[b]furanil, 5-benzo[b]furanil, 6-benzo[b]furanil, 7-benzo[b]furanil), 2,3-dihydro-benzo[b]furanil (2-(2,3-dihydro-benzo[b]furanil), 3-(2,3-dihydro-benzo[b]furanil), 4-(2,3-dihydro-benzo[b]furanil), 5-(2,3-dihydro-benzo[b]furanil), 6-(2,3-dihydro-benzo[b]furanil), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) Zolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzimidazolyl, 2-benzimidazolyl), benzothiazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), carbazolyl (1-benzimidazolyl, 2-benzimidazolyl, 3-benzimidazolyl, 4-benzimidazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepine-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5 H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,Examples include, but are not limited to, azepine-5-yl (f).

[0367] As used herein, the term “heterocyclylalkyl” refers to an alkyl group as defined herein in which a hydrogen or carbon bond of the alkyl group as defined herein is replaced by a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0368] As used herein, the term "arylalkyl" refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0369] As used herein, the term “heteroarylalkyl” refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0370] As used herein, the term “alkoxy” refers to an oxygen atom connected to an alkyl group, including cycloalkyl groups as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further contain double or triple bonds, and may also contain heteroatoms. For example, the allyloxy group or methoxyethoxy group is also an alkoxy group within the scope of this specification, as is the methylenedioxy group in the context in which two adjacent atoms in the structure are substituted by them.

[0371] As used herein, the term “amine” refers, for example, to primary, secondary, and tertiary amines of formula N(group)3, where each group can independently be H or non-H such as alkyl or aryl. Examples of amines include, but are not limited to, R-NH2, e.g., alkylamines, arylamines, alkylarylamines; R2NH (where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.); and R3N (where each R is independently selected, such as trialkylamines, diarylamines, alkyldiarylamines, triarylamines, etc.). The term “amine” also includes ammonium ions as used herein.

[0372] As used herein, the term "amino group" refers to -NH2, -NHR, -NR2, -NR3 + Substituents in the form of (each R selected independently), and non-protonable -NR3 +This refers to each protonation form except for the one specified above. Therefore, any compound substituted with an amino group can be considered an amine. Within the scope of this specification, "amino group" can be a primary, secondary, tertiary, or quaternary amino group. The "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0373] As used herein, the terms “halo,” “halogen,” or “halide” group mean, either alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom unless otherwise specified.

[0374] As used herein, the term “haloalkyl” group includes monohaloalkyl groups, polyhaloalkyl groups in which all halo atoms may be the same or different, and perhaloalkyl groups in which all hydrogen atoms are replaced by halogen atoms such as fluoro. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, and perfluorobutyl.

[0375] As used herein, the terms “epoxy functional” or “epoxy substituted” refer to a functional group in which an epoxy substituent oxygen atom is directly bonded to two adjacent carbon atoms in 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-epoxysilohexyl)propyl, 2-(3,4-epoxycyclohexyl)ethyl, 2-(2,3-epoxysilopentyl)ethyl, 2-(4-methyl-3,4-epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcyclohexyl)-2-methylethyl, and 5,6-epoxyhexyl.

[0376] As used herein, the term “monovalent” refers to a substituent that is connected to the substituted molecule via a single bond. When a substituent is monovalent, such as F or Cl, it is bonded to an atom and substituted by a single bond.

[0377] As used herein, the terms “hydrocarbon” or “hydrocarbyl” refer to molecules or functional groups that contain carbon atoms and hydrogen atoms. These terms may also refer to molecules or functional groups that typically contain both carbon atoms and hydrogen atoms, but in which all hydrogen atoms are substituted with other functional groups.

[0378] As used herein, the term "hydrocarbyl" refers to a functional group derived from a linear, branched, or cyclic hydrocarbon, which may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. The hydrocarbyl group is (C a -C b ) can be expressed as hydrocarbyl, where a and b are integers and mean having any of a to b carbon atoms. For example, (C1-C4)hydrocarbyl means that the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-C b )Hydrocarbyl means that, in certain embodiments, the hydrocarbyl group is absent.

[0379] When used herein, "C 6-10 The term "-5~6 member heterobiaryl" refers to a C18 that is covalently bonded to a 5- or 6-membered heteroaryl portion via a single bond. 6-10 This refers to the aryl portion. C 6-10 The aryl moiety and the 5-6 membered heteroaryl moiety can be any of the preferred aryl and heteroaryl groups described herein. 6-10 - Non-exclusive examples of 5- to 6-membered heterobiaryls include: [ka] These are some examples.

[0380] C 6-10 -When a 5- to 6-membered heterobiaryl is listed as a substituent (e.g., an "R" group), C 6-10 -5~6 member heterobiaryl, C 6-10 It is bonded to the rest of the molecule via a portion.

[0381] When used herein, "5-6 member-C" 6-10 The term "heterobiaryl" is C 6-10 -Same as 5-6 member heterobiaryl, but 5-6 member -C 6-10 When heterobiaryls are listed as substituents (e.g., "R" groups), they are 5-6 member-C 6-10 The heterobiaryl is attached to the rest of the molecule via a 5-6 member heteroaryl moiety.

[0382] When used herein, "C 6-10 -C 6-10 The term "biaryl" refers to another C through a single bond. 6-10 C is covalently bonded to the aryl portion. 6-10 This refers to the aryl portion. C 6-10 The aryl portion can be any of the preferred aryl groups described herein. 6-10 -C 6-10 Non-limiting examples of biaryls include biphenyls and binaphthyls.

[0383] The terms “pharmaceutically acceptable salt” or “salt” are used throughout this specification to describe one or more salt forms of the compositions herein that are presented for increasing the solubility of the compound in saline for parenteral delivery or in gastric juice of a patient’s gastrointestinal tract in order to promote the dissolution and bioavailability of the compound. Pharmacologically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Preferred salts include those derived from alkali metals such as potassium and sodium, and alkaline earth metals such as calcium, magnesium, and ammonium salts, among many other acids well known in the pharmaceutical field. Sodium and potassium salts may be preferred as neutralization salts of carboxylic acids and free phosphoric acid comprising the compositions according to the present invention. The term “salt” shall mean any salt consistent with the use of the compound according to the present invention. When the compound is used for pharmaceutical indications including the treatment of prostate cancer, including metastatic prostate cancer, the term “salt” shall mean a pharmaceutically acceptable salt consistent with the use of the compound as a pharmaceutical agent.

[0384] The term "co-administration" means that at least two compounds or compositions are administered to a patient simultaneously such that an effective amount or concentration of each of the two or more compounds can be observed in the patient at a given time. The compounds according to the present invention may be co-administered to a patient simultaneously, but this term encompasses both simultaneous or at different time points of administration of two or more drugs, provided that an effective concentration of all co-administered compounds or compositions is observed in the subject at a given time. The chimeric antibody-mobilizing compounds according to the present invention may be administered together with one or more additional anticancer agents or other drugs used to treat or improve the symptoms of cancer, particularly prostate cancer, including metastatic prostate cancer.

[0385] The terms “anticancer agent” or “additional anticancer agent” refer to compounds other than the chimeric compounds of the present invention that may be used in combination with the compounds of the present invention for the treatment of cancer. Exemplary anticancer agents that may be co-administered in combination with one or more chimeric compounds of the present invention include, among others, antimetabolites, topoisomerase I and II inhibitors, alkylating agents, and microtubule inhibitors (e.g., Taxol). Exemplary anticancer compounds for use in the present invention include everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, dekatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batablin, ofatumumab (Arzerra), zanorimumab, edtecarin, tetrandrin, lubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silendite, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Le Quanton, LY 317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Taranpanel, Atracentane, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C1, CHIR-258,); 3-[5-(methylsulfonylpiperazinmethyl)-indolylj-quinone, batatinib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10](Pyr-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate salt [x = 1 to 2.4, C 59 H 84 N 18 Oi4-(C2H4O2) XAcetates of ], 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, ronafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ82 4. Subeloylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arunsacrine, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine Fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Grivac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptozocin, teniposide, test Steron, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimasut, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416,SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (Monoclonal) Antibodies) and Erbitux, Cremofol-free paclitaxel, Epitilon B, BMS-247550, BMS-310705, Doroxifene, 4-hydroxytamoxifene, Pipendoxifene, ERA-923, Alzoxifene, Fulvestrant, Acorbifen, 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, Waltmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte colony-stimulating factor, Zolendronate, Prednisone, Cetuximab, Granulocyte-macrophage colony-stimulating factor, Histrelin, Pegylated interferon alpha-2a, Interferon alpha-2a, Pegylated interferon alpha-2b, Interferon alpha -2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwiner-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor antagonist, palonosetron,Aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib (in particular, immunotherapeutic agents, e.g., IDO inhibitors (indoleamine 2,3-dioxygenate) Examples include inhibitors of the IDO pathway, such as indoximod (NLG-8187), navoximod (GDC-0919), and NLG802; PDL1 inhibitors (inhibitors of programmed death-ligand 1) (e.g., nivolumab, durvalumab, and atezolizumab); PD1 inhibitors, such as pembrolizumab (Merck); and CTLA-4 inhibitors (inhibitors of cytotoxic T lymphocyte-associated protein 4 / differentiation antigen group 152) (e.g., ipilimumab and tremelimumab).

[0386] In addition to anticancer agents, several other drugs may be co-administered with the chimeric compounds according to the present invention in the treatment of cancer. These include active agents, minerals, vitamins, and nutritional supplements that have shown some efficacy in inhibiting cancer tissue or its growth, or that are otherwise useful in the treatment of cancer. For example, one or more of the following may be used in combination with the compounds to treat cancer: dietary selenium, vitamin E, lycopene, soy products, curcumin (turmeric), vitamin D, green tea, omega-3 fatty acids, and phytoestrogens, including beta-sitosterol.

[0387] Although not limited to theory, the compounds according to the present invention, which include a CPBM binding moiety (CPBM) and a CRBM / ASGPR binding moiety, selectively bind to circulating proteins and, through this binding, facilitate the introduction of cellular proteins into hepatocytes or other cells (degrading cells) that selectively bind to CRBM / ASGPRBM, where the circulating proteins within the hepatocytes or other degrading cells are degraded and removed from circulation. Therefore, the compounds according to the present invention perform both binding to MIF proteins and removal of MIF proteins from circulation, resulting in a dual effect that is particularly effective in treating pathological conditions and states.

[0388] A pharmaceutical composition comprising, in an effective amount, at least one compound disclosed herein, often a bifunctional chimeric compound according to the present invention (containing at least one MIFBM group or antibody-binding moiety and at least one ASGRBM), and one or more combinations of compounds separately described herein, all in an effective amount, in combination with a pharmaceutically effective amount of a carrier, excipient, 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 separately disclosed herein.

[0389] 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. Examples of 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, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partially glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and wool fats.

[0390] The compositions of the present invention may, in particular, be administered orally, parenterally, by inhalation spray, topically, rectally, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally (including intubation into the stomach through the mouth or nose), intraperitoneally, or intravenously.

[0391] The sterile injection forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injection preparation may also be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injections, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia (Ph. Helv) or similar alcohols.

[0392] The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or aqueous solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Smoothing agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorings may also be added, if desired.

[0393] Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0394] The pharmaceutical compositions of the present invention may also be administered topically, particularly to treat skin cancer, psoriasis, or other diseases occurring in or on the skin. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestine can be done with rectal suppositories (see above) or suitable enema formulations. Topically acceptable transdermal patches may also be used.

[0395] For topical application, the pharmaceutical composition may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water.

[0396] Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0397] For ophthalmic use, this pharmaceutical composition may be formulated as a microparticle suspension in isotonic pH-adjusted sterile saline, with or without preservatives such as benzylalkonium chloride, or preferably as a solution in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, this pharmaceutical composition may be formulated as an ointment such as petrolatum.

[0398] The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or nasal inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0399] The amount of compound in the pharmaceutical composition of the present invention, which can be combined with a carrier material to produce a single dosage form, varies depending on the host and disease being treated and the specific mode of administration. Preferably, the composition should be formulated to contain about 0.05 mg to about 1.5 g, 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 the active ingredient, either alone or in combination with at least one additional compound that can be used to treat cancer, prostate cancer or metastatic prostate cancer, or its secondary effects or conditions.

[0400] Methods for treating specific pathological conditions or states, particularly cancer, as described elsewhere herein, involve administering an effective amount of a pharmaceutical composition comprising a therapeutic amount 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 ingredient(s) used in the therapeutic methods of the present invention, which can be combined with a carrier material to produce a single dosage form, varies depending on the host being treated and the specific mode of administration. For example, the compositions can be formulated to administer novel compounds to patients receiving these compositions in therapeutically effective doses of approximately 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 patient / day, or in some embodiments, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or more than 200 mg / kg.

[0401] Furthermore, it should be understood that a specific medication and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compounds used, age, weight, general health, sex, dietary restrictions, administration time, elimination rate, drug combinations, as well as the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0402] Patients or subjects (e.g., humans) suffering from autoimmune diseases, inflammatory diseases, or cancer may be treated by administering to the patient (subject) an effective amount of the chimeric / bifunctional compound according to the present invention (including its pharmaceutically acceptable salts, solvates, or polymorphs) in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known pharmaceutical agents, preferably, agents that can adjunct the treatment of autoimmune diseases and / or inflammatory diseases or cancer, including metastatic or recurrent cancer, or that can adjunct the improvement of secondary effects and / or symptoms associated with these conditions and / or states, at the discretion of the patient (subject). This treatment may also be administered in combination with other conventional therapies, such as radiation therapy or surgery for cancer.

[0403] The compounds of the present invention can be administered alone or in combination with other agents described herein by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, or in liquid, cream, gel, or solid form, or in aerosol form.

[0404] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient for the desired indication without causing serious toxic effects in the patient being treated. For all the conditions mentioned herein, the preferred dose of the active compound is in the range of approximately 10 ng / kg to 300 mg / kg per day, preferably 0.1 to 100 mg / kg, and more generally, 0.5 to approximately 25 mg per kilogram of recipient / patient body weight per day. Typical topical doses are in the range of approximately 0.01 to 3 wt / wt% in a preferred carrier.

[0405] This compound may contain less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of the active ingredient per unit dosage form, but is not limited to these amounts. It can be conveniently administered in any suitable unit dosage form. An oral dose of approximately 25 to 500 mg is often convenient.

[0406] The active ingredient is administered to achieve a peak plasma concentration of the active compound, preferably about 0.00001 to 30 mM, more preferably about 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient in physiological saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for generating an effective plasma concentration of the active agent.

[0407] The concentration of the active compound in a drug composition will depend on the drug's absorption, distribution, inactivation, and elimination rates, as well as other factors known to those skilled in the art. It should be noted that the dosage values ​​will also vary depending on the severity of the condition being alleviated. For any particular subject, a specific drug regimen should be adjusted over time according to individual requirements and the professional judgment of the person administering or supervising the administration of the composition. It should be further understood that the concentration ranges described herein are illustrative and not intended to limit the scope or implementation of the claimed composition. The active ingredient may be administered in a single dose or divided into several smaller doses administered at various time intervals.

[0408] Oral compositions will generally contain an inert diluent or an edible carrier. These may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivatives may be incorporated with excipients and used in the form of tablets, lozenges, or capsules. A pharmaceutically compatible binder and / or adjuvant material may be included as part of the composition.

[0409] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring, or compounds of similar properties. If the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the above types of materials. In addition, the unit dosage form may contain various other materials that alter the physical form of the dosing unit, such as sugar, shellac, or enteric coatings.

[0410] The active compound or a pharmaceutically acceptable salt thereof can be administered as an ingredient in elixirs, suspensions, syrups, wafers, chewing gum, and the like. In addition to the active compound, the syrup may contain sucrose as a sweetener, as well as certain preservatives, pigments, colorants, and flavorings.

[0411] The active compound or a pharmaceutically acceptable salt thereof may also be mixed with other active materials that do not impair the desired effect, or materials that complement the desired effect, such as other anticancer agents, anti-inflammatory agents, immunosuppressants, antibiotics, antifungal agents, or antiviral compounds. In certain preferred embodiments of the present invention, one or more chimeric / bifunctional CPBM-conjugated compounds according to the present invention are co-administered with another anticancer agent and / or another bioactive agent, as separately described herein.

[0412] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical applications may contain the following components: sterile diluents such as water for injection, physiological saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetic acid, citric acid, or phosphoric acid; and tonicity-adjusting agents such as sodium chloride or dextrose. Parenteral preparations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0413] When administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS).

[0414] In one embodiment, the active compound is prepared using a carrier that protects the compound from rapid removal from the body, such as a controlled and / or sustained-release formulation including an implant and a microcapsule encapsulation delivery system. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0415] Liposome suspensions or cholesterolosomes can also be pharmaceutically acceptable carriers. These can be prepared, for example, by methods known to those skilled in the art, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, a liposome formulation can be prepared by dissolving a suitable lipid(s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, aracadoylphosphatidylcholine, and cholesterol) in an inorganic solvent, then evaporating it to leave a thin film of dry lipid on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then manually swirled to release the lipid material from the sides of the container, dispersing lipid aggregates, thereby forming a liposome suspension.

[0416] The compounds according to embodiments of the present invention may be those listed in Table 1 below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0417] The present invention is further illustrated by the following non-limiting examples.

[0418] Example 1. Procedure for preparing target A011A [ka]

[0419] Preparation of intermediate 1: [ka]

[0420] To a 100 mL solution of intermediate 9 (5.00 g, 26.15 mmol, 1.00 equivalent) in Py (100 mL), propanoylpropanoate (27.23 g, 209.23 mmol, 8.00 equivalent) was added. The mixture was stirred at 20°C for 12 hours. LC-MS detected the desired mass, indicating that the reactants had been consumed. The reaction mixture was concentrated under reduced pressure to obtain intermediate 1 (10.86 g, crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: RT = 0.715 min, MS calculated value: 415.2, measured value: [M + H] + = 416.2.

[0421] Preparation of intermediate 2: [ka]

[0422] To a 50 mL solution of MeOH containing 5.40 g of intermediate 1 (13.00 mmol, 1.00 equivalent), NaOMe (2.81 g, 51.99 mmol, 4.00 equivalent) was added. The mixture was stirred at 20°C for 2 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was neutralized by adding 1 M HCl. The resulting solution was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 10 / 1-5 / 1) to obtain intermediate 2 (4.20 g, 16.99 mmol, yield 65.3%) as a yellow solid. LC-MS: RT = 0.174 min, MS calculated value: 247.1, measured value: [M+H] + = 248.3. 1 H 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).

[0423] Preparation of intermediate 3: [ka]

[0424] To a solution of intermediate 2 (2.10 g, 8.49 mmol, 1.00 equivalent) in DMF (15 mL), [(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (1.06 g, 4.25 mmol, 0.5 equivalent) and 2A (4.42 g, 42.47 mmol, 5.00 equivalent) were added. The mixture was stirred at 70°C for 12 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was diluted with water (30 mL) and extracted with SiO (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1-0 / 1) to obtain intermediate 3 (4.25 g, 14.79 mmol, yield 87.0%) as a white solid. LCMS: RT = 0.426 min, MS calculated value: 287.1, measured value: [M+H] + = 288.2. 1 H NMR (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).

[0425] Preparation of intermediate 4: [ka]

[0426] To a solution of intermediate 3 (2.20 g, 7.66 mmol, 1.00 equivalent) in THF (20 mL), NaH (3.06 g, 76.57 mmol, 60% purity, 10.00 equivalent) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, then 3A (4.54 g, 13.78 mmol, 1.80 equivalent) was added at 0°C, and the mixture was stirred at 20°C for 1 hour. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1-0 / 1) to obtain intermediate 4 (3.70 g, 7.57 mmol, yield 49.4%) as a white solid. LCMS: RT = 1.475 min, MS calculated value: 488.2, measured value: [M+H] + = 489.3. 1 H 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).

[0427] Preparation of intermediate 6: [ka]

[0428] To a 25 mL solution of intermediate 5 (2.50 g, 7.45 mmol, 1.00 equivalent) in DCM, TFA (10 mL) was added at 0°C. The mixture was stirred at 20°C for 2 hours. TLC (DCM:MEOH = 5:1, Rf A reading of 0.43 indicated that new spots and reactants had been consumed. The reaction mixture was concentrated under reduced pressure to obtain intermediate 6 (1.75 g, crude product) as a colorless oil, which was used directly in the next step.

[0429] Preparation of intermediate 7: [ka]

[0430] To a 10 mL solution of 6A (1.56 g, 7.44 mmol, 1.00 equivalent) in DMF (10 mL), HATU (2.83 g, 7.44 mmol, 1.00 equivalent) and DIEA (4.81 g, 37.19 mmol, 6.48 mL, 5.00 equivalent) were added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Intermediate 6 (1.75 g, 7.44 mmol, 1.00 equivalent) was added to the mixture. The mixture was stirred at 20°C for 2 hours. LC-MS showed that 6A had been consumed. The reaction mixture was diluted with water (20 mL) and extracted with SiO2 (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain intermediate 7 (1.02 g, 2.39 mmol, yield 32.1%) as a white solid. LCMS: RT = 2.188 min, MS calculated value: 426.2, measured value: [M+H] + = 427.3. 1 H NMR (400 MHz, CDCl3) 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).

[0431] Preparation of intermediate 8: [ka]

[0432] To a DMSO (8 mL) solution of intermediate 7 (552.0 mg, 1.28 mmol, 99.0% purity, 1.00 equivalent) and intermediate 4 (1.88 g, 3.84 mmol, 3.00 equivalent), sodium ascorbate (634.6 mg, 3.20 mmol, 2.50 equivalent) and CuSO4.5H2O (320.0 mg, 1.28 mmol, 1.00 equivalent) were added. The mixture was stirred at 25°C for 2 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10μm, mobile phase: [water(NH4HCO3)-ACN], B%: 30%-60%, 8 min) to obtain intermediate 8 (1.25 g, 660.66 μmol, yield 51.6%) as a yellow oil. LCMS: RT=2.065 min, MS calculated value: 1891.9, measured value: [M+2H] 2+ =947.2. 1 H NMR (400MHz, DMSO-d6) δ ppm = 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).

[0433] Preparation of target A011A_Cpd.17: [ka]

[0434] To a solution of intermediate 8 (400.0 mg, 211.41 μmol, 1.00 equivalent) in THF (1.0 mL), Pd / C (5.00 mg, 21.14 μmol, purity 10%) was added. The mixture was stirred under H2 (15 Psi) at 20°C for 2 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain target A011A_Cpd.17 (330.3 mg, 187.89 μmol, yield 88.8%) as a yellow oil. LC-MS: RT = 1.810 min, MS calculated value: 1757.9, measured value: [M + 2H] 2+ = 880.1. 1 H NMR (400 MHz, DMSO-d6) δ= 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).

[0435] Preparation of target A011A: [ka]

[0436] A mixture of target A011A_Cpd.17 (90.0 mg, 51.20 μmol, 1.00 equivalent) in HCl / H2O (2.0 M, 1.0 mL) and MeCN (0.5 mL) was stirred at 20°C for 1 hour. The mixture was freeze-dried to obtain target A011A (85.0 mg, 45.69 μmol, purity 90.0%, yield 89.3%, HCl salt) as a colorless solid. LCMS: RT=0.705 min, MS calculated value: 1637.73, measured value: [M+2H] 2+ = 819.600.

[0437] Example 2. Procedure for preparing target A093. [ka]

[0438] Preparation of target A093: [ka]

[0439] Intermediate 4 (500.0 mg, 1.02 mmol, 1.00 equivalent) was dissolved in HCl (1 M, 5 mL, 10.05 equivalents). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the starting material was consumed and the desired product mass was detected. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 5%-35%, 8 min) to obtain target A093 (305.0 mg, 680.09 ml, yield 66.4%) as a colorless oil. LC-MS: RT = 1.810 min, MS calculation: 448.5, observed mass: [M + H] + = 449.3. 1 H NMR (400 MHz, METHANOL-d4) δ = 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).

[0440] Example 3. Procedure for preparing target A092. [ka]

[0441] Preparation of intermediate 9: [ka]

[0442] To a 50 mL solution of 6A (4.00 g, 22.83 mmol, 1.05 equivalents) in DMF (50 mL), HATU (9.12 g, 23.98 mmol, 1.05 equivalents) and DIEA (8.85 g, 68.50 mmol, 11.93 mL, 3.00 equivalents) were added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Then, intermediate 6 (9.17 g, 22.83 mmol, purity 87.0%, 1.00 equivalent, TFA) was added, and the mixture was stirred at 20°C for 1 hour. LC-MS showed that 6A was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 9 (6.50 g, 16.56 mmol, yield 72.5%) as a colorless oil. LCMS: RT = 2.143 min, MS calculation value: 392.2, [M+H] + = 393.3.

[0443] Preparation of target A092: [ka]

[0444] A solution of intermediate 9 (5.00 g, 12.74 mmol, 1.00 equivalent) in HCl / siRNA (4 M, 50 mL) was stirred at 20°C for 3 hours. LC-MS showed that intermediate 9 was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Agela DuraShell C18 250 × 70 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 15%-45%, 8 min) to obtain target A092 (2.10 g, 7.18 mmol, yield 56.4%, purity 100.0%) as a yellow oil. LC-MS: RT = 1.519 min, MS calculation: 292.3, [M+H] + = 293.2. 1 ¹H NMR (400 MHz, methanol-d4): δ = 4.15 (d, J = 2.38 Hz, 6 H), 3.82 (s, 6 H), 3.23 (s, 2 H), 2.84 (t, J = 2.44 Hz, 3 H).

[0445] Example 4. Procedure for preparing target A096. [ka]

[0446] Preparation of intermediate 11: [ka]

[0447] To a 1 mL solution of DCM (40.0 mg, 171.51 μmol, 1.00 equivalent), oxalyl chloride (25.2 mg, 205.8 μmol, 18.9 μL, 1.20 equivalent) and DMF (1.25 mg, 17.15 μmol, 1.32 μL, 0.10 equivalent) were added. The mixture was stirred at 0°C for 0.5 hours. TLC (DCM:MeOH = 10:1, R) f A reaction ratio of 0.6 indicated that the reactants were consumed and one main spot was formed. Intermediate 11 (43.0 mg, 170.86 μmol, crude product) was used directly in the next step.

[0448] Preparation of intermediate 12: [ka]

[0449] To a 1 mL solution of target A011A_cpd 17 (210.0 mg, 119.46 μmol, 1.00 equivalent) in DCM, DIEA (46.3 mg, 358.38 μmol, 62.42 μL, 3.00 equivalent) was added, followed by the addition of intermediate 11 (30.0 mg, 119.46 μmol, 1.00 equivalent) to the mixture. The mixture was stirred at 20°C for 1 hour. LC-MS showed that the desired mass and reactants were consumed. Intermediate 12 (230.0 mg, crude product) was obtained as a yellow oil and used in the next step without further purification. LC-MS: RT = 1.990 min, MS calculation: 1971.9, [M+2H] 2+ = 987.6.

[0450] Preparation of target A096: [ka]

[0451] A solution of intermediate 12 (230.0 mg, 116.57 μmol, 1.00 equivalent) in HCl (3 M, 1 mL) was stirred at 40°C for 1 hour. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 10%-40%, 8 min) to obtain target A096 (72.0 mg, 38.86 μmol, yield 33.3%) as a white solid. LC-MS: RT = 1.521 min, MS calculation: 1851.8, [M+2H] 2+ = 927.7. 1H NMR (400MHz, 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).

[0452] Example 5. Procedure for preparing target A098. [ka]

[0453] Preparation of intermediate 11: [ka]

[0454] To a 5 mL solution of intermediate 10 (400.0 mg, 1.72 mmol, 1.00 equivalent) in DCM, oxalyl chloride (252.1 mg, 2.06 mmol, 189.58 μL, 1.20 equivalent) and DMF (12.5 mg, 171.51 μmol, 13.20 μL, 0.10 equivalent) were added. The mixture was stirred at 0°C for 0.5 hours. TLC (DCM:MeOH = 10:1, R) f The reaction ratio of 0.43 indicated that the reactants were consumed and one main spot was formed. Intermediate 11 (420.0 mg, 1.67 mmol, crude product) was used directly in the next step.

[0455] Preparation of intermediate 14: [ka]

[0456] To a 20 mL solution of DCM containing intermediate 13 (950.0 mg, 1.47 mmol, 1.00 equivalent), DIEA (952.1 mg, 7.37 mmol, 1.28 mL, 5.00 equivalent) was added, followed by the addition of intermediate 11 (370.8 mg, 1.47 mmol, 1.00 equivalent). The mixture was stirred at 20°C for 1 hour. LC-MS showed that the desired mass and reactants were consumed. Intermediate 14 (1.20 g, crude product) was obtained as a yellow oil and used in the next step without further purification. LC-MS: RT = 1.645 min, MS calculation: 859.4, [M+H] + = 860.4.

[0457] Preparation of target A098: [ka]

[0458] Intermediate 14 (1.20 g, 1.40 mmol, 1.00 equivalent) was dissolved in HCl (3 M, 1 mL). The mixture was stirred at 40°C for 0.5 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 5%-35%, 8 min) to obtain target A098 (350.0 mg, 426.90 μmol, yield 30.6%) as a white solid. LC-MS: RT = 1.283 min, MS calculation: 819.4, [M+H] + = 820.3. 1H NMR (400MHz, DMSO-d6) δ = 8.05 (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).

[0459] Example 6. Procedure for preparing target A097. [ka]

[0460] Preparation of intermediate 16: [ka]

[0461] To a 1 mL solution of DCM containing intermediate 10 (40.0 mg, 171.51 μmol, 1.00 equivalent), oxalyl dichloride (26.12 mg, 205.81 μmol, 18.02 μL, 1.20 equivalent) and DMF (12.5 mg, 171.51 μmol, 13.20 μL, 1.00 equivalent) were added at 0°C. The mixture was stirred at 25°C for 0.5 hours. Subsequently, intermediate 15 (140.0 mg, 116.54 μmol, 1.00 equivalent) and DIEA (45.1 mg, 349.62 μmol, 60.90 μL, 3.00 equivalent) were dissolved in the mixture. The mixture was stirred at 25°C for 0.5 hours. LC-MS showed that intermediate 15 was completely consumed and a single main peak with the desired mass was detected. After filtration, intermediate 16 was obtained as a colorless liquid and used directly in the next step. LCMS: RT=1.818 min, MS calculation value: 1415.7 [M+2H] 2+ = 709.3.

[0462] Preparation of target A097: [ka]

[0463] HCl (3M, 376.51 μL, 10.00 equivalents) was added to the intermediate 16 solution. The mixture was stirred at 40°C for 1 hour. LC-MS showed that intermediate 16 was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 25%-45%, 8 min) to obtain target A097 (64.0 mg, 47.89 μmol, yield 42.4%, purity 100.0%) as a colorless oil. LC-MS: RT = 1.459 min, MS calculation: 1335.6, [M+2H] 2+ = 669.3. 1 H NMR (400 MHz, DMSO-d6) δ = 8.05 (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).

[0464] Example 7. Procedure for preparing target A090. [ka]

[0465] Preparation of intermediate 18: [ka]

[0466] To a DMSO (4 mL) solution of intermediate 17 (420.0 mg, 773.75 μmol, 90.0% purity, 1.00 equivalent) and intermediate 4 (269.5 mg, 928.50 μmol, 1.20 equivalent), sodium ascorbate (168.6 mg, 851.12 μmol, 1.10 equivalent) and CuSO4.5H2O (193.1 mg, 773.75 μmol, 1.00 equivalent) were added at 25°C. The reaction mixture was then stirred at 25°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex C18 80×40mm×3μm, mobile phase: [water(NH4HCO3)-ACN], B%: 20%-50%, 8 min) to obtain intermediate 18 (300.0 mg, 385.19 μmol, yield 49.8%) as a yellow oil. LCMS: RT=1.793 min, MS calculation value: 778.4, [M+H] + = 779.6. 1 H NMR (400 MHz, CDCl3) δ = 7.74 (s, 1H), 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).

[0467] Preparation of intermediate 13: [ka]

[0468] Intermediate 18 (400.0 mg, 513.58 μmol, 1.00 equivalent) was added to a 1 mL THF solution with Pd / C (100 mg, 10% purity) at 25°C. The reaction mixture was then stirred at 25°C for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 13 (200.0 mg, 310.22 μmol, 60.4% yield) as a yellow oil. LC-MS: RT = 1.218 min, MS calculation: 644.3, [M+H] + = 645.4. 1 H NMR (400 MHz, CDCl3) δ = 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).

[0469] Preparation of target A090: [ka]

[0470] Intermediate 13 (70.0 mg, 108.58 μmol, 1.00 equivalent) was degassed with HCl (1 M, 2 mL), purged three times with N2, and then stirred at 40°C for 1 hour under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction product was concentrated under reduced pressure to obtain target A090 (60.0 mg, 99.23 μmol, yield 91.3%) as a colorless oil. LC-MS: RT = 1.471 min, MS calculation: 604.3, [M+H] + = 605.2. 1 H NMR (400 MHz, MeOH-d4) δ = 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).

[0471] Example 8. Procedure for the preparation of BH0003610, BH0003665, BH0003611, BH0003782, and BH0003795. [ka]

[0472] Preparation of intermediate 21: [ka]

[0473] The peptides were synthesized using standard Fmoc chemistry (Rink AM resin). 1) Resin preparation: A container containing Rink Amide AM resin (15.62 g, 5.00 mmol, 0.32 mmol / g) and DMF (100 mL) was aerated with N2 at 25°C for 2 hours. Then, 20% piperidine DMF solution (200 mL) was added, and the mixture was aerated with N2 at 25°C for 30 minutes. The mixture was filtered and washed five times with DMF (100 mL) before proceeding to the next step. 2) Coupling: A 100 mL solution of Fmoc-Thr(tBu)-OH (5.95 g, 15.00 mmol, 3.00 equivalents), HBTU (5.48 g, 14.25 mmol, 2.85 equivalents), and DIEA (3.87 g, 30.00 mmol, 6.00 equivalents) in DMF was added to the resin while aeration with N2 at 25°C for 30 minutes. The coupling reaction was monitored by the ninhydrin test. The resin was then washed five times with DMF (200 mL). 3) Deprotection: A 20% piperidine DMF solution (200 mL) was added to the resin, and the mixture was aerated with N2 at 25°C for 30 minutes. The deprotection reaction was monitored by the ninhydrin test. The resin was then washed five times with DMF (200 mL). 4) For the following amino acid elongations: Steps 2 and 3 were repeated for numbers 2-14 in Table 1. 5) After all steps were completed, the resin was washed five times with DMF (100 mL) and five times with MeOH (100 mL), and then dried under reduced pressure to obtain resin-bound peptide intermediate 19 (Rink AM resin, 12.3 g, 5.00 mmol). [Table 1]

[0474] Peptide cleavage and cyclization. 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 250 mL) was added at 25°C to a flask containing side-chain protective resin-bound peptide intermediate 19 (Rink AM resin, 12.3 g, 5.00 mmol) and stirred for 2 hours. 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 twice with isopropyl ether (1.5 L), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 20 (10.1 g, crude product) as a white solid. 4) To the HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 3.0 L) mixture of intermediate 20 (10.1 g, crude product), 0.1 M I2 / AcOH was added dropwise until the yellow color persisted, and the mixture was then stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 21 (2.00 g, purity 92.1%, yield 24.6%) as a white solid. LCMS: RT = 1.764 min, MS calculation value: M av =1623.85, observed mass: [M+H] + =1625.0, [M+2H] 2+ = 813.1.

[0475] Preparation of BH0003610 (click reaction): [ka]

[0476] To a 5 mL solution of intermediate 21 (65.7 mg, 40.5 μmol, 1.00 equivalent) and target A096 (75.0 mg, 40.5 μmol, 1.00 equivalent) in DMF, CuSO4 (0.4 M, 101.25 μL, 40.5 μmol, 1.00 equivalent), sodium ascorbate (0.4 M, 405.0 μL, 162.0 μmol, 4.00 equivalent), and THPTA (tris-hydroxypropyltriazolylmethylamine, 17.6 mg, 40.5 μmol, 1.00 equivalent) were added at 0°C under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 3 hours. After monitoring by LC-MS was completed, the reaction product was filtered off and purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to obtain BH0003610 (30.5 mg, purity 91.8%, yield 21.7%) as a white solid. LC-MS: RT=9.0 min, MS calculation value: M av =3476.79, observed mass: [M+2H] 2+ =1738.80, [M+3H] 3+ =1159.53, [M+4H] 4+ =869.90, [M+5H] 5+ = 696.12. [ka]

[0477] BH0003665, BH0003611, BH0003782, BH0003781, and BH0003795 were synthesized using the same procedure as BH0003610, which was performed according to the procedure described in

[0050] to

[0051] .

[0478] From 58.0 mg of target A097, BH0003665 (17.9 mg, purity 95.6%, yield 13.9%) was obtained as a white solid. LCMS: RT=9.1 min, MS calculation value: M av =2960.25, observed mass: [2M+3H] 3+ =1974.23, [M+2H] 2+ =1480.67, [M+3H] 3+ =987.79, [M+4H] 4+ = 740.84. [ka]

[0479] From 57.9 mg of target A098, BH0003611 (29.2 mg, purity 95.7%, yield 16.9%) was obtained as a white solid. LCMS: RT=9.0 min, MS calculation value: M av =2443.71, observed mass: [2M+3H] 3+ =1629.74, [M+2H] 2+ =1223.06, [M+3H] 3+ =815.04, [M+4H] 4+ = 611.53. [ka]

[0480] From 130 mg of target A100, BH0003795 (98 mg, purity 94.5%, yield 22.3%) was obtained as a white solid. LCMS: RT=1.34 min, MS calculation value: M av =2363.62, observed mass: [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. [ka]

[0481] From 110 mg of target A099, BH0003782 (149 mg, purity 96.0%, yield 54.6%) was obtained as a white solid. LCMS: RT=1.34 min, MS calculation value: M av =2800.07, observed mass: [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. [ka]

[0482] From 26 mg of target A094, BH0003781 (19 mg, purity 95.5%, yield 35.9%) was obtained as a white solid. LCMS: RT=1.32 min, MS calculation value: M av =3311.69, observed mass: [M+2H] 2+ =1656.3, [M-203+2H] 2+ =1554.7, [M+3H] 3+ = 1104.7. [ka]

[0483] Example 9. Procedure for the preparation of BH0003080, BH0003081, BH0003083, and BH0003050. [ka]

[0484] Preparation of intermediate 24: [ka]

[0485] The peptides were synthesized using standard Fmoc chemistry (CTC resin). 1) Resin preparation: In a container containing a DCM (10 mL) solution of 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 equivalent), DIEA (4.00 equivalent) was added dropwise, and the mixture was mixed for 2 hours while aerating with N2 at 25°C. Then, MeOH (2.0 mL) was added, and N2 was aerated for a further 30 minutes. The resin was washed 5 times with DMF (10 mL), followed by the addition of a 20% piperidine DMF solution (10 mL), and N2 was aerated for 30 minutes at 25°C for Fmoc deprotection. The mixture was filtered, and after washing the resin 5 times with DMF (10 mL), the process proceeded to the next step. 2) Coupling: A solution of Fmoc-Leu-OH (0.53 g, 1.5 mmol, 3.00 equivalents) and HBTU (0.41 g, 1.43 mmol, 2.85 equivalents) in DMF (10 mL) was added to the resin while aeration with N2. Then, DIEA (6.00 equivalents) was added dropwise to the mixture, and N2 was aerated at 25°C for 30 minutes. The coupling reaction was monitored by the ninhydrin test, and if it showed no color, the coupling was complete. The resin was then washed five times with DMF (10 mL). 3) Deprotection: 10 mL of 20% piperidine DMF solution was added to the resin, and the mixture was aerated with N2 at 25°C for 30 minutes. The resin was then washed five times with 10 mL of DMF. 4) For the following amino acid elongations: Steps 2 and 3 were repeated for numbers 2-14 in Table 2. 5) After all steps were completed, the resin was washed five times with DMF (100 mL) and five times with MeOH (100 mL), and then dried under reduced pressure to obtain resin-bound peptide intermediate 22 (CTC resin, 1.10 g, 0.50 mmol). [Table 2]

[0486] Peptide cleavage and cyclization. 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 20 mL) was added at 25°C to a flask containing side-chain protective resin-bound peptide intermediate 22 (1.23 g, 0.50 mmol), and the mixture was stirred for 2 hours. 2) After filtration, the filtrate was collected. 3) The filtrate was precipitated with cold isopropyl ether (100 mL). After filtration, the solid was washed twice with isopropyl ether (100 mL), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 23 (768 mg, crude product) as a white solid. 4) To a mixture of intermediate 23 (768 mg, crude product) in MeCN / H2O (4 / 6, v / v, 500 mL), 0.1 M I2 / AcOH was added dropwise until the yellow color persisted, and the mixture was then stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 24 (56.2 mg, purity 90.0%) as a white solid.

[0487] Preparation of BH0003080 [ka]

[0488] Click reaction: BH0003080 was synthesized using the same procedure as BH0003610, which was performed according to the procedure described in

[0050] to

[0051] .

[0489] From 50.0 mg of target A043, BH0003080 (28 mg, purity 95.4%, yield 50.1%) was obtained as a white solid. LCMS: RT=1.44 min, MS calculation value: M av =3237.51, observed mass: [M+2H] 2+ =1620.10, [M-203+2H] 2+ =1519.10, [M-2×203+2H] 2+ =1417.10, [M+3H] 3+ = 1080.50. [ka]

[0490] BH0003081, BH0003083, and BH0003050 were synthesized using the same procedure as BH0003080, which was performed according to the procedure described in

[0059] to

[0063] .

[0491] From 50.0 mg of target A044, BH0003081 (53.0 mg, purity 95.8%, yield 49.2%) was obtained as a white solid. LCMS: RT=1.44 min, MS calculation value: M av =3253.51, observed mass: [M+2H] 2+ =1628.70, [M-203+2H] 2+ =1526.50, [M-2×203+2H] 2+ =1424.50, [M+3H] 3+ = 1085.80. [ka]

[0492] From 50.0 mg of target A042, BH0003083 (45.0 mg, purity 95.8%, yield 43.7%) was obtained as a white solid. LCMS: RT=1.45 min, MS calculation value: M av =3295.59, observed mass: [M+2H] 2+ =1649.10, [M-203+2H] 2+ =1547.50, [M-2×203+2H] 2+ =1446.00, [M+3H] 3+ = 1099.80. [ka]

[0493] From 20 mg of target A041, BH0003050 (19.8 mg, purity 97.2%, yield 37.7%) was obtained as a white solid. LCMS: RT=0.84 min, MS calculation value: M av =3383.70, observed mass: [M+2H]2+ =1692.40, [M-sugar+2H] 2+ =1590.90, [M+3H] 3+ = 1128.50. [ka]

[0494] Example 10. Procedure for the preparation of BH0003746 and BH-0003602. [ka]

[0495] Preparation of compound 1562: [ka]

[0496] The peptides were synthesized using standard Fmoc chemistry (CTC resin). 1) Resin preparation: In a container containing a DCM (10 mL) solution of CTC resin (0.50 g, 0.50 mmol, 1.00 mmol / g) and Fmoc-Gly-OH (148.8 mg, 0.5 mmol, 1.00 equivalent), DIEA (4.00 equivalent) was added dropwise, and the mixture was stirred with N2 at 25°C for 2 hours. Then, MeOH (2.0 mL) was added, and N2 was stirred for a further 30 minutes. The resin was washed five times with DMF (10 mL), followed by the addition of a 20% piperidine DMF solution (10 mL), and N2 was stirred for 30 minutes at 25°C for Fmoc deprotection. The mixture was filtered, and the resin was washed five times with DMF (10 mL) before proceeding to the next step. 2) Coupling: A solution of Fmoc-Leu-OH (0.53 g, 1.5 mmol, 3.00 equivalents) and HBTU (0.41 g, 1.43 mmol, 2.85 equivalents) in DMF (10 mL) was added to the resin while aeration with N2. Then, DIEA (6.00 equivalents) was added dropwise to the mixture, and N2 was aerated at 25°C for 30 minutes. The coupling reaction was monitored by the ninhydrin test, and if it showed no color, the coupling was complete. The resin was then washed five times with DMF (10 mL). 3) Deprotection: 10 mL of 20% piperidine DMF solution was added to the resin, and the mixture was aerated with N2 at 25°C for 30 minutes. The resin was then washed five times with 10 mL of DMF. 4) For the following amino acid elongation: Steps 2 and 3 were repeated for numbers 3-15 in Table 3. 5) After all steps were completed, the resin was washed five times with DMF (100 mL) and five times with MeOH (100 mL), and then dried under reduced pressure to obtain resin-bound peptide intermediate 25 (CTC resin, 1.10 g, 0.5 mmol). [Table 3]

[0497] Peptide cleavage and cyclization, TFA deprotection, and disulfide formation: 1) Cutting: 20 mL of 1% TFA / DCM solution was added to the above resin at room temperature and stirred for 2 hours. After filtration, the filtrate was collected (which contained intermediate 26). 2) Cyclization from head to tail: The filtrate was diluted to 500 mL (1 mM) with DCM, then HATU (380.2 mg, 1.0 mmol, 2.00 equivalents) was added, followed by DIEA (348.6 μL, 2.0 mmol, 4.00 equivalents), and the resulting mixture was stirred at 25°C for 30 minutes. After monitoring by LC-MS was completed, the reaction was washed with 1 M HCl (300 mL), and then with H2O (300 mL). The organic layer was collected and concentrated under reduced pressure to obtain the residue. 3) Deprotection: To the residue from step 2, TFA / TIS / H2O / 3-mercaptopropanoic acid solution (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 50 mL) was added, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was precipitated with cold isopropyl ether (cold, 300 mL). After filtration, the solid was washed twice with isopropyl ether (100 mL), and the crude peptide was dried under reduced pressure. 4) Disulfide formation: To a solution of the crude peptide from step 3 in MeCN / H2O (1 / 1, v / v, 500 mL), 0.1 M I2 / AcOH was added dropwise until the yellow color persisted, and the mixture was stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain compound 1562 (164.8 mg, purity 96.6%, yield 19.4%) as a white solid. LCMS: RT = 7.9 min, MS calculation: M av =1696.95, observed mass: [M+H] + =1696.76, [2M+3H] 3+ =1132.18, [M+2H] 2+ =848.88, [M+3H] 3+ = 566.26. [ka]

[0498] BH-0003602 was synthesized using the same procedure as compound 1562, which was prepared according to the steps described in sections

[0069] to

[0070] . From 0.50 mmol of resin, BH-0003602 (110.4 mg, purity 95.0%, yield 12.9%) was obtained as a white solid. LCMS: RT = 1.78 min, MS calculation value: M av =1706.94, observed mass: [M+H] + =1707.1, [M+2H] 2+ = 854.1. [ka]

[0499] Preparation of intermediate 27: [ka]

[0500] A mixture of 27A (151.1 mg, 329.7 μmol, 3.00 equivalents) in DMF (0.5 mL) was added at 0°C to a mixture of target A011A (180.0 mg, 109.9 μmol, 1.00 equivalents) and DIEA (76.6 μL, 439.63 μmol, 4.00 equivalents) in DMF (0.5 mL). The resulting reaction was stirred at 0°C for 5 minutes. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 27 (160.0 mg, yield 75.4%) as a colorless oil. LCMS: RT=0.828 min, MS calculation: M av =1929.92, observed mass: [M+2H] 2+ =965.7.

[0501] Preparation of BH0003746: [ka]

[0502] To a mixture of intermediate 27 (24.9 mg, 12.9 μmol, 1.00 equivalent) and compound 1562 (21.9 mg, 12.9 μmol, 1.00 equivalent) in DMF (0.2 mL), DIEA (22.0 μL, 129 μmol, 10.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain BH0003746 (8.1 mg, purity 92.5%, yield 18.1%) as a white solid. LCMS: RT=9.3 min, MS calculation: M av =3460.79, observed mass: [M+2H] 2+=1730.80, [M+3H] 3+ =1154.54, [M+4H] 4+ = 865.90.

[0503] Example 11. Procedure for the preparation of BH0003716, BH0003789, and BH0003082. [ka]

[0504] Preparation of BH0003716: [ka]

[0505] SPPS (resin loading amount 0.50 mmol) was performed using the amino acid elongation shown in Table 4, following the procedure described in Section

[0048] .

[0506] Acetylation: Ac2O / NMM / DMF solution (2 / 1 / 17, v / v / v, 40 mL) was added to the resin, and the mixture was aerated with N2 for 20 minutes. The acetylation reaction was monitored by the ninhydrin test. Subsequently, the resin was washed five times with DMF (20 mL) and three times with MeOH (20 mL), and then dried under reduced pressure to obtain intermediate 28 (peptide resin, 0.50 mmol). [Table 4]

[0507] Peptide cleavage and disulfide formation: 5) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 mL) was added at 25°C to a flask containing a side-chain protective resin-bound peptide (Rink AM resin, 1.84 g, 0.50 mmol) and stirred for 2 hours. 6) After filtration, the filtrate was collected. 7) The filtrate was precipitated with cold isopropyl ether (150 mL). After filtration, the solid was washed twice with isopropyl ether (150 mL), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 28 (785 mg, crude product) as a white solid. 5) Disulfide formation: To a solution of intermediate 28 in MeCN / H2O (1 / 1, v / v, 500 mL), 0.1 M I2 / AcOH was added dropwise until the yellow color persisted, and the mixture was stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH0003716 (59.7 mg, purity 95.2%, yield 7.2%) as a white solid. LCMS: RT = 1.23 min, MS calculation value: M av =1586.79, observed mass: [M+H] + =1586.79, [M+2H] 2+ = 794.1. [ka]

[0508] Preparation of BH0003789: [ka]

[0509] BH0003789 and BH-0003082 were synthesized using the same procedure as BH0003746, which was performed according to the procedure described in

[0072] to

[0075] .

[0510] Preparation of BH0003789: [ka]

[0511] Intermediate 30 was synthesized using the same procedure as described in

[0048] to

[0049] .

[0512] From 50.0 mg of intermediate 29, BH0003789 (20.3 mg, purity 93.2%, yield 22.8%) was obtained as a white solid. LCMS: RT=1.31 min, MS calculation value: M av =3570.90, observed mass: [M+2H] 2+ =1786.7, [M+3H] 3+ =1191.1, [M+4H] 4+ =893.7, [M+5H] 5+ = 715.3. [ka]

[0513] Preparation of BH0003082: [ka]

[0514] Intermediate 31 was synthesized using the same procedure as described in

[0059] to

[0060] .

[0515] Intermediate 32 was synthesized using the same procedure as intermediate 27, which was synthesized according to the procedure described in

[0072] .

[0516] From 8 mg of target A001A, BH-0003082 (5 mg, purity 94.6%, yield 32.2%) was obtained as a white solid. LCMS: RT=0.83 min, MS calculation value: M av =3227.52, observed mass: [M+2H] 2+ =1614.17, [M-sugar+4H] 4+ =1076.40, [M+3H] 3+ = 1076.40. [ka]

[0517] Example 12. Procedure for the preparation of BH-0003714, BH-0003715, and BH-0003786 [ka]

[0518] Preparation of BH-0003714: [ka]

[0519] BH-0003714 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 5. [Table 5]

[0520] Peptide cleavage and disulfide formation: 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 mL) was added at 25°C to a flask containing a side-chain protective resin-bound peptide (Rink AM resin, 1.84 g, 0.50 mmol) and stirred for 2 hours. 2) After filtration, the filtrate was collected. 3) The filtrate was precipitated with cold isopropyl ether (150 mL). After filtration, the solid was washed twice with isopropyl ether (150 mL), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 33 (785 mg, crude product) as a white solid. 4) Disulfide formation: 0.1 M I2 / AcOH was added dropwise to a solution of intermediate 30 in MeCN / H2O (1 / 1, v / v, 500 mL) until the yellow color persisted, and the mixture was then stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH-0003714 (156 mg, purity 96.5%, yield 19.3%) as a white solid. LCMS: RT = 1.26 min, MS calculation: Mav = 1561.78, observed mass: [M+H]+= 1561.9, [M+2H] 2+ = 781.6. [ka]

[0521] BH-0003715 was synthesized using the same procedure as BH-0003714, which was performed according to the procedure described in

[0089] to

[0091] . From 1.00 mmol of resin, BH-0003715 (495.2 mg, purity 95.8%, yield 31.2%) was obtained as a white solid. LCMS:RT=1.25, MS calculation value:M av =1519.75, observed mass: [M+H] + =1519.75, [M+2H] 2+ = 760.5. [ka]

[0522] Preparation of BH0003786 [ka]

[0523] BH0003786 was synthesized using the same procedure as BH0003746, which was performed according to the procedure described in

[0072] to

[0075] .

[0524] From 54.0 mg of intermediate 34, BH-0003786 (28.3 mg, purity 96.7%, yield 28.7%) was obtained as a white solid. LCMS: RT=1.31 min, MS calculation value: M av =3217.52, observed mass: [M+2H] 2+ =1609.5, [M-sugar+2H] 2+ =1508.0, [M-2×sugar+2H] 2+ =1406.4, [M-3×sugar+2H] 2+ =1304.6, [M+3H] 3+ = 1073. [ka]

[0525] Example 13. Procedure for the preparation of BH-0003787 [ka]

[0526] Preparation of intermediate 36: [ka]

[0527] Intermediate 35 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 6. [Table 6]

[0528] Intermediate 36 was synthesized using the same procedure as BH-0003714, which was carried out according to the steps described in

[0086] to

[0088] . After filtration, the filtrate was separated and purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently freeze-dried to obtain intermediate 36 (156 mg, purity 90%, yield 15.7%) as a white solid.

[0529] Preparation of intermediate 37: [ka]

[0530] Intermediate 37 was synthesized using the same procedure as that used for BH0003746, which was carried out according to the procedure described in

[0074] to

[0075] . From 92.0 mg of intermediate 34, intermediate 37 (80 mg, yield 51.27%) was obtained as a white solid.

[0531] Preparation of BH-0003787: [ka]

[0532] Intermediate 37 (80 mg, 23.55 μmol, 1.00 equivalent) was added to a 2% DBU / DMF (1.0 mL) mixture. The mixture was stirred at 25°C for 15 minutes. After monitoring by LC-MS, the mixture was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH-0003787 (35.7 mg, purity 97.1%, yield 35.5%) as a white solid. LC-MS: RT = 1.24 min, MS calculation value: M av =3175.48, observed mass: [M+2H] 2+ =1588.6, [M-sugar+2H] 2+ =1487.1, [M-2×sugar+2H] 2+ =1385.4, [M+3H] 3+ = 1059.1. [ka]

[0533] Example 14. Procedure for the preparation of BH0003710 and BH0003711. [ka]

[0534] Preparation of intermediate 38: [ka]

[0535] To a 5 mL mixture of intermediate 38A (2.35 g, 5.13 mmol, 3.0 equivalents) in DMF, a 2 mL mixture of target A092 (0.50 g, 1.71 mmol, 1.0 equivalent) and DIEA (582.3 uL, 3.42 mmol, 2.0 equivalents) in DMF was added, and the resulting reaction was stirred at 0°C for 5 minutes. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 38 (750.0 mg, yield 75.1%) as a white solid. LC-MS: RT=1.11 min, MS calculation: M av =584.51, observed mass: [M+H] + = 585.28.

[0536] Preparation of intermediate 41: [ka]

[0537] Intermediate 39 (resin-bound peptide) was synthesized according to the procedure described in Section

[0069] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 7. [Table 7]

[0538] Intermediate 41 (peptide cleavage, cyclization, TFA deprotection, disulfide formation) was synthesized according to the procedure described in Section

[0070] . After lyophilization, intermediate 41 (200.0 mg, purity 95.4%, yield 23.8%) was obtained as a white solid from 0.50 mmol of resin. LCMS: RT = 0.863 min, MS calculation value: M av =1677.94, observed mass: [M+H] + =1678.7, [M+2H] 2+ = 839.6. [ka]

[0539] Preparation of intermediate 42: [ka]

[0540] To a DMSO (0.5 mL) mixture of intermediate 41 (103.2 mg, 61.5 μmol, 1.00 equivalent), a DMSO (0.2 mL) mixture of intermediate 38 (35.9 g, 61.5 μmol, 1.00 equivalent) and DIEA (20.9 μL, 123.0 μmol, 2.00 equivalent) was added, and the resulting reaction was stirred at 0°C for 30 minutes. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain intermediate 42 (44.7 mg, yield 34.7%) as a white solid. LC-MS: RT=1.76 min, MS calculation: M av =2096.39, observed mass: [M+2H] 2+ = 1048.96.

[0541] Preparation of BH0003710: [ka]

[0542] To a 0.5 mL solution of intermediate 42 (45.0 mg, 21.5 μmol, 1.00 equivalent) and target A093 (30.8 mg, 68.7 μmol, 3.20 equivalents) in DMF (0.5 mL), CuSO4 (10.2 mg, 64.5 μmol, 3.00 equivalent), sodium ascorbate (51.0 mg, 258.0 μmol, 12.00 equivalent), and THPTA (27.9 mg, 64.5 μmol, 3.00 equivalent) were added at 0°C under a nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 1 hour. After monitoring by LC-MS was completed, the reaction product was filtered off and purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to obtain BH0003710 (22.1 mg, purity 96.7%, yield 28.9%) as a white solid. LC-MS: RT = 1.437 min, MS calculation value: Mav =3441.79, observed mass: [M+2H] 2+ =1721.80, [M+3H] 3+ =1148.20, [M+4H] 4+ = 861.40. [ka]

[0543] Preparation of BH0003711: [ka]

[0544] BH-0003711 was synthesized using the same procedure as BH0003710, which was performed according to the steps described in

[0103] to

[0111] .

[0545] From 16.8 mg of target A093 containing intermediate 46, BH-0003711 (23.7 mg, purity 93.7%, yield 59.3%) was obtained as a white solid. LCMS: RT=1.37 min, MS calculation value: M av =3485.80, observed mass: [M+2H] 2+ =1743.6, [M+3H] 3+ =1162.8, [M+4H] 4+ = 872.5. [ka]

[0546] Example 15. Procedure for the preparation of BH-0003788 and BH-0003787. [ka]

[0547] Preparation of intermediate 49:

[0548] Intermediate 48 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 8. [Table 8]

[0549] Intermediate 49 was synthesized using the same procedure as intermediate 21, which was prepared according to the procedure described in

[0049] . After filtration, the filtrate was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently freeze-dried to obtain intermediate 49 (162 mg, purity 90%, yield 16.5%) as a white solid.

[0550] Preparation of intermediate 50: [ka]

[0551] Intermediate 50 was synthesized using the same procedure as intermediate 38, which was prepared according to the procedure described in

[0104] . The mixture was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently freeze-dried to obtain intermediate 50 (380 mg, yield 75.1%) as a colorless oil.

[0552] Preparation of intermediate 52: [ka]

[0553] Intermediate 52 was synthesized using the same procedure as BH0003710, which was carried out according to the steps described in

[0108] to

[0111] . The reaction products were filtered off, purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 52 (36 mg, yield 38.89%).

[0554] Preparation of BH0003788:

[0555] BH0003788 was synthesized using the same procedure as BH-0003787, which was performed according to the steps described in

[0101] to

[0102] . [ka]

[0556] From 38.89 mg of intermediate 52, BH0003788 (11.8 mg, purity 92.9%, yield 30.0%) was obtained as a white solid. LCMS: RT=1.88 min, MS calculation value: M av =3528.86, observed mass: [M+2H] 2+ =1765.2, [M+3H] 3+ =1177.5, [M+4H] 4+ =883.1, [M+5H] 5+ = 706.8. [ka]

[0557] Example 16. Procedure for preparing BH0003780. [ka]

[0558] Preparation of compound 1569: [ka]

[0559] Intermediate 53 (resin-bound peptide) was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 9.

[0560] Acetylation: Ac2O / NMM / DMF solution (2 / 1 / 17, v / v / v, 40 mL) was added to the resin, and the mixture was aerated with N2 for 20 minutes. The acetylation reaction was monitored by the ninhydrin test. Subsequently, the resin was washed five times with DMF (20 mL) and three times with MeOH (20 mL), and then dried under reduced pressure to obtain intermediate 53 (peptide resin, 0.50 mmol). [Table 9]

[0561] Peptide cleavage and double disulfide formation: 1) Cutting: A TFA / TIS / H2O solution (95 / 2.5 / 2.5, v / v / v, 40 mL) was added to a flask containing a side-chain protective resin-bound peptide (intermediate 53), and the resulting mixture was stirred at 25°C for 2 hours. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 mL), then filtered off, and the solid was washed twice with isopropyl ether (100 mL). The crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 54 (0.50 mmol, crude product) as a white solid. 2) First disulfide formation: NaHCO3 was added at 25°C to a mixture of intermediate 54 (0.50 mmol, crude product) in MeCN / H2O (4 / 6, v / v, 500 mL) to adjust the pH to 8. The mixture was then exposed to air and stirred at 25°C for 24 hours. After filtration, the mixture was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN) to obtain intermediate 55 (355.4 mg, yield 20.1%) 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), 1 M aqueous HCl (1.5 mL) and AcOH (3.0 mL) were added to adjust the pH to 1. 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and the mixture was then stirred at 25°C for 5 hours. The mixture was quenched by dropwise addition of 0.1 M aqueous Na2S2O3 until the yellow color disappeared. After filtration, the filtrate was separated and purified directly by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain compound 1569 (245.4 mg, purity 91.7%, yield 69.0%) as a white solid. LCMS: RT = 1.294 min, MS calculation value: M av =1767.04, observed mass: [M+H] + =1767.7, [M+2H] 2+ = 884.6. [ka]

[0562] Preparation of BH0003780 [ka]

[0563] Compound 1569 (98.4 mg, 51.0 μmol, 1.00 equivalent) and intermediate 27 (90.1 mg, 51.0 μmol, 1.00 equivalent) were mixed in DMSO (0.5 mL) and DIEA (87.0 μL, 510 μmol, 10.0 equivalent) at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain BH0003780 (36.2 mg, purity 96.9%, yield 20.1%) as a white solid. LCMS: RT=1.346 min, MS calculation value: M av =3530.88, observed mass: [M+2H] 2+ =1766.1, [M+3H] 3+=1177.7, [M+4H] 4+ = 883.7. [ka]

[0564] Example 17. Procedure for the preparation of BH0003794 and BH-0003793. [ka]

[0565] Preparation of intermediate 59: [ka]

[0566] Intermediate 56 (resin-bound peptide) was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 10, numbers 1-15. [Table 10]

[0567] Intermediate 59 was synthesized using the same procedure as compound 1569, which was synthesized according to the procedure described in

[0128] .

[0568] Preparation of intermediate 60: [ka]

[0569] Intermediate 60 was synthesized using the same procedure as BH0003780, which was performed according to the procedure described in

[0129] to

[0130] .

[0570] Preparation of BH-0003794: [ka]

[0571] Intermediate 60 (29 mg, 7.76 μmol, 1.00 equivalent) was added to a 2% DBU / DMF (0.5 mL) mixture. The mixture was stirred at 25°C for 15 minutes. After monitoring by LC-MS, the mixture was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH0003794 (16.2 mg, purity 97.0%, yield 58.0%) as a white solid. LC-MS: RT = 1.32 min, MS calculation value: M av =3488.84, observed mass: [M+2H] 2+ =1745.1, [M+3H] 3+ =1164.1, [M+4H] 4+ =873.2, [M+5H] 5+ = 698.7. [ka]

[0572] Preparation of BH-0003793: [ka]

[0573] BH-0003793 was synthesized using the same procedure as BH0003794, which was performed according to the steps described in

[0131] to

[0137] .

[0574] From intermediate 64, BH-0003793 (13.4 mg, purity 97.3%, yield 47.8%) was obtained as a white solid. LCMS: RT=1.32 min, MS calculation value: M av =3513.85, observed mass: [M+2H] 2+ =1757.7, [M+3H] 3+ =1172.3, [M+4H] 4+ =879.4, [M+5H] 5+ = 703.6. [ka]

[0575] Example 18. Procedure for the preparation of BH-0003921, BH-0001685, BH-0003783, and BH-0003785. [ka]

[0576] Preparation of intermediate 68: [ka]

[0577] Intermediate 65 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.30 mmol) was synthesized using the amino acid elongation shown in Table 11, numbers 1-15. [Table 11]

[0578] Peptide cleavage and cyclization: 1) Cutting: A TFA / TIS / H2O solution (95 / 2.5 / 2.5, v / v / v, 40 mL) was added to a flask containing a side-chain protective resin-bound peptide (intermediate 50), and the resulting mixture was stirred at 25°C for 2 hours. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 mL), then filtered off, and the solid was washed twice with isopropyl ether (100 mL). The crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 51 (0.30 mmol, crude product) as a white solid. 2) Thioether ring formation: NaHCO3 was added at 25°C to a mixture of intermediate 66 (0.30 mmol, crude product) in MeCN / H2O (4 / 6, v / v, 300 mL) to adjust the pH to 8. The mixture was then stirred at 25°C for 24 hours under an N2 atmosphere. After filtration, the mixture was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN) to obtain intermediate 67 (240 mg, purity 90, yield 38.6%) 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), 1.5 mL of 1 M HCl aqueous solution and 3.0 mL of AcOH were added to adjust the pH to 1. 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and the mixture was then stirred at 25°C for 5 hours. After filtration, the filtrate was separated and directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 68 (173 mg, purity 95%, yield 76.5%) as a white solid. LCMS: RT = 0.82 min, MS calculation value: M av =1719.91, observed mass: [M+2H] 2+ = 860. [ka]

[0579] BH-0001685 was synthesized using the same procedure as intermediate 68, which was prepared according to the steps described in

[0141] to

[0143] . From 0.3 mmol of resin, BH-0001685 (8.6 mg, purity 91.1%, yield 1.51%) was obtained as a white solid. LCMS: RT = 1.41 min, MS calculation value: M av =1729.96, observed mass: [M+H] + =1729.9, [M+2H] 2+ = 865.6. [ka]

[0580] Preparation of intermediate 69: [ka]

[0581] To a mixture of intermediate 68 (173 mg, 100.0 μmol, 1.00 equivalent) and intermediate 38 (59 mg, 100.0 μmol, 1.00 equivalent) in DMF (0.5 mL), DIEA (70.0 μL, 402 μmol, 4.00 equivalent) was added at 25°C. The mixture was stirred at 25°C for 0.5 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 69 (95 mg, purity 95%, yield 44.1%) as a white solid. LC-MS: RT=0.96 min, MS calculation value: M av =2138.42, observed mass: [M+2H] 2+ =1069.7, [M+3H] 3+ = 713.9. [ka]

[0582] Preparation of BH-0003921: [ka]

[0583] To a mixture of intermediate 69 (30.0 mg, 14.3 μmol, 1.00 equivalent) and target A093 (25.2 mg, 56.1 μmol, 4.00 equivalent) in DMF (0.5 mL), CuSO4.5H2O (0.4 M, 105.2 μL, 3.00 equivalent), sodium ascorbate (0.5 M, 252.5 μL, 9.00 equivalent), and THPTA (18.6 mg, 42.1 μmol, 3.00 equivalent) were added. The resulting reaction product was degassed and purged three times with N2. The mixture was then stirred under an N2 atmosphere at 25°C for 2 hours. LC-MS showed that intermediate 69 was completely consumed and a single major peak was shown on LC-MS, indicating the detection of the desired compound. The resulting reaction mixture was purified by preparative HPLC (A: 0.075% HOAc / H2O solution, B: MeCN) to obtain BH-0003921 (20.1 mg, purity 92.4%, 38.0%) as a white solid. LCMS: RT=1.305 min, MS calculation value: M av =3483.84, observed mass: [M+2H] 2+ =1742.6, [M+3H] 3+ =1162.2, [M+4H] 4+ = 872.0. [ka]

[0584] Preparation of BH-0003783: [ka]

[0585] BH-0003783 was synthesized using the same procedure as BH0003921, which was performed according to the steps described in

[0141] to

[0148] .

[0586] From 33.1 mg of target A093 containing intermediate 73, BH-0003783 (18.1 mg, purity 93.7%, yield 26.1%) was obtained as a white solid. LCMS: RT=1.30 min, MS calculation value: M av =3508.81, observed mass: [M+2H] 2+=1755.2, [M+3H] 3+ =1170.5, [M+4H] 4+ = 878.0. [ka]

[0587] Preparation of BH-0003785: [ka]

[0588] BH-0003785 was synthesized using the same procedure as BH0003921, which was performed according to the steps described in

[0141] to

[0148] . [ka]

[0589] From 34.6 mg of target A093 containing intermediate 74, BH-0003785 (39.5 mg, purity 97.3%, yield 53.3%) was obtained as a white solid. LCMS: RT=1.31 min, MS calculation value: M av =3279.08, observed mass: [M+2H] 2+ =1864.9, [M+3H] 3+ =1244.0, [M+4H] 4+ =933.2, [M+5H] 5+ = 746.9. [ka]

[0590] Example 19. Procedure for the preparation of BH003779 and BH-0003713. [ka]

[0591] Preparation of compound 1512: [ka]

[0592] Intermediate 75 (resin-bound peptide) was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 12, numbers 1-15. [Table 12]

[0593] Peptide cleavage and double disulfide formation: 1) Cutting: A TFA / TIS / H2O solution (95 / 2.5 / 2.5, v / v / v, 40 mL) was added to a flask containing a side-chain protective resin-bound peptide (intermediate 75), and the resulting mixture was stirred at 25°C for 2 hours. After filtration, the filtrate was collected and precipitated with cold isopropyl ether (200 mL), then filtered off, and the solid was washed twice with isopropyl ether (100 mL). The crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 76 (0.50 mmol, crude product) as a white solid. 2) First disulfide formation: NaHCO3 was added at 25°C to a mixture of intermediate 76 (0.50 mmol, crude product) in MeCN / H2O (4 / 6, v / v, 500 mL) to adjust the pH to 8. The mixture was then exposed to air and stirred at 25°C for 24 hours. After filtration, the mixture was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN) to obtain intermediate 77 (439.5 mg, yield 25.3%) as a white solid. 3) Second disulfide formation: To the MeCN / H2O (4 / 6, v / v, 300 mL) mixture of intermediate 77 (439.5 mg, yield 25.3%), 1.5 mL of 1 M HCl aqueous solution and 3.0 mL of AcOH were added to adjust the pH to 1. 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and then the mixture was stirred at 25°C for 5 hours. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified directly by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain compound 1512 (160.5 mg, purity 95.8%, yield 36.5%) as a white solid. LCMS: RT = 1.355 min, MS calculation value: M av =1735.00, observed mass: [M+H] + =1735.8, [M+2H] 2+ = 868.6. [ka]

[0594] Preparation of BH0003779: [ka]

[0595] Compound 1512 (49.2 mg, 25.5 μmol, 1.00 equivalent) and intermediate 27 (44.2 mg, 25.5 μmol, 1.00 equivalent) were mixed in DMSO (0.5 mL) and DIEA (43.5 μL, 255 μmol, 10.0 equivalent) at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain BH0003779 (9.0 mg, purity 95.0%, yield 10.1%) as a white solid. LCMS: RT=1.407 min, MS calculation value: M av =3498.84, observed mass: [M+2H] 2+ =1750.6, [M+3H] 3+=1167.1, [M+4H] 4+ = 876.1. [ka]

[0596] Preparation of BH0003713: [ka]

[0597] BH-0003713 was synthesized using the same procedure as BH0003779, which was performed according to the steps described in

[0156] to

[0159] . [ka]

[0598] From 30 mg of intermediate 27 containing intermediate 80, BH-0003713 (27.7 mg, purity 88.4%, yield 44.3%) was obtained as a white solid. LCMS: RT=1.32 min, MS calculation value: M av =3555.89, observed mass: [M+2H] 2+ =1778.7, [M+3H] 3+ =1186.1, [M+4H] 4+ = 889.7. [ka]

[0599] Example 20. Procedure for the preparation of BH0003712. [ka]

[0600] Preparation of intermediate 85: [ka]

[0601] Intermediate 81 was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 13, numbers 1 to 15.

[0602] Acetylation: Ac2O / NMM / DMF solution (2 / 1 / 17, v / v / v, 40 mL) was added to the resin, and the mixture was aerated with N2 for 20 minutes. The acetylation reaction was monitored by the ninhydrin test. Subsequently, the resin was washed five times with DMF (20 mL) and three times with MeOH (20 mL), and then dried under reduced pressure to obtain peptide resin (0.50 mmol). [Table 13]

[0603] Peptide cleavage and fragment coupling, TFA deprotection, and double disulfide formation: 1) Dissection from resin: 50 mL of 20% HFIP / DCM solution was added to the above resin at room temperature and stirred for 1 hour. After filtration, the filtrate was collected and concentrated under reduced pressure to obtain fully protected peptide intermediate 81 (1.40 g, crude product) as a white solid. 2) Fragment coupling: EDCI (285.6 mg, 1.49 mmol, 3.00 equivalent) was added at 0°C to a mixture of intermediate 81 (1.40 g, crude product, 496.72 μmol, 1.00 equivalent), 59A (238.7 mg, 1.49 mmol, 3.00 equivalent), and HOBt (201.2 mg, 1.49 mmol, 3.00 equivalent) in DMF (2.0 mL). The resulting reaction was stirred at 0°C for 2 hours. After monitoring by LC-MS, the reaction was added to a flask containing cold 0.1 M HCl (30 mL), and the precipitate was filtered off to obtain the crude product as intermediate 82. 3) Deprotection: A TFA / TIS / H2O / 3-mercaptopropanoic acid solution (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 20 mL) was added to the flask containing intermediate 82 (crude product) from step 2, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was precipitated with cold isopropyl ether (100 mL), then filtered off, and the solid was washed twice with isopropyl ether (50 mL). The crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 83 (858.3 mg, crude product) as a white solid. 4) First disulfide formation: A solution of intermediate 83 (858.3 mg, crude product) in MeCN / H2O (4 / 6, v / v, 500 mL) was basicized to pH=8 with NaHCO3. The mixture was exposed to air and stirred at 25°C for 24 hours. After filtration, the mixture was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN) to obtain intermediate 84 (260.9 mg, yield 30.4%) 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), 1.5 mL of 1 M HCl aqueous solution and 3.0 mL of AcOH were added to adjust the pH to 1. 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and the mixture was then stirred at 25°C for 5 hours. The mixture was quenched by dropwise addition of 0.1 M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified directly by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 85 (86.1 mg, yield 33.0%) as a white solid. UPLC: RT = 0.845 min, MS calculation: M av =1819.11, observed mass: [M+H] + =1819.69, [M+2H] 2+ =910.04. [ka]

[0604] Preparation of BH0003712: [ka]

[0605] To a mixture of intermediates 85 (36.7 mg, 20.21 μmol, 1.30 equivalents) and 27 (30.0 mg, 15.54 μmol, 1.00 equivalent) in DMSO (0.5 mL), DIEA (6.03 mg, 46.63 μmol, 8.12 μL, 3.00 equivalents) was added at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain BH0003712 (13.5 mg, purity 92.2%, yield 22.3%) as a white solid. LCMS: RT=1.401 min, MS calculation value: M av =3582.96, observed mass: [M+2H] 2+ =1792.7, [M+3H] 3+ =1195.1, [M+4H] 4+ = 896.7. [ka] Example 21. Procedure for the preparation of BH0003844. [ka]

[0606] Preparation of intermediate 87: [ka]

[0607] To a mixture of target A092 (200 mg, 684.1 μmol, 1.00 equivalent) and dihydrofuran-2,5-dione (68.47 mg, 684.1 μmol, 1.00 equivalent) in DMF (2 mL), DIEA (176.8 mg, 1.37 mmol, 238.3 μL, 2.00 equivalent) was added at 25°C. The mixture was stirred at 15°C for 1 hour. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was freeze-dried to obtain intermediate 86 (250 mg, yield 93.12%) as a colorless oil. Intermediate 86 (250 mg, 637.1 ml, 1.00 equivalent) and 2,3,5,6-tetrafluorophenol (423.2 mg, 2.55 mmol, 4.00 equivalent) were mixed in DMF (3 mL), to which EDCI (244.2 mg, 1.27 mmol, 2.00 equivalent) was added at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 87 (160 mg, yield 46.4%) as a colorless oil.

[0608] Preparation of intermediate 92: [ka]

[0609] Intermediate 88 was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 14, numbers 1-15. [Table 14]

[0610] Intermediate 92 was synthesized using the same procedure as intermediate 85, which was prepared according to the procedure described in

[0166] , to obtain intermediate 92 (86.1 mg, yield 33.0%). [ka]

[0611] Preparation of intermediate 93: [ka]

[0612] To a mixture of intermediates 92 (73.9 mg, 37.0 μmol, 1.00 equivalent) and 87 (20.0 mg, 37.0 μmol, 1.00 equivalent) in DMSO (1.0 mL), DIEA (19.1 mg, 148.0 μmol, 25.8 μL, 4.00 equivalent) was added at 25°C. The mixture was stirred at 25°C for 2 hours. After monitoring by LC-MS, the mixture was acidified to pH=5 with 1 M HCl, and then directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN). Subsequently, it was lyophilized to obtain intermediate 93 (26 mg, purity 90%, yield 26.6%) as a white solid.

[0613] Preparation of intermediate 94: [ka]

[0614] Intermediate 93 (26 mg, 10.9 μmol, 1.00 equivalent) was added to a 2% DBU / DMF (1.0 mL) mixture. The mixture was stirred at 25°C for 15 minutes. After monitoring by LC-MS, the mixture was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 94 (15 mg, purity 90%, yield 57.3%) as a white solid.

[0615] Preparation of BH-0003844: [ka]

[0616] Intermediate 94 (15 mg, 6.97 μmol, 1.00 equivalent) and target A093 (11.8 mg, 27.9 μmol, 4.00 equivalent) were dissolved in DMF (1 mL) under a nitrogen atmosphere with CuSO4 (0.4 M, 52.3 μL, 20.9 μmol, 3.00 equivalent), sodium ascorbate (0.4 M, 156.8 μL, 62.7 μmol, 9.0 equivalent), and THPTA (tris-hydroxypropyltriazolylmethylamine). 9.09 mg (20.9 μmol, 3.00 equivalents) was added at 0°C, and the resulting mixture was stirred at 0°C for 3 hours. After monitoring by LC-MS, the reaction product was filtered off and purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), followed by lyophilization to obtain BH0003844 (7.1 mg, purity 93.2%, yield 27.1%) as a white solid. LC-MS: RT = 0.82 min, MS calculation value: M av =3496.87, observed mass: [M+2H] 2+ =1748.40, [M+3H] 3+ =1166.17, [M+4H] 4+ = 874.88. [ka]

[0617] Example 22. Procedure for the preparation of BH2640 (FcIII-GN3). [ka]

[0618] Preparation of intermediate 96: [ka]

[0619] A solution of 2-methyltetrahydrofuran (450 mL) containing 95a (60.0 g, 400 mmol, 2.00 equivalents) was added to a solution of 2-methyltetrahydrofuran (160 mL) containing 95 (34.2 g, 200 mmol, 1.00 equivalent) at 0°C. The mixture was stirred at 25°C for 2 hours. TLC (DCM:MeOH = 20:1, R f A reading of 0.70 indicated that the reaction was complete and a new, less polar primary spot was detected. HCl / EA (1 N, 27.0 mL) was added to the reaction mixture and stirred for 30 minutes. The white precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 96 (crude product, 105.0 g, 370.6 mmol) as a yellow oil. LCMS: RT = 0.797 min, MS calculation: 283.14, observed mass: [M + Na] + = 306.1. 1 H 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, 1H).

[0620] Preparation of intermediate 97: [ka]

[0621] To a 500 mL solution of 96a (100.0 g, 257 mmol, 1.00 equivalent) in DCE, TMSOTf (85.6 g, 385 mmol, 1.50 equivalent) was added and the mixture was stirred at 60°C for 2 hours. The reaction mixture was then cooled to room temperature (25°C) and stirred for another hour. A mixture of intermediate 96 (80.0 g, 282 mmol, 1.10 equivalent) and 4 Å powdered molecular sieve (50.0 g) in DCE (500 mL) was added to the reaction mixture. The resulting mixture was stirred under an N2 atmosphere for 30 minutes. Then, a DCE solution of intermediate 96a (100.0 g, 257 mmol, 1.00 equivalent) was added dropwise to the mixture at 0°C. The mixture was stirred under an N2 atmosphere at 25°C for 16 hours. TLC (DCM:MeOH = 10:1, R) f The result (=0.42) indicated that intermediate 96a was completely consumed and a new, more polar primary spot was detected. The reaction mixture was filtered and washed with saturated 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 obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA=3:1-1:6, then DCM:MeOH=20:1) to obtain intermediate 97 (90.0 g, 146.9 mmol, purity 91.6%, yield 57.2%) as a yellow oil. LCMS:RT=0.860 min, MS calculation: 612.25, observed mass: [M+H] + = 613.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J = 9.03 Hz, 1 H), 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).

[0622] Preparation of intermediate 98: [ka]

[0623] In a reaction bottle (purged three times with Ar), 9.00 g of Pd / C (10% purity) was slowly mixed with 180 mL of THF. Then, a solution of TFA (16.7 g, 147 mmol, 1.00 equivalent) and intermediate 97 (90.0 g, 147.0 mmol, 1.00 equivalent) in 720 mL of THF was slowly added to the reaction under N2 conditions. The reaction mixture was degassed, purged three times with N2 and H2, and then stirred at 25°C for 3 hours under an H2 atmosphere (40 psi). TLC (DCM:MeOH = 10:1, R) was performed. fA value of 0.20 indicated that intermediate 97 was completely consumed and a new, more polar primary spot was detected. The reaction mixture was dissolved in THF (100 mL), carefully filtered through siliceous earth under an N2 atmosphere, washed the filter cake with THF (100 mL x 2), and concentrated the filtrate under reduced pressure to obtain the residue. The residue was diluted with water (1000 mL), washed with DCM (300 mL x 3), and the aqueous layer was freeze-dried to obtain intermediate 98 (80.0 g, 139.0 mmol, purity 95.1%, yield 91.8%, TFA salt) as a white solid. LCMS: RT = 0.484 min, MS calculation: 478.22, observed mass: [M + H] + = 478.9. 1 H NMR (400 MHz, DMSO-d6) δ 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 (br t, J = 5.14 Hz, 3 H), 3.50 - 3.56 (m, 6 H), 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).

[0624] Preparation of intermediate 100: [ka]

[0625] To a mixture of 99 (60.0 g, 495.0 mmol, 1.00 equivalent) and DMSO (166 mL), an aqueous NaOH solution (5.0 M, 9.91 mL, 0.10 equivalent) was added dropwise over 5 minutes at 0-15°C. After the dropwise addition, the mixture was stirred at 0-15°C for 5 minutes, and then 99a (254.0 g, 1.98 mol, 287 mL, 4.00 equivalent) was added dropwise to the reaction mixture at 20°C. The resulting mixture was stirred at 25°C for 16 hours. TLC (DCM:MeOH = 10:1, R f A value of 0.7) indicated that intermediate 99 was completely consumed and a new, less polar, primary spot was detected. The resulting reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was dissolved in siRNA (400 mL), quenched by adding water (400 mL), and extracted with siRNA (400 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 100 (100.0 g, 197.8 mmol, purity 96.0%, yield 40.0%) as a colorless oil. 1 H 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).

[0626] Preparation of intermediate 101: [ka]

[0627] To a solution of intermediate 100 (40.0 g, 79.1 mmol, 1.00 equivalent) in MeCN (400 mL), HOBt (10.7 g, 79.1 mmol, 1.00 equivalent) was added. Subsequently, 100a (16.5 g, 79.1 mmol, 1.00 equivalent) and DCC (16.3 g, 79.1 mmol, 1.00 equivalent) were added. The reaction mixture was stirred at 25°C for 16 hours. TLC (PE:EA = 1:1, R fThe result (=0.80) indicated that intermediate 100 was completely consumed and a new, less polar primary spot was detected. MeCN was evaporated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1-1:1) to obtain intermediate 101 (40.0 g, 57.4 mmol, purity 82.9%, yield 72.5%) as a white solid. LCMS: RT = 1.151 min, MS calculation: 696.38, observed mass: [M+H] + =697.3, [M+Na] + = 719.3. 1 H 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).

[0628] Preparation of intermediate 102: [ka]

[0629] Intermediate 101 (30.0 g, 43.0 mmol, 1.00 equivalent) was dissolved in HCOOH (300 mL) and stirred at 25°C for 16 hours. TLC (PE:EA = 1:1, R f A value of 0.04 indicated that intermediate 101 was completely consumed and a new, more polar primary spot was detected. The solvent was evaporated under reduced pressure, then co-evaporated with toluene (50 mL x 3) under reduced pressure, and dried under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (A: 0.1% FA conditions / H2O, B: MeCN) to obtain intermediate 102 (20.0 g, 37.8 mmol, purity 98.2%, yield 87.9%). 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 = 6.27Hz, 6H). LCMS: RT=0.790 min, MS calculated value: 528.20, Observed mass: [M+H] + = 529.2.

[0630] Preparation of intermediate 103: [ka]

[0631] To a stirred solution of intermediate 102 (20.0 g, 37.8 mmol, 1.00 equivalent) and intermediate 98 (78.5 g, 132 mmol, 3.50 equivalents, TFA salt) in DMF (400 mL), HOBT (20.4 g, 151 mmol, 4.00 equivalents), EDCI (29.0 g, 151 mmol, 4.00 equivalents), and DIEA (22.0 g, 170 mmol, 4.50 equivalents) were sequentially added. The reaction mixture was stirred at 25°C for 2 hours. TLC (DCM:MeOH = 10:1, R f A reading of 0.4) indicated that intermediate 102 was completely consumed and a new, more polar primary spot was detected. The reaction mixture was slowly poured into a 0.5 mol / L cold HCl stirring solution (900 mL) and stirred for 10 minutes. A white precipitate formed, which was filtered, and the aqueous phase was extracted twice with DCM (600 mL × 2). The combined organic layers were washed with 5% NaHCO3 (450 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100:1-5:1) to obtain intermediate 103 (58.0 g, 30.4 mmol, purity 82.7%, yield 80.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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, 3H), 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 calculated value: 1908.81, Observed mass: [M+2H] 2+ =955.7.

[0632] Preparation of intermediate 104: [ka]

[0633] MeOH (230 mL) was slowly added to Pd / C (4.6 g, 25.13 mmol, 10% purity, 1.00 equivalent) in a reaction bottle (purged three times with N2). Then, a solution of TFA (2.75 g, 24.1 mmol, 1.00 equivalent) and intermediate 103 (46.0 g, 24.1 mmol, 1.00 equivalent) in MeOH (230 mL) was slowly added to the reactant under an N2 atmosphere. The reactant was degassed, purged three times with N2 and H2, and stirred at 25°C for 2 hours under an H2 atmosphere (15 psi). TLC (DCM:MeOH=10:1, R fA value of 0.3 indicated that intermediate 103 was completely consumed and a new, more polar primary spot was detected. The reaction mixture was dissolved in MeOH (250 mL), carefully filtered through siliceous earth under an N2 atmosphere, washed the filtrate with MeOH (250 mL x 2), and concentrated under reduced pressure to obtain intermediate 104 (crude product, 42.0 g, 22.4 mmol, purity 94.1%, yield 92.2%, TFA salt) as a white solid. 1 H 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, 8H), 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 calculated value: 1774.78, Observed mass: [M+H] + =1775.7, [M+2H] 2+ = 888.7.

[0634] Preparation of intermediate 105: [ka]

[0635] DIEA (8.62 g, 66.6 mmol, 3.00 equivalents), EDCI (6.69 g, 33.3 mmol, 1.50 equivalents), and HOBt (6.38 g, 33.3 mmol, 1.50 equivalents) were added to a solution of intermediates 104 (42.0 g, 22.2 mmol, 1.00 equivalent, TFA salt) and 104a (7.77 g, 33.3 mmol, 1.50 equivalents) in DMF (420 mL). The mixture was stirred at 25°C for 2.0 hours. LC-MS showed that intermediate 104 was completely consumed and several new peaks were shown on LC-MS, indicating the detection of the desired compounds. The reaction mixture was slowly poured into a 0.5 mol / L HCl stirred solution (cold, 500 mL). The aqueous phase was extracted with DCM (500 mL x 3). The combined organic layers were washed with 5% NaHCO3 (500 mL), dried over Na2SO4, and then concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100:1-5:1) to obtain intermediate 105 (34.0 g, 17.1 mmol, purity 93.3%, yield 77.0%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 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, 9H). LCMS: RT=0.501 min, MS calculated value: 1989.87, Observed mass: [M+2H] 2+ = 996.3.

[0636] Preparation of target A043: [ka]

[0637] To a solution of intermediate 105 (34.0 g, 12.6 mmol, 1.00 equivalent) in MeOH (400 mL), NaOMe (5.4 M MeOH solution, 9.91 mL, 4.26 equivalents) was added at 0°C. The solution was then stirred at 0°C for 0.5 hours. LC-MS showed that intermediate 105 was completely consumed, and several new peaks were shown on LC-MS, indicating the detection of the desired compound. The reaction mixture was adjusted to pH 6 with a 1.0 M HCl solution at 0°C, washed three times with DCM (250 mL x 3), and the aqueous layer was freeze-dried to obtain target A043 (crude product, containing NaCl, 20.0 g, 12.4 mmol, purity 96.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 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 calculated value: 1611.77, Observed mass: [M+H] + =1612.8, [M+2H] 2+ = 807.2.

[0638] Preparation of intermediate 107: [ka]

[0639] The peptides were synthesized using standard Fmoc chemistry (Rink AM resin). 1) Resin preparation: A container containing Rink Amide AM resin (624.80 g, 200.00 mmol, 0.32 mmol / g) and DMF (2 L) was aerated with N2 at 25°C for 2 hours. Then, 20% piperidine DMF solution (4 L) was added, and the mixture was aerated with N2 at 25°C for 30 minutes. The mixture was filtered and washed five times with DMF (4 L), after which the next step was performed. 2) Coupling: A solution of Fmoc-Thr(tBu)-OH (238.00 g, 600.00 mmol, 3.00 equivalents), DIC (75.60 g, 600.00 mmol, 3.00 equivalents), and HOBt (81.20 g, 600.00 mmol, 3.00 equivalents) in DMF (2 L) was added to the resin while aeration with N2 at 25°C for 1 hour. The coupling reaction was monitored by the ninhydrin test. Subsequently, the resin was washed five times with DMF (4 L). 3) Deprotection: A 20% piperidine DMF solution (2 L) was added to the resin, and the mixture was aerated with N2 at 25°C for 30 minutes. The resin was then washed five times with DMF (4 L). 4) For the following amino acid elongation: Steps 2 and 3 were repeated for numbers 2-14 and Table 15. 5) After all steps were completed, the resin was washed five times with DMF (4L) and five times with MeOH (4L), and then dried under reduced pressure to obtain resin-bound peptide (Rink AM resin, 450.5g, 200 mmol). [Table 15]

[0640] Peptide cleavage and cyclization. 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 5L) was added at 25°C to a flask containing a side-chain protective resin-bound peptide (Rink AM resin, 450.5g, 200 mmol) and stirred for 2 hours. 2) After filtration, the filtrate was collected. 3) The filtrate was precipitated with cold isopropyl ether (30 L). After filtration, the solid was washed twice with isopropyl ether (5 L), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 106 (320.0 g, crude product) as a white solid. 4) To the HOAc / MeCN / H2O (4 / 3 / 3, v / v / v, 70L) mixture of intermediate 106 (320.0g, crude product), 0.1M I2 / AcOH was added dropwise until the yellow color persisted, and the mixture was then stirred at 25°C for 5 minutes. The mixture was quenched by dropwise addition of 0.1M Na2S2O3 aqueous solution until the yellow color disappeared. After filtration, the filtrate was separated and purified by HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 107 (109.0g, purity 90.7%, yield 30.4%) as a white solid. LCMS: RT = 10.492 min, MS calculation value: M av =1623.85, observed mass: [M+H] + =1625.57, [M+2H] 2+ = 813.02. 5) Using 200 mmol of resin, intermediate 107 (107.8 g) was obtained.

[0641] Preparation of BH0002640 (FcII-GN3): [ka]

[0642] To a mixture of NH4HCO3 (0.2M, 100mL, 3.67 equivalents) and t-BuOH (100mL) containing target A043 (15.0g, crude product, 9.30 mmol, 1.00 equivalent) and intermediate 107 (8.86g, 5.46 mmol, 1.00 equivalent), CuSO4.5H2O (0.4M, 13.64mL, 1.00 equivalent) and sodium ascorbate (4.32g, 21.8 mmol, 4.00 equivalent) was added. The resulting reaction product was degassed and purged three times with N2. The mixture was then stirred under an N2 atmosphere at 25°C for 0.5 hours. LC-MS showed that target A043 was completely consumed and several new peaks were shown on LC-MS, indicating the detection of the desired compound. The resulting reaction mixture was lyophilized to obtain the residue. The residue was purified by preparative HPLC (A: 0.075% HOAc / H2O solution, B: MeCN) to obtain BH0002640 (7.0 g, 2.16 mmol, purity 98.4%, yield 23.2%, TFA content 0.42%, HOAc content <0.05%, water content 2.00%) as a white solid. LCMS: RT = 1.554 min, MS calculation value: 3234.47, observed mass: [M + H] + =3235.44, [M+2H] 2+ = 1618.72. 1H NMR (400 MHz, DMSO-d6) δ 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 = 8.53 Hz, 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). .

[0643] Example 23. Procedure for the preparation of BH-0003924. [ka]

[0644] Intermediate 108 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 16. [Table 16]

[0645] Cutting and cyclization. 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 30 mL) was added at 25°C to a flask containing side-chain protective resin-bound peptide intermediate 108 (Rink AM resin, 1.87 g, 0.50 mmol) and stirred for 2 hours. 2) After filtration, the filtrate was collected. 3) The filtrate was precipitated with cold isopropyl ether (150 mL). After filtration, the solid was washed twice with isopropyl ether (150 mL), and the crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 108 (793 mg, crude product) as a white solid.

[0646] Intermediate 108 (793 mg, crude product) was mixed with MeCN / H2O (4 / 6, v / v / , 500 mL) to which CH2I2 (15.0 equivalents) and Et3N (6.00 equivalents) were added. The mixture was then stirred under N2 at 25°C for 8 hours. The mixture was quenched by adding 1 M HCl. After filtration, the filtrate was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH-0003924 (94.0 mg, purity 96.4%, yield 11.4%) as a white solid. LCMS: RT = 1.41 min, MS calculation value: M av =1585.80, observed mass: [M+H] + =1586.80, [M+2H] 2+ = 793.6. [ka]

[0647] Example 24. Procedure for the preparation of BH-0003925. [ka]

[0648] Intermediate 109 (resin-bound peptide) was synthesized according to the procedure described in Section

[0048] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 17. [Table 17]

[0649] BH-0003925 (peptide cleavage, disulfide formation) was synthesized according to the procedure described in Section

[0049] . After lyophilization, BH-0003925 (80.6 mg, purity 97.8%, yield 8.60%) was obtained as a white solid from 0.50 mmol of resin. LCMS: RT=1.38 min, MS calculation value: M av =1833.05, observed mass: [M+H] + =1834.0, [M+2H] 2+ =917.2. [ka]

[0650] Example 25. Procedure for the preparation of BH-0003174. [ka]

[0651] Intermediate 120 (resin-bound peptide) was synthesized according to the procedure described in Section

[0059] . SPPS (resin loading amount 0.50 mmol) was synthesized using the amino acid elongation shown in Table 18. [Table 18]

[0652] BH-0003174 (peptide cleavage, disulfide formation) was synthesized according to the procedure described in Section

[0060] . From 0.5 mmol of resin, BH-0003174 (93 mg, purity 94.6%, yield 11.6%) was obtained as a white solid. LCMS: RT=0.81 min, MS calculation value: M av =1521.76, observed mass: [M+H] + =1521.76, [M+2H] 2+ =761.50 [ka] Example 26. Procedure for the preparation of BH-0003747. [ka]

[0653] BH-0003747 was synthesized according to the procedure described in Section

[0059] . SPPS (1.00 mmol resin) was synthesized using the amino acid elongation shown in Table 19, numbers 1-58. [Table 19-1] [Table 19-2]

[0654] Peptide cleavage. 1) The cleavage solution (TFA / TIS / H2O, 95 / 2.5 / 2.5, v / v / v, 250 mL) was added at 25°C to a flask containing side-chain protective resin-bound peptide (7.89 g, 1.00 mmol) and stirred for 2 hours. 2) After filtration, the filtrate was collected. 3) The filtrate was precipitated with cold isopropyl ether (600 mL). After filtration, the solid was washed twice with isopropyl ether (600 mL), and the crude peptide was dried under reduced pressure for 2 hours to obtain BH-0003747 (6.53 g, crude product) as a white solid. 4) Crude BH-0003747 was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain BH-0003747 (547.1 mg, purity 97.8%, yield 8.05%) as a white solid. LCMS: RT=0.72 min, MS calculation value: Mav=6640.26, observed mass: [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. [ka]

[0655] Example 27. Procedure for the preparation of BH-0003784. [ka]

[0656] Intermediate 121 was synthesized according to the procedure described in Section

[0059] . SPPS (1.00 mmol resin) was synthesized using the amino acid elongation shown in Table 20, numbers 1 to 59. [Table 20-1] [Table 20-2]

[0657] Peptide cleavage and fragment coupling. 1) Dissection from resin: 50 mL of 20% HFIP / DCM solution was added to the above resin at room temperature and stirred for 1 hour. After filtration, the filtrate was collected and concentrated under reduced pressure to obtain fully protected peptide intermediate 121 (6.51 g, crude product) as a white solid. 2) Fragment coupling: Intermediate 121 (1.40 g, crude product, 122.0 μmol, 1.00 equivalent), target A101 (120.9 mg, 244.0 mmol, 2.00 equivalent), and HOBt (49.4 mg, 366.0 mmol, 3.00 equivalent) were mixed in DMF (2.0 mL) and EDCI (69.9 mg, 366.0 mmol, 3.00 equivalent) at 0°C. The resulting reaction was stirred at 25°C for 8 hours. The reaction was added to a flask containing cold 0.1 M HCl (30 mL), and the precipitate was filtered off to obtain the crude product as intermediate 122. 3) Deprotection: A TFA / TIS / H2O / 3-mercaptopropanoic acid solution (v / v / v / v, 92.5 / 2.5 / 2.5 / 2.5, 20 mL) was added to the flask containing intermediate 122 (crude product) from step 2, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was precipitated with cold isopropyl ether (100 mL), then filtered off, and the solid was washed twice with isopropyl ether (50 mL). The crude peptide was dried under reduced pressure for 2 hours to obtain intermediate 123 (845 mg, crude product) as a white solid. 5) Crude intermediate 123 was purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN), and subsequently lyophilized to obtain intermediate 123 (120 mg, yield 13.8%) as a white solid.

[0658] Preparation of BH0003784 (click reaction): [ka]

[0659] The click reaction BH0003784 was synthesized using the same procedure as BH0003610, which was performed according to the procedure described in

[0050] to

[0051] .

[0660] From 30.2 mg of target A093, BH0003784 (92 mg, purity 90.7%, yield 58.5%) was obtained as a white solid. LCMS: RT=1.26 min, MS calculation value: M av =8463.21, observed mass: [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. [ka]

[0661] Example 28. Procedure for preparing target A041_intermediate 2. [ka]

[0662] Preparation of target A041_intermediate 2: [ka]

[0663] To a solution of intermediate 104A (100 mg, 263.57 umol, 1 equivalent) in DMF (2 mL), HATU (110.24 mg, 289.93 umol, 1.1 equivalents) and DIEA (102.19 mg, 790.71 umol, 137.73 uL, 3 equivalents) were added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. Then, intermediate 104 (514.85 mg, 289.93 umol, 1.1 equivalents) was added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. TLC indicated that the reaction was complete. The reaction mixture 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 obtain the crude product. The crude product was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1-10:1) to obtain target 041_intermediate 2 (310 mg, 145.05 umol, yield 55.03%, purity 100%) as a yellow solid. LCMS: RT = 2.596 min, MS calculated value: 2135.9, measured value: [M / 3+H] + = 713.2. 1 H NMR (400 MHz, MeOH-d4) δ 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, 9H), 2.03 (s, 9H), 1.95 (d, J = 5.92 Hz, 18 H). Theoretical H number: 149, measured value: 141, exchange rate H: 8.

[0664] Example 29 Procedure for preparing target A042. [ka]

[0665] Preparation of intermediate 124: [ka]

[0666] To a solution of intermediate 104B (100 mg, 343.29 umol, 1 equivalent) in DMF (20 mL), HATU (143.58 mg, 377.62 umol, 1.1 equivalents) and DIEA (133.10 mg, 1.03 mmol, 179.38 uL, 3 equivalents) were added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. Then, intermediate 104 (609.61 mg, 343.29 umol, 1 equivalent) was added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. TLC indicated that the reaction was complete. The reaction mixture 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 obtain the crude product. The crude product was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1-10:1) to obtain intermediate 124 (200 mg, 97.60 umol, yield 28.43%) as a white solid. LCMS: RT = 1.821 min, MS calculated value: 2049.1, measured value: [M / 2 + H] + = 1025.6. 1 H NMR (400 MHz, MeOH-d4) δ = 5.34 (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 H-number: 141, Measured value: 133, Exchange rate H: 8.

[0667] Preparation of target A042 [ka]

[0668] To a solution of intermediate 124 (230 mg, 112.25 umol, 1 equivalent) in MeOH (3 mL), NaOMe (3.03 mg, 56.12 umol, 0.5 equivalents) was added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that reactant 1 was consumed and a new peak of one of the desired compounds was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain target A042 (183.04 mg, 109.56 umol, yield 97.60%) as a yellow oil. LC-MS: RT = 0.553 min, MS calculation: 1669.81, [M / 2 + H] + = 836.3. 1 H NMR (400MHz, 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 = 6.4 Hz, 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 = 6.1 Hz, 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 H-number: 123, Measured value: 106, Exchange rate H: 17.

[0669] Example 30 Procedure for preparing target A044 [ka]

[0670] Preparation of intermediate 91: [ka]

[0671] To a solution of intermediate 104C (80 mg, 422.90 umol, 1.0 equivalent) in DMF (10 mL), HATU (176.88 mg, 465.19 umol, 1.1 equivalents) and DIEA (163.97 mg, 1.27 mmol, 220.98 uL, 3.0 equivalents) were added at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. Intermediate 104 (750.99 mg, 422.90 umol, 1.0 equivalent) was added to the reaction mixture at 0°C, and the reaction mixture was stirred at 0°C for 0.5 hours. TLC indicated that the reaction was complete. The reaction mixture was poured into H2O (100 mL) and extracted with SiO (100 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH=100 / 1-10 / 1) to obtain intermediate 125 (270 mg, yield 32.79%) as a colorless oil. LCMS:RT=1.750 min, MS calculation: 1946.9, [M / 2+H] + =974.5. 1 H NMR (400 MHz, MeOH-d4) δ = 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 H-number: 133, Measured value: 125, Exchange rate H: 8.

[0672] Preparation of target A044 [ka]

[0673] To a solution of intermediate 125 (270.00 mg, 138.68 umol, 1.0 equivalent) in MeOH (3 mL), NaOMe (7.49 mg, 138.68 umol, 1.0 equivalent) was added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that reactant 1 was consumed and a new peak of one of the desired compounds was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain target A044 (205.41 mg, 130.95 umol, yield 94.43%) as a white solid. LC-MS: RT = 1.833 min, MS calculation: 1567.75, [M / 2 + H] + = 785.0. 1 H 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 H-number: 113, measured value: 96, exchangeability H: 17.

[0674] Example 31. Procedure for preparing target A094 [ka] [ka] [ka]

[0675] Preparation of intermediate 126: [ka]

[0676] To a solution of intermediate 96a (5.00 g, 12.84 mmol, 1.00 equivalent) in DCM (500 mL), FeCl3 (6.25 g, 38.53 mmol, 2.23 mL, 3.00 equivalent) was added. The mixture was stirred at 25°C for 3 hours. TLC (DCM:MeOH = 10:1, starting material R) was performed. f =0.6, product R f A reaction (=0.7) indicated the detection of a new dot, suggesting that the reactant had been consumed. The reaction mixture was diluted with DCM (100 mL) and extracted with H2O (500 mL x 5). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 126 (4.10 g, crude product) as a white solid, which was used in the next step without further purification.

[0677] Preparation of intermediate 127: [ka]

[0678] To a solution of intermediate 126 (4.10 g, 12.45 mmol, 1.00 equivalent) and intermediate 126A (2.59 g, 12.45 mmol, 1.00 equivalent) in DCM (80 mL), TMSOTf (830.17 mg, 3.74 mmol, 674.94 uL, 0.30 equivalent) and 4A molecular sieve (4.10 g) were added at 0°C. The mixture was stirred at 25°C for 12 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was diluted with H2O (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1-30 / 1) to obtain intermediate 127 (3.60 g, 6.70 mmol, yield 53.79%) as a yellow solid. LCMS: RT = 1.970 min, MS calculated value: 537.2, measured value: [M - H] + = 536.2. 1H NMR (400 MHz, DMSO-d6) δ = 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 H-number: 35, Measured value: 35.

[0679] Preparation of intermediate 128: [ka]

[0680] To a solution of intermediate 127 (3.00 g, 5.58 mmol, 1.00 equivalent) in THF (90 mL), Pd / C (1.00 g, 10% purity) and TFA (63.63 mg, 558.08 µl, 41.32 µL, 0.10 equivalent) were added. The solution was degassed, purged three times with H2, and stirred at 25°C for 1 hour under an H2 atmosphere. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain intermediate 128 (2.40 g, 5.36 mmol, 96.11% yield) as a yellow oil, which was used in the next step without further purification. LC-MS: RT=0.926 min, MS calculated value: 447.17, measured value: [M+H] + = 448.2. 1H NMR (400 MHz, DMSO-d6) δ = 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 H-number: 29, Measured value: 29.

[0681] Preparation of intermediate 129: [ka]

[0682] To a solution of intermediate 100 (38.00 g, 75.15 mmol, 1.00 equivalent) in CH2Cl2 (323 mL), Na2CO3 (31.86 g, 75.15 mmol, 25% purity, 1.00 equivalent) was added while stirring. Then, CbzCl (39.74 g, 232.97 mmol, 3.00 equivalent) was added dropwise, and the reaction mixture was stirred at 20°C for 24 hours. TLC (petroleum ether:ethyl acetate = 5:1, starting material R) was used. f =0.5, product R f A reading of 0.3 indicated that the reaction was complete. The reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100 / 1-10 / 1) to obtain intermediate 129 (104.71 g, 163.67 mmol, yield 72.59%) as a colorless oil.

[0683] Preparation of intermediate 130: [ka]

[0684] To a solution of intermediate 129 (25.7 g, 40.17 mmol, 1.00 equivalent) in HCOOH (400 mL), formic acid (5.55 g, 120.51 mmol, 4.55 mL, 3.00 equivalent) was added, and the reaction mixture was stirred at 20°C for 18 hours. After completion, the four parallel reaction products were combined for workup. The reaction solution was concentrated under reduced pressure to obtain intermediate 130 (17.00 g, yield 89.76%) as a colorless oil, which was used directly in the next step without further purification.

[0685] Preparation of intermediate 131: [ka]

[0686] To a solution of intermediate 130 (1.00 g, 2.12 mmol, 1.00 equivalent) in DMF (10 mL), HATU (2.42 g, 6.36 mmol, 3.00 equivalent) and DIEA (1.92 g, 14.85 mmol, 2.59 mL, 7.00 equivalent) were added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then, intermediate 130A (1.11 g, 6.36 mmol, 1.11 mL, 3.00 equivalent) was added, and the mixture was stirred at 25°C for 0.5 hours. LC-MS showed that the reactants were completely consumed and a single main peak with the 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 10 mL of brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1-10 / 1) to obtain intermediate 131 (1.9 g, 2.02 mmol, yield 95.28%) as a yellow solid. LCMS: RT = 2.264 min, MS calculated value: 939.55, measured value: [M+H] + =940.8.

[0687] Preparation of intermediate 132: [ka]

[0688] Intermediate 131 (2.00 g, 2.13 mmol, 1.00 equivalent) was degassed in a solution of DCM (20 mL) and TFA (4 mL), purged three times with N2, and then the mixture was stirred at 25°C for 1 hour under an N2 atmosphere. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain intermediate 132 (1.30 g, 2.03 mmol, yield 95.51%) as a yellow oil. LC-MS: RT = 1.170 min, MS calculated value: 639.4, measured value: [M+H] + = 640.5. 1 H NMR (400 MHz, DMSO-d6) δ = 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 H number: 53, actual value: 53.

[0689] Preparation of intermediate 133: [ka]

[0690] To a 10 mL solution of intermediate 128 (2.00 g, 4.47 mmol, 3.00 equivalents) in DMF (10 mL), HATU (1.70 g, 4.47 mmol, 3.00 equivalents) and DIEA (577.71 mg, 4.47 mmol, 778.58 uL, 3.00 equivalents) were added at 0°C for 0.5 hours. Intermediate 132 was then added at 0°C. The mixture was stirred at 20°C for 1 hour. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=100 / 1-30 / 1) to obtain intermediate 133 (1.20 g, 622.40 umol, yield 41.77%) as a yellow solid. LCMS: RT=1.900 min, MS calculated value: 1928.06, measured value: [M / 2+H] + =965.1. 1 H 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, measured value: 134.

[0691] Preparation of intermediate 134: [ka]

[0692] Intermediate 133 (1.00 g, 518.66 umol, 1.00 equivalent), Pd / C (500 mg, 518.66 umol, 10% purity, 1.00 equivalent), and TFA (59.14 mg, 518.66 umol, 38.40 uL, 1.00 equivalent) were degassed in a THF (30 mL) solution, purged three times with H2, and then the mixture was stirred under an H2 atmosphere at 25°C for 0.5 hours. LC-MS showed that the reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain intermediate 134 (760.00 mg, 423.66 umol, yield 81.68%) as a yellow oil, which was used in the next step without further purification. LC-MS: RT=1.673 min, MS calculated value: 1792.85, measured value: [M / 2+H] + = 898.2.

[0693] Preparation of intermediate 135: [ka]

[0694] To a solution of intermediate 100a (93.29 mg, 445.96 umol, 1.00 equivalent) in DMF (8 mL), HATU (169.57 mg, 445.96 umol, 1.00 equivalent) and DIEA (57.64 mg, 445.96 umol, 77.68 μL, 1.00 equivalent) were added at 0°C for 0.5 hours. Then, intermediate 134 (800.00 mg, 445.96 umol, 1.00 equivalent) was added, and the mixture was stirred at 25°C for 0.5 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10um, mobile phase: [water (TFA)-ACN], B%: 30%-50%, 8 min) to obtain intermediate 135 (200.00 mg, 100.75 umol, yield 22.59%) as a yellow solid. LC-MS: RT=1.982 min, MS calculated value: 1983.9, measured value: [M / 2+H] + =993.5. 1H NMR (400 MHz, DMSO-d6) δ = 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, measured value: 137.

[0695] Preparation of intermediate 136: [ka]

[0696] To a solution of intermediate 135 (180.00 mg, 90.68 umol, 1.00 equivalent) in THF (3 mL), Pd / C (150 mg, 90.68 umol, 10% purity, 1.00 equivalent) and TFA (15.51 mg, 136.01 umol, 10.07 μL, 1.50 equivalent) were added at 25°C, and the reaction mixture was stirred at 25°C for 0.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 136 (80.00 mg, 43.22 umol, yield 47.67%) as a white solid. LC-MS: RT = 1.685 min, MS calculation: 1849.8, [M / 2 + H] + = 926.6.

[0697] Preparation of intermediate 137: [ka]

[0698] To a solution of oxalyl dichloride (13.06 mg, 102.91 umol, 9.01 uL, 1.20 equivalents) in DCM (0.30 mL), intermediate 10 (20.00 mg, 85.76 umol, 1.00 equivalent) and DMF (0.10 mL) were added, and the reaction mixture was stirred at 0°C for 1 hour. TLC (DCM:MeOH = 10:1, starting material R) was used. f =0.3, product R f A reading of 0.4 indicated that the reaction was complete. Subsequently, a DCM (2 mL) solution of TEA (19.68 mg, 194.49 umol, 27.07 uL, 3.00 equivalent) and intermediate 136 (120.00 mg, 64.83 umol, 1.00 equivalent) was added dropwise to the above solution at 0°C, and the mixture was then stirred at 25°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain intermediate 137 (125 mg, crude product) as a yellow oil. LC-MS: RT = 1.724 min, MS calculation: 2064.96, measured value: [M / 2 + H] + = 1034.3.

[0699] Preparation of target A094: [ka]

[0700] To a solution of intermediate 137 (119.80 mg, 57.98 umol, 1.00 equivalent) in MeOH (2 mL), NaOMe (3.13 mg, 57.98 umol, 1.00 equivalent) was added. The mixture was stirred at 25°C for 17 hours. LC-MS showed that the desired mass and reactants were consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: C18-1 150 × 30 mm × 5 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 5%-35%, 10 min) to obtain target A094 (26 mg, 15.40 umol, yield 26.57%) as a white solid. LC-MS: RT = 1.078 min, MS calculated value: 1686.87, measured value: [M / 2 + H] + = 845.1. 1H NMR (400 MHz, CD3OD) δ = 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 H-number: 126, Measured value: 106, Exchangeable H-number: 20.

[0701] Example 32. Procedure for preparing target A099 [ka] [ka]

[0702] Preparation of intermediate 96 [ka]

[0703] To a solution of intermediate 95a (50 g, 335.15 mmol, 1 equivalent) in MeOH (500 mL), CbzCl (62.89 g, 368.66 mmol, 52.41 mL, 1.1 equivalents) and TEA (78.00 g, 770.84 mmol, 107.29 mL, 2.3 equivalents) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed that reactant 1 was completely consumed and a single main peak with the desired mass was detected. TLC (dichloromethane:methanol = 10:1 R) fA reading of 0.7) indicated that reactant 1 was completely consumed and a new spot was formed. The reaction mixture was diluted with H2O (500 mL) and extracted with siRNA (300 mL x 2). The combined organic layer was washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 1 / 0-10 / 1) to obtain intermediate 96 (52 g, 183.54 mmol, yield 54.76%) as a colorless oil. LCMS: RT = 1.522 min, MS calculated value: 283.14, measured value: [M+H] + = 284.2. 1 ¹H NMR (400 MHz, chloroform-d): δ = 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, 1 H). Theoretical H number: 21, experimental value: 21.

[0704] Preparation of intermediate 126 [ka]

[0705] To a solution of intermediate 96a (20 g, 51.37 mmol, 1 equivalent) in DCM (2000 mL), FeCl3 (25.00 g, 154.10 mmol, 8.93 mL, 3 equivalents) was added. The mixture was stirred at 25°C for 3 hours. LC-MS detected the desired mass, indicating that the reactants had been consumed. The reaction mixture was diluted with water (2000 mL), extracted with water (2000 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain residue intermediate 126 (14 g, 42.51 mmol, yield 82.77%) as a white oil. LC-MS: RT = 1.421 min, MS calculated value: 329.11, measured value: [M + H] + = 330.2. 1H NMR (400 MHz, CDCl3-d) δ = 6.00 (d, J = 6.8 Hz, 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 H number: 19, actual value: 19.

[0706] Preparation of intermediate 97: [ka]

[0707] To a solution of intermediate 126 (13.5 g, 41.00 mmol, 1 equivalent) and intermediate 96 (11.61 g, 41.00 mmol, 1 equivalent) in DCM (280 mL), TMSOTf (2.73 g, 12.30 mmol, 2.22 mL, 0.3 equivalent) and 4A molecular sieve (14 g, 41.00 mmol, 1 equivalent) were added at 0°C. The mixture was stirred at 25°C for 16.5 hours. LC-MS detected the desired mass, indicating that the reactants had been consumed. The reaction mixture was concentrated under reduced pressure to remove the DCM. The residue was diluted with water (300 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1-0 / 1) to obtain intermediate 97 (22 g, 35.91 mmol, yield 87.60%) as a white solid. LCMS: RT = 1.857 min, MS calculated value: 612.3, measured value: [M+H] + = 613.4. 1H NMR (400MHz, MeOD-d4) 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 H number: 40, actual value: 38, exchangeability H: 2.

[0708] Preparation of intermediate 98: [ka]

[0709] To a solution of intermediate 97 (2 g, 3.26 mmol, 1 equivalent) in THF (20 mL), TFA (37.22 mg, 326.47 µl, 24.17 µL, 0.1 equivalent) and Pd / C (500 mg, 3.26 mmol, 10% purity, 1 equivalent) were added. The mixture was stirred at 25°C for 1 hour. LC-MS detected the desired mass, indicating that the reactants had been consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain intermediate 98 (1.5 g, 3.13 mmol, yield 96.02%) as a yellow oil. LC-MS: RT = 0.369 min, MS calculated value: 478.2, measured value: [M + H] + = 479.4. 1H NMR (400MHz, MeOD-d4) δ = 5.34 (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 H number: 34, actual value: 31, exchangeability H: 3.

[0710] Preparation of intermediate 139: [ka]

[0711] To a DMSO (500 mL) solution of intermediate 138 (50 g, 548.80 mmol, 1 equivalent) and intermediate 139a (154.74 g, 1.21 mol, 175.25 mL, 2.2 equivalents), NaOH (439.00 g, 548.80 mmol, 5% purity, 1 equivalent) was added. The mixture was stirred at 25°C for 24 hours. LC-MS showed that reactant 1 was completely consumed and a single main peak with the desired mass was detected. TLC (petroleum ether:ethyl acetate = 1:1 R) f A reaction coefficient of 0.67 indicated that reactant 1 was completely consumed and a new spot was formed. The reaction mixture was diluted with H2O (500 mL) and extracted with siRNA (300 mL x 2). The combined organic layer was washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 139 (37.6 g, 108.22 mmol, yield 19.72%) as a colorless oil. LCMS: RT = 2.826 min, MS calculated value: 333.22, measured value: [M+CH3] + = 348.3. 1H NMR (400 MHz, chloroform-d) δ = 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 H number: 34, actual value: 31, exchangeability H: 3.

[0712] Preparation of intermediate 140: [ka]

[0713] To a 500 mL solution of intermediate 139 (30 g, 86.34 mmol, 1 equivalent) in DCM, Na2CO3 (36.61 g, 86.34 mmol, 315 mL, 25% purity, 1 equivalent) and CbzCl (44.19 g, 259.03 mmol, 36.82 mL, 3 equivalents) were added. The mixture was stirred at 25°C for 14 hours. LC-MS detected the desired product mass, indicating that the reactants were completely consumed. TLC (PE:EA=2:1, R f A reading of 0.6) indicated that reactant 1 was completely consumed and a new spot was 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 x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1-3 / 1) to obtain intermediate 140 (28 g, 58.14 mmol, yield 67.34%) as a white solid. LCMS: RT = 2.826 min, MS calculated value: 481.27, measured value: [M+H] + = 482.4. 1H NMR (400 MHz, chloroform-d) δ = 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 = 7.2Hz, 1H). Theoretical H-number: 39, measured value: 38, exchangeability H: 1.

[0714] Preparation of intermediate 141: [ka]

[0715] A mixture of intermediate 140 (28 g, 58.14 mmol, 1 equivalent) and HCOOH (500 mL) was stirred at 25°C for 17 hours. LC-MS showed that reactant 1 was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was dried and concentrated under reduced pressure to obtain intermediate 141 (21.24 g, 57.50 mmol, yield 98.90%) as a yellow oil. LC-MS: RT = 0.514 min, MS calculated value: 369.14, measured value: [M + H] + = 370.3. 1 H NMR (400 MHz, chloroform-d) δ = 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 = 6.1 Hz, 3H). Theoretical H number: 23, actual value: 19, exchangeability H: 4.

[0716] Preparation of intermediate 142: [ka]

[0717] To a solution of intermediate 141 (1.4 g, 3.79 mmol, 1 equivalent) in DMF (25 mL), HATU (2.88 g, 7.58 mmol, 2 equivalents) and DIEA (2.94 g, 22.74 mmol, 3.96 mL, 6 equivalents) were added at 0°C. The mixture was stirred at 0°C for 0.5 hours, then intermediate 98 (3.63 g, 7.58 mmol, 2 equivalents) was added at 0°C, followed by stirring at 25°C for 1 hour. LC-MS showed that reactant 1 was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250×70mm #10um, mobile phase: [water (NH4HCO3)-ACN], B%: 20%-50%, 20 min) to obtain intermediate 142 (1.7g, 1.32 mmol, yield 34.76%) as a yellow oil. LCMS: RT=1.862 min, MS calculated value: 1289.55, measured value: [M+H] + = 1290.9. 1 H NMR (400 MHz, chloroform-d) δ = 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 H number: 87, actual value: 82, exchangeability H: 5.

[0718] Preparation of intermediate 143: [ka]

[0719] TFA (88.37 mg, 775.01 umol, 57.38 uL, 1 equivalent) was added to a THF (40 mL) solution of intermediate 142 (1 g, 775.01 umol, 1 equivalent). The mixture was stirred at 25°C for 1 hour under 15 psi. ...

Claims

1. Chemical structure: 【Chemistry 1】 A difunctional compound that conforms to the following [CPBM] is a circulating protein binding site that binds to immunoglobulin G (IgG) in the target, and IgG mediates a pathological state or condition and is removed by the action of hepatocytes or other cells of the target, and [CPBM] 【Chemistry 2-1】 【Chemistry 2-2】 A portion selected from, or including it [CRBM] is a cell receptor binding portion that binds to the asialoglycoprotein receptor or other cell receptor of hepatocytes in the subject, and [CRBM] has the following chemical structure: 【Transformation 3】 A [ASGPRBM] group conforming to, or containing, Each [CON] is an optional connector chemical part that connects the [linker] to the [CPBM] or [CRBM] if present. The [linker] is a chemical moiety having a valency of 1 to 15 that is covalently bonded to one or more [CRBM] groups or [CPBM] groups via [CON], and the [linker] itself optionally 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 independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. i Ｌ However, the values ​​are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. However, h, h', and i Ｌ A bifunctional compound, provided that at least one of the following is at least one. or its salt, stereoisomer, or solvate.

2. k', j', h, h', and i Ｌ The compound according to claim 1, wherein each of them is independently 1, 2, or 3.

3. In [ASGPRBM], when X is two-atom long, -O-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-O-, -S-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-S-, -N(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-N(R Ｎ１ )-, or -C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, and In [ASGPRBM], X is -O-C(R) when X has a length of 3 atoms. Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-,-C(R Ｎ１ ) (Caution Ｎ１ )-O-C(R Ｎ１ ) (Caution Ｎ１ )-,-O-C(R Ｎ１ ) (Caution Ｎ１ )-O-, -OC(R Ｎ１ ) (Caution Ｎ１ )-S-, -OC(R Ｎ１ ) (Caution Ｎ１ )-N(R Ｎ１ )-,-S-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-,-C(R Ｎ１ ) (Caution Ｎ１ )-S-C(R Ｎ１ ) (Caution Ｎ１ )-,-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-S, -S-C(R Ｎ１ ) (Caution Ｎ１ )-S-, -S-C(R Ｎ１ ) (Caution Ｎ１ )-O-, -S-C(R Ｎ１ ) (Caution Ｎ１ )-N(R Ｎ１ )-,-N(R Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-,-C(R Ｎ１ ) (Caution Ｎ１ )-N(R Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-,-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-N(R Ｎ１ )-,-N(R Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-N(R Ｎ１ )-, or-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ )-C(R Ｎ１ ) (Caution Ｎ１ ) and In [ASGPRBM], X is, when X is 4 atoms in length, -O-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-O-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, -O-C(R Ｎ１ )(R Ｎ１ )-O-C(R Ｎ１ )(R Ｎ１ )-, -S-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-S-C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R Ｎ１ )-, -C(R Ｎ１ )(R Ｎ１ )-C(R Ｎ１ )(R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

4. X is OCH ２ or CH ２ O and R Ｎ１ The compound according to claim 1, wherein is H.

5. The [CRBM] / [ASGPRBM] group has a chemical structure: 【Chemistry 4】 The compound according to claim 1, which is a group that follows, or a salt, stereoisomer, or solvate thereof.

6. The [CRBM] / [ASGPRBM] group has a chemical structure: 【Transformation 5】 The compound according to claim 1, which is a group that follows, or a salt, stereoisomer, or solvate thereof.

7. The aforementioned [ASGPRBM] group has the following chemical structure: 【Transformation 6】 It is a base that follows, R Ａ However, C is optionally substituted with 1 to 5 halo groups. １ -C ３ It is alkyl, Z Ａ However, - (CH ２ ) ＩＭ -, -O-(CH ２ ) ＩＭ -, -S-(CH ２ ) ＩＭ -, -NR Ｍ - (CH ２ ) ＩＭ -, -C(O)-(CH ２ ) ＩＭ -, a PEG group containing 1 to 8 ethylene glycol residues, or -C(O)(CH ２ ) ＩＭ NR Ｍ - and Z Ｂ However, absent, - (CH ２ ) ＩＭ -, -C(O)-(CH ２ ) ＩＭ -, or -C(O)-(CH ２ ) ＩＭ -NR Ｍ - The compound according to claim 1.

8. R Ａ However, it is a methyl group or an ethyl group that is optionally substituted with one to three fluoro groups, or Z Ａ The compound according to claim 7, wherein at least one of the following is true: the PEG group contains 1 to 4 ethylene glycol residues.

9. R １ and R ３ Each of them independently has the following chemical structure: 【Transformation 7】 The compound according to claim 1, which is a group that follows [the specified formula].

10. The R of the [CRBM] / [ASGPRBM] group １ and R ３ Each of them operates independently, 【Chemistry 8-1】 【Chemistry 8-2】 The compound according to claim 1, which is a portion selected from the group consisting of the following.

11. The R of the [CRBM] / [ASGPRBM] group ２ but, 【Chemistry 9】 The compound according to claim 1, which is a portion selected from the group consisting of the following.

12. The linker has the following chemical structure: 【Chemistry 10】 Or, Alternatively, a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing 1 to 100 alkylene glycol units, R ａ However, H, C １ -C ３ Alkyl, or alkanol, or R ３ Together, they form a cyclic ring, forming a pyrrolidine group or a hydroxypyrroline group, R ３ However, alanine (methyl), arginine (propylene guanidine), asparagine (methylene carboxamide), aspartic acid (ethaneic acid), cysteine ​​(thiol, reduced or oxidized dithiol), glutamine (ethyl carboxamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethyl methyl thioether), phenylalanine (benzyl), proline, hydroxyproline (R) ３ However, R ａ The side chain is derived from a D-amino acid or L-amino acid selected from the group consisting of serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methylene indole), tyrosine (methylenephenol), or valine (isopropyl), and also forms a cyclic ring with adjacent nitrogen groups to form a pyrrolidine group or a hydroxypyrrolidine group. The compound according to claim 1, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

13. The linker has the chemical formula: 【Chemistry 11】 It is a base that follows, R ａｍ However, C is optionally substituted with H or one or two hydroxyl groups. １ -C ３ It is alkyl, na is between 1 and 15. m is an integer in the range of 1 to 100, or The linker has the chemical formula: 【Chemistry 12】 It is a base that follows, Z and Z' are each independent, bonded, -(CH ２ ) ｉ -O-, -(CH ２ ) ｉ -S-, -(CH ２ ) ｉ -N(R)-, 【Chemistry 13】 And, - (CH ２ ) ｉ If the group is present in Z or Z', it is coupled to the connector group [CON], [MIFBM] / [IgGBM], or [ASGPRBM]. Each R is either H or C １ -C ３ It is an alkyl or alkanol, Each R ２ H or C １ -C ３ It is alkyl, Each Y is independently a bond, O, S, or N-R. Each i is independent and ranges from 0 to 100. D is 【Chemistry 14】 or Or a combination, provided that Z, Z', and D are not simultaneously combined. j is an integer in the range of 1 to 100. m' is an integer in the range of 1 to 100. n is an integer in the range of 1 to 100. X １ However, it is O, S, or N-R. R is H or C １ -C ３ The compound according to claim 1, wherein it is an alkyl or alkanol.

14. The linker has the following chemical structure: 【Chemistry 15】 It is a base that follows or includes it. 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 The linker has the chemical formula: It is a group represented by PEG-[CON]-PEG, Each PEG independently comprises a polyethylene glycol group containing 1 to 12 ethylene glycol residues, and [CON] is a triazole group. 【Chemistry 16】 The compound according to claim 1.

15. The aforementioned [CON] has the following structure: 【Chemistry 17】 It is a base that follows, R ＣＯＮ１ and R ＣＯＮ２ Each of these independently represents H, methyl, a bond (for bonding to another part), or structure: [Chemistry 18] It is a diamide group that follows the formula, X ２ However, CH ２ O, S, NR ４ , C(O), S(O), S(O) ２ , -S(O) ２ O, -OS(O) ２ , or OS(O) ２ It is O, X ３ However, O, S, or NR ４ And, R ４ However, H, C １ -C ３ Alkyl or alkanol, or -C(O)(C １ -C ３ It is alkyl, R １ However, H or C １ -C ３ It is alkyl, n'' is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8, or The above [CON] has the following chemical structure: 【Chemistry 19】 It is a base that follows, R １ＣＯＮ , R ２ＣＯＮ , and R ３ＣＯＮ Each of them is independent of H, -(CH ２ ) ＭＣ１ -, - (CH ２ ) ＭＣ１ａ C(O) ＸＡ (NR ４ ) ＸＡ - (CH ２ ) ＭＣ１ａ -, - (CH ２ ) ＭＣ１ａ (NR ４ ) ＸＡ C(O) ＸＡ - (CH ２ ) ＭＣ１ａ - or - (CH ２ ) ＭＣ１ａ O-(CH ２ ) ＭＣ１ -C(O)NR ４ - However, R １ＣＯＮ , R ２ＣＯＮ , and R ３ＣＯＮ The condition is that both are not H at the same time, Each MC1 is independently 1, 2, 3, or 4. Each MC1a is independently 0, 1, 2, 3, or 4. Each XA is either 0 or 1, R ４ However, H, C １ -C ３ Alkyl or alkanol, or -C(O)(C １ -C ３ It is alkyl, but The compound according to claim 1, provided that, in a certain portion, MC1a and XA are not all zero at the same time.

16. The above [CON] has the following chemical structure: 【Chemistry 20】 The compound according to claim 1, which is a group that follows [the specified formula].

17. At least one [CON] is 【Chemistry 21】 The compound according to claim 1, which is or contains the same.

18. [Linker] 【Chemistry 22】 The compound according to claim 1, which is or contains the same.

19. Chemical structure: 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 [Chemistry 23-4] 【Chemistry 23-5】 【Chemistry 23-6】 【Chemistry 23-7】 【Chemistry 23-8】 【Chemistry 23-9】 【Chemistry 23-10】 【Chemistry 23-11】 【Chemistry 23-12】 【Chemistry 23-13】 [Chemistry 23-14] 【Chemistry 23-15】 A difunctional compound that conforms to the following The extracellular protein-targeting ligand is a portion that binds to immunoglobulin G (IgG) in the target, and IgG is to be removed by the action of hepatocytes or other cells of the target, and the extracellular protein-targeting ligand is 【Chemistry 24-1】 【Chemistry 24-2】 A portion selected from, or including it X １ However, O, S, N(R ６ ), and C (R ４ ) (Caution ４ ) are 1 to 5 groups independently selected from the group consisting of X １ If X is a single atom, １ O, S, N(R ６ ), or C (R ４ ) (Caution ４ ) and X １ If X has two atoms, １ One or fewer atoms are O, S, or N (R ６ ) and X １ If X has 3, 4, or 5 atoms, １ Two or fewer atoms are O, S, or N (R ６ ) and R ２ but, (i) Aryl, heterocyclic, and heteroaryl compounds comprising one or two heteroatoms independently selected from the group consisting of N, O, and S, wherein each of the aryl, heterocyclic, and heteroaryl compounds is optionally substituted with one, two, three, or four substituents. 【Chemistry 25】 (iii) Each is optionally substituted with 1, 2, 3, or 4 substituents, -NR ８ -S(O)-R ３ , -NR ８ -C(S)-R ３ , -NR ８ -S(O)(NR ６ )-R ３ , -N=S(O)(R ３ ) ２ , -NR ８ C(O)NR ９ S(O) ２ R ３ , -NR ８ -S(O) ２ -R １０ , and -NR ８ -C (NR ６ )-R ３ , and (iv) Hydrogen, R １０ , alkyl-C(O)-R ３ , -C(O)-R ３ , alkyl, haloalkyl, -OC(O)R ３ , and -NR ８ -C(O)R １０ Selected from the group consisting of, R １０ However, R １０ Each of the aryl, alkyl-NR is optionally substituted with one, two, three, or four substituents. ８ -C(O)-R ３ , alkyl-aryl, alkyl-heteroaryl having 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR ６ , alkyl-NR ６ R ８ , NR ８ -NR ６ -C(O)R ３ , NR ８ -S(O) ２ -R ３ Alkenyl, Allyl, Alkinyl, -NR ６ -Alkenyl, -O-Alkenyl, -NR ６ -alkynyl, -O-alkynyl, -NR ６ -heteroaryl, -NR ６ Selected from the group consisting of -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, R １ and R ５ Each of these is independently and optionally substituted with 1, 2, 3, or 4 substituents, and consists of hydrogen, heteroalkyl, and C ０ -C ６ Alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C ０ -C ６ Alkyl-OR ６ , C ０ -C ６ Alkyl-SR ６ , C ０ -C ６ Alkyl-NR ６ R ７ , C ０ -C ６ Alkyl-C(O)R ３ , C ０ -C ６ Alkyl-S(O)R ３ , C ０ -C ６ Alkyl-C(S)R ３ , C ０ -C ６ Alkyl-S(O) ２ R ３ , C ０ -C ６ Alkyl-N(R) ８ )-C(O)R ３ , C ０ -C ６ Alkyl-N(R) ８ )-S(O)R ３ , C ０ -C ６ Alkyl-N(R) ８ )-C(S)R ３ , C ０ -C ６ Alkyl-N(R) ８ )-S(O) ２ R ３ C ０ -C ６ Alkyl-O-C(O)R ３ , C ０ -C ６ Alkyl-O-S(O)R ３ , C ０ -C ６ Alkyl-O-C(S)R ３ , -N=S(O)(R ３ ) ２ , C ０ -C ６ AlkiN ３ , and C ０ -C ６ Alkyl-O-S(O) ２ R ３ Selected from the group consisting of, R ３ However, at each occurrence, independently, hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR ８ , and -NR ８ R ９ Selected from the group consisting of, R ４ However, at each occurrence, independently, hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -OR ６ , -NR ６ R ７ , C(O)R ３ S(O)R ３ , C(S)R ３ , and S(O) ２ R ３ Selected from the group consisting of, R ６ and R ７ However, at each appearance, independently, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocyclic, -alkyl-OR ８ , -alkyl-NR ８ R ９ , C(O)R ３ S(O)R ３ , C(S)R ３ , and S(O) ２ R ３ Selected from the group consisting of, R ８ and R ９ However, at each occurrence, a group consisting of hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle is independently selected. The ring is a 3- to 8-membered fused ring group optionally substituted with 1, 2, 3, or 4 substituents. Each linker Ａ However, the [ASGPRBM] group is linked to the linker Ｂ A bond or part that is covalently connected to, Linker Ｂ However, Linker Ａ A bond or portion that covalently links the base to the extracellular protein targeting ligand, Linker Ｃ However, each linker Ａ This is a chemical group that links the group to the extracellular protein targeting ligand. Linker Ｄ However, each linker Ａ This is a chemical group that links the group to the extracellular protein targeting ligand. R ２ ga-NR ６ -Alkenil, -NR ６ -Alkinyl, -NR ８ -C(O)R １０ , -NR ８ -S(O) ２ -Alkenil, -NR ８ -S(O) ２ -Alkinyl, -NR ６ -heteroaryl, or -NR ６ - If it is an aryl ligand, the extracellular protein targeting ligand does not contain oligonucleotides. The optional substituents are allowed by valence so as to obtain a stable compound, such as alkyl, alkenyl, alkynyl, haloalkyl, -OR ６ , F, Cl, Br, I, -NR ６ R ７ , heteroalkyl, cyano, nitro, C(O)R ３ , 【Chemistry 26】 A bifunctional compound selected from the group consisting of the following, a pharmaceutically acceptable salt thereof, or its salt, stereoisomer, or solvate.

20. Linker Ａ but, 【Chemistry 27】 The compound according to claim 19, which is or contains the same.

21. Linker Ｂ but, 【Chemistry 28】 The compound according to claim 19, which is or contains the same.

22. Linker Ｃ but, 【Chemistry 29】 The compound according to claim 19, which is or contains the same.

23. Linker Ｄ but, 【Transformation 30】 The compound according to claim 19, which is or contains the same.

24. A compound selected from the compounds listed in Table 1 of this specification, or its salt, stereoisomer, or solvate.

25. A pharmaceutical composition comprising an effective amount of a compound described in any one of the prior claims, a pharmaceutically acceptable carrier, additive, or excipient, and optionally further comprising an additional bioactive agent that is effective in treating cancer, autoimmune disease, or inflammatory disease in a patient, or that is related to the upregulation of circulating proteins in said patient.

26. The aforementioned composition contains everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, and ON 0910. Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, Aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, adhesion plaque kinase inhibitors, Map kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, dekatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batabulin, ofatumumab (Arzerra), zanorimumab, edotecarin, tetrandrin, rubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silenditide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR １ KRX-0402, Le Quenton, LY 317615, Neurodiab, Vitespan, Rta 744, Sdx 102, Taranpanel, Atracentane, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Irinotecan, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Cericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl) [Chill]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-(methylsulfonylpiperazine methyl)-indolyl j-quinolone, batalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly 10](Pyrro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH ２ Acetate [x = 1 to 2.4, C ５９ H ８４ N １８ Oi ４ - (C ２ H ４ O ２ ) Ｘ Acetates of ], 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, ronafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ82 4. Subeloylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arunsacrine, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine Fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptozocin, teniposide, testosterone Steron, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimasut, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416,SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab, Erbitux, Cremofol-free paclitaxel, Epitilon B, BMS-247550, BMS-310705, Doroxifen, 4-hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Waltmannin, ZM336372, L-779, 450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte colony-stimulating factor, Zolendronate, Prednisone, Cetuximab, Granulocyte-macrophage colony-stimulating factor, Histrelin, Pegylated interferon alpha-2a, Interferon alpha-2a, Pegylated interferon alpha-2b, Interferon alpha-2b, Azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwiner-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor antagonist, palonosetron, aprepitant,The composition according to claim 25, comprising diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, vemurafenib, immunotherapy agents, PDL1 inhibitors, PD1 inhibitors, and CTLA-4 inhibitors, plus an additional anticancer agent selected from this group.

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